Structural Simplification of Natural Products - Chemical Reviews (ACS

3 days ago - Biography. Shengzheng Wang received his bachelor's degree in pharmacy (2009) and Ph.D. in medicinal chemistry (2014) from Second ...
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Structural Simplification of Natural Products Shengzheng Wang,†,‡,# Guoqiang Dong,†,# and Chunquan Sheng*,† †

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Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, P.R. China ‡ Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, 169 Changle West Road, Xi’an, 710032, P.R. China ABSTRACT: Natural products (NPs) are important sources of clinical drugs due to their structural diversity and biological prevalidation. However, the structural complexity of NPs leads to synthetic difficulties, unfavorable pharmacokinetic profiles, and poor drug-likeness. Structural simplification by truncating unnecessary substructures is a powerful strategy for overcoming these limitations and improving the efficiency and success rate of NP-based drug development. Herein, we will provide a comprehensive review of the structural simplification of NPs with a focus on design strategies, case studies, and new technologies. In particular, a number of successful examples leading to marketed drugs or drug candidates will be discussed in detail to illustrate how structural simplification is applied in lead optimization of NPs.

CONTENTS 1. Introduction 2. Strategies for the Structural Simplification of NPs 3. Structural Simplification of NPs: Case Studies 3.1. Structural Simplification Leading to Clinical Drugs 3.1.1. Structural Simplification of Morphine: A Classic Story in Medicinal Chemistry 3.1.2. Structural Simplification of Schisandrin C: Discovery of Bicyclol 3.1.3. Structural Simplification of Myriocin: Discovery of Fingolimod 3.1.4. Structural Simplification of Trichostatin A: Discovery of Vorinostat 3.1.5. Structural Simplification of Halichondrin B: Discovery of Eribulin 3.2. Structural Simplification Leading to Clinical Candidates 3.2.1. Structural Simplification of Staurosporine: Discovery of Ruboxistaurin and Enzastaurin 3.2.2. Structural Simplification of Asperlicin: Discovery of Devazepide 3.3. Structural Simplification Leading to Preclinical Candidates or Lead Compounds 3.3.1. Structural Simplification by Reducing the Ring Number 3.3.1.1. Structural Simplification of Trabectedin 3.3.1.2. Structural Simplification of Erythrinane 3.3.1.3. Structural Simplification of Sampangine 3.3.1.4. Structural Simplification of Gambogic Acid © XXXX American Chemical Society

3.3.1.5. Structural Simplification of Sanguinarine 3.3.1.6. Structural Simplification of Dynemicin 3.3.1.7. Structural Simplification of Merrilactone A 3.3.1.8. Structural Simplification of Pyripyropene A 3.3.1.9. Structural Simplification of Pladienolide B 3.3.1.10. Structural Simplification of Melicobisquinolinone B 3.3.1.11. Structural Simplification of Campotothecin 3.3.1.12. Structural Simplification of Yohimbine 3.3.1.13. Structural Simplification of Withanolide A 3.3.2. Structural Simplification by Removing Chiral Centers 3.3.2.1. Structural Simplification of Podophyllotoxin 3.3.2.2. Structural Simplification of Taxuspine X 3.3.2.3. Structural Simplification of Cortistatin A 3.3.2.4. Structural Simplification of Bryostatin 1 3.3.2.5. Structural Simplification of Cyclopamine 1 3.3.2.6. Structural Simplification of Carolacton 3.3.2.7. Structural Simplification of Promysalin

B D E E G I I J J K

K L M N N P

S S T T U U V V W W W AA AA AA AA AA AB

P Received: August 9, 2018

Q A

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Chemical Reviews 3.3.3. Structural Simplification by Truncating Unnecessary Substructures 3.3.3.1. Structural Simplification of Chaetocin 3.3.3.2. Structural Simplification of Largazole 3.3.3.3. Structural Simplification of Lobatamide C 3.3.3.4. Structural Simplification of Sanglifehrin A 3.3.3.5. Structural Simplification of Anguinomycin 3.3.3.6. Structural Simplification of Caprazamycin B 3.3.3.7. Structural Simplification of Militarinone D 3.3.3.8. Structural Simplification of Bistramide A 3.3.3.9. Structural Simplification of Withaferin A 3.3.3.10. Structural Simplification of Rakicidin A 3.3.3.11. Structural Simplification of Spongistatins 3.3.3.12. Structural Simplification of Migrastatin 3.3.4. Recent Examples of Structural Simplification 4. Conclusions and Perspectives Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments Abbreviations References

Review

biological prevalidation and structural diversity have made NPs valuable lead compounds for drug discovery, particularly in the field of cancerous and infectious diseases.19 Currently, three strategies have been widely used for NPbased drug discovery and development (Figure 1). The first strategy is the developing and marketing the NP itself.20 On the basis of the small-molecule drugs approved by the FDA from 1981 to 2014, the percentage of unaltered NPs is 6% of the drugs.7 However, most NP-derived drugs are NP derivatives, which account for 26% of FDA approved smallmolecule drugs.7 The shortcomings of unmodified NPs mainly include limited compound availability, poor solubility, and metabolic instability.21 More importantly, the structural complexity of NPs results in synthetic difficulties and unfavorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.18 Due to their complex chemical structures, NPs rarely meet the demands for druglikeness (e.g., Lipinski’s rule-of-five, RO5), and thus their drug development is always hampered by low absorption from the gut into the blood and poor oral bioavailability.22 In addition, clarifying the mode of action and molecular target of NPs also remains a major bottleneck. Therefore, structural modification of NPs is generally required before they can be developed into clinical drugs (the second strategy in Figure 1).21−23 For structural optimization of NPs, a general procedure includes the design, synthesis, and evaluation of analogues of NPs, and clarifying the structure−activity relationship (SAR).21 Selective modifications can be designed to improve the pharmacokinetic (PK)/pharmacodynamic (PD) properties, such as potency, selectivity, water solubility, metabolic stability, and oral bioavailability. Moreover, reducing side effects is also an important goal in structural optimization. This strategy has been successfully applied in the development of a number of clinical therapeutics to treat various human diseases. NPs generally have a structurally complex framework and a high molecular weight (MW), leading to synthetic difficulty and an unfavorable ADMET profile. In some cases, standard structural modification and SAR approaches fail to generate drug-like NP derivatives because the PK limitations are always caused by the “heavy” or “fat” structures of NPs. Moreover, a number of bioactive NPs (e.g., marine NPs) are still synthetically intractable due to the highly complex structures. In these circumstances, simplifying the complex structures of NPs without interfering with the desired biological activity provides an alternative approach for both NP lead optimization and the development of new generation of NP-based drugs (the third strategy in Figure 1). Different from standard NP SAR, structural simplification could lead to new, simpler, and synthetically more accessible compounds that show improved drug-likeness. However, the structural simplification of NPs is a highly challenging task because maintaining potency and selectivity may be daunting and the molecular targets (or binding modes) of the NPs are typically unknown at the early stage of lead optimization. Different from standard NP modifications focusing on derivatization, simplification design is generally based on the SAR obtained from step-by-step truncation of NP structures.4,24 After the pharmacophores essential to the desired activity are identified, substructures that are unnecessary for the biological activity can be removed or modified. This strategy has been successfully used in the lead optimization of NPs and yielded a number of marketed drugs and drug candidates.

AB AB AB AB AB AC AC AC AD AD AD AD AE AE AE AE AE AE AE AE AE AF AF AF

1. INTRODUCTION Natural products (NPs) have historically been the primary source of medicines for the treatment of a wide range of human disease.1,2 In modern drug discovery and development, NPs continue to play a vital role and inspire innovative research in chemistry, biology, and medicine.3−6 Detailed analysis of the new drugs approved by the U.S. Food and Drug Administration (FDA) between 1981 and 2014 revealed that more than half of the clinical drugs were derived from NPs or their synthetic derivatives.7 Moreover, NPs are also rich sources of chemical probes for chemical biology studies investigating biological mechanisms.8−11 NPs are biologically prevalidated because they are produced by evolutionary selection.12 During their biosynthesis, NPs have already interacted with various enzymes and proteins, which are similar to the environment of the drug targets.13 Thus, NPs inherently fall into biologically relevant chemical space as their molecular scaffolds (or pharmacophores) have evolved as preferred ligand-target binding motifs, which are often considered privileged structures in drug discovery.14 Structurally, NPs possess unique features in terms of diversity and complexity.15 Compared with synthetic compounds, NPs generally have more stereogenic centers, fewer rotatable bonds, more oxygen atoms, fewer nitrogen, sulfur, and halogen atoms, more fused, bridged, or spiro rings, and so on.16−18 This B

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Figure 1. Strategies for NP-based drug discovery and development.

Figure 2. General process for structural simplification of NPs.

Due to its importance in NP-based drug discovery, we herein present a comprehensive review of the structural

simplification of NPs. The focus will be on design strategies, representative examples, and new technologies. A number of C

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Figure 3. Process of the structural simplification of morphine.

unknown during the early stage of structural simplification. The simplification strategies mainly include step by step dissection of the complex structure, the elimination of redundant chiral centers, the reduction of the number of rings, and scaffold hopping.32−34 During the simplification process, structural units should be systematically removed to determine the relative importance of the different components. On the basis of the SAR and pharmacophores, the essential substructures are retained in the simplified analogues. Recently, important progress has been made in identifying the targets of NPs.35,36 If the target of the NP is known, the binding mode should be clarified by structural biology, chemical biology, or molecular modeling studies. Then, the key structural motifs responsible for the ligand−target interactions can be obtained, which will guide the rational design of simplified derivatives via the removal of unnecessary fragments. Several issues should be considered during the structural simplification process. First, the biological activity is not the only criteria in simplification. The main purpose of structural simplification is to overcome the drawbacks of the lead compound and improve the drug-likeness. In some cases, the activity of the simplified compounds may be lower than that of the lead, but it is more important to achieve a balance between the pharmacological potency and the ADMET properties. In addition to the activity, drug-likeness filters, such as RO5 and ligand efficiency (LE), should be considered. However, it is also should be noted that several classes of drugs, such as antibiotics and antitumor agents, tend to violate RO5 guidelines.37−40 Second, as the size of a molecule decreases,

case studies of particularly successful examples leading to marketed drugs or drug candidates will be discussed in detail to illustrate how structural simplification is applied in lead optimization of NPs.

2. STRATEGIES FOR THE STRUCTURAL SIMPLIFICATION OF NPS “Molecular obesity” is considered an important factor in the high attrition rates of drug candidates in pharmaceutical industries.25−27 According to Polanski’s analysis, less complex drugs were more likely to achieve better market success.28 To reduce molecular obesity, structural simplification by the appropriate removal of nonessential groups represents a practical and powerful strategy in the process of lead optimization.25−27 Structural simplification is defined as the reduction of molecular complexity of a target compound. Thus, the first step of structural simplification design is to analyze the molecular complexity of NPs (Figure 2). Although there is not a global definition for molecular complexity, it is generally associated with MW, the number and connectivity (linked, fused or bridged) of rings, the number and configuration of chiral centers, and so on.29 Molecular complexity is a crucial concept in drug discovery because it is associated with target selectivity, ADMET, and safety profiles.30,31 Recently, progress has been made in the quantification of the molecular complexity and complexity− property relationships.31 The strategy for designing simplified analogues of NPs depends on whether the binding targets are known. In most cases, the molecular target or binding mode of the NP is D

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Figure 4. Structural simplification of schisandrin C.

Figure 5. Structural simplification of ISP-1.

Figure 6. Structural simplification of trichostatin A (A) and the binding modes of trichostatin A (B, PDB code: 1C3R) and vorinostat (C, PDB code: 1C3S) with HDAC.

the simplified derivatives may act by a new mode of action.41 NPs gain some of their high binding affinity and exquisite selectivity from their structural complexity and overly simple analogues may bind well to other targets. Therefore, the structural simplification must be moderate. Overly simplified molecules tend to show reduced biological activity and target selectivity. Third, notably, not all lead compounds can be simplified (e.g., digitalis).42 NPs are often metabolites that evolved for their unique structural features, and form specific interactions with the targets. As a result, structural simplification of NPs does not always work.

3. STRUCTURAL SIMPLIFICATION OF NPs: CASE STUDIES 3.1. Structural Simplification Leading to Clinical Drugs

The effectiveness of structural simplification in NP-based drug development has been validated by several clinical drugs. Structural simplification of morphine has successfully generated a series of semisynthetic and synthetic analgesics that are widely used in the clinic. Bicyclol, fingolimod, vorinostat, and eribulin also represent successful examples of structural simplification of NPs. From the five case studies discussed in the following sections, the initial impetus for structural simplification is to reduce the synthetic difficulty. The most E

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Figure 7. Structural simplification of complex NP halichondrin B and the binding mode of eribulin with tubulin (PDB code: 5JH7).

Figure 8. Structural simplification of staurosporine.

Table 1. Inhibitory Activity of Simplified Analogues of Staurosporine towards PKC Isoforms PKC subtypes (IC50, μM) enzastaurin ruboxistaurin staurosporine

α

βI

βII

γ

δ

ε

ζ

η

0.8 0.36 0.045

0.03 0.0047 0.023

0.03 0.0059 0.019

2 0.3 0.11

1 0.25 0.028

0.3 0.6 0.018

8 >100 >1.5

0.4 0.052 0.005

frequently used simplification strategies include reducing the ring number and removing chiral centers. For the biological

activity, the simplified derivatives generally showed comparable activity or even slightly lower activity at the molecular and F

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Figure 9. Structural simplification of asperlicin.

and eribulin), MW is only one of the factors in reducing the structural complexity. The MW of several morphine derivatives (e.g., compounds 3−6, 9, and 11) and bicyclol is even slightly higher than their parent molecules because a reoptimization process is often required to achieve favorable potency, selectivity and other drug-like properties. Even though, better synthetic accessibility can be observed in all the five cases. 3.1.1. Structural Simplification of Morphine: A Classic Story in Medicinal Chemistry. The development of simplified morphine derivatives as analgesics is a classic example of the structural simplification of a NP (Figure 3).43 The chemical structure of morphine (1)44 features a complex five-ring system. It is mainly a μ-opioid receptor agonist (Ki = 1.8 nM).45 The elimination of the bridging furan ring (E ring) of morphine afforded morphinans (Figure 3, compounds 2 and 3), which have a similar stereo configuration to that of morphine. For example, levorphanol (2)46 was obtained after several chemical transformations of morphine, including the elimination of the E ring, reductive hydrogenation of the C ring, and removal of the hydroxyl group. Levorphanol showed an excellent analgesic effect (4-fold more potent than morphine). Mechanism study revealed that levorphanol was 6−8 times as potent as morphine at the μ-opioid receptor (Ki

Table 2. In Vitro Antitumor Activity of Trabectedin and Phthalascidin (IC50, nM)

compounds

A549

HCT116

A375

PC3

trabectedin phthalascidin

0.95 1.0

0.38 0.50

0.17 0.15

0.55 0.70

cellular level compared with the original NP. The reduced structural complexity is helpful to improve the synthetic accessibility, and PK/PD profiles and contributes to the clinical development. Although MW is always significantly decreased during the simplification process (e.g., fingolimod, vorinostat,

Table 3. Structural Simplification and Binding Affinity of Simplified Erythrinane Analogues towards nAChRs

binding affinity toward nAChRs (Ki, μM) compounds

R

R’

α4β2

α4β4

α3β4

α7/5-HT3A

38 39 40

CH3 CH3 CH3

CH3 CH3 CH3

∼100 5.5 0.87

∼100 ∼100 ∼300

∼100 ∼300 ∼300

∼30 >500 >500

G

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Table 4. Structural Simplification of Antifungal NP Sampangine and In Vitro Antifungal Activity (MIC80, μg/mL)a

compounds

C. alb.

C. par.

C. neo.

C. gla.

A. f um.

T. rub.

M. gyp.

42 43 44 sampangine

4 0.5 0.5 0.5

8 0.5 1 4

0.25 0.25 0.5 2

4 0.25 2 ≤0.125

1 2 4 16

2 1 1 16

2 0.125 1 >64

a

Abbreviations: A. fum., Aspergillus f umigatus; C. neo., Cryptococcus neoformans; C. alb., Candida albicans; C. par., Candida parapsilosis; C. gla., Candida glabrata; T. rub., Trichophyton rubrum; M. gyp., Microsporum gypseum.

Table 5. Structural Simplification and Antitumor Activity of GA and Its Simplified Analogues (IC50, μM)a

compounds

MCF-7

BGC-823

SMMC-7721

HepG2

MDA-MB-231

46 47 gambogic acid

9.16 68.3 2.19

3.59 81.1 2.35

8.06 147 3.20

2.37 95 2.40

0.32 1.5

a

Abbreviations: MCF-7, mammary carcinoma; BGC-823, gastric carcinoma; SMMC-7721, hepatocellular carcinoma; HepG2, liver carcinoma; MDA-MB-231, breast cancer.

agonist (K i = 2.5 nM) and μ receptor competitive antagonist,49,50 and is widely used for the treatment of moderate to severe pain, such as postoperative pain, trauma, cancer pain, and renal or biliary colic. The elimination of both the C and E rings of morphine led to benzomorphans (4−6, Figure 3), whose conformations were similar to that of morphine. The introduction of hydrophobic substituents on the nitrogen atom could adjust the analgesic and addictive effects. The analgesic effect of phenazocine (4)51 was 10-fold more potent than that of morphine. Although pentazocine (5)52 was 3-fold less active than morphine, it displayed lower addictive side effects and was approved as the first nonaddictive opioid analgesic. Similar to butorphanol, pentazocine is a κ-opioid receptor agonist and μ receptor antagonist.50 Although pethidine (7),53 also known as meperidine, was not discovered by the direct structural simplification of morphine, it could be seen as a simplified analogue of morphine by the elimination of the B, C, and E rings. Compared with morphine, pethidine displayed a better analgesic effect and oral potency. Further structural modifications led to the development of a series of synthetic analgesics such as α-prodine (8)54 and fentanyl (9).55 Like morphine, fentanyl exerts its analgesic effects by acting as an agonist of μ-opioid receptor. Synthetic aminoketone analgesic methadone (11)56 was derived from the optimization of the derivatives of fluorene-9-carboxylate analgesic 10.57 Methadone can be regarded as the ring-opened analogue of piperidine analgesics without the B, C, D, and E rings of

Table 6. In Vitro Antibacterial Activities of Simplified Analogues of Sanguinarinea

compounds

S. aureus

S. aureus PR

S. epidermidis

S. pyogenes

B. subtilis

B. pumilus

49 50 51 sanguinarine

0.06 0.06 0.06 8

0.25 0.25 1 4

0.125 0.125 0.25 8

1 1 2 4

0.06 0.125 0.125 4

0.06 0.125 0.125 4

a

Abbreviations: S. aureus, Staphylococcus aureus ATCC25923 (penicillin-susceptible strain); S. aureus PR, Staphylococcus aureus PR (penicillin-resistant strain); S. epidermidis, Staphylococcus epidermidis; S. pyogenes, Staphylococcus pyogenes; B. subtilis, Bacillus subtilis; B. pumilus, Bacillus pumilus.

= 0.21 nM), and was also an agonist of the δ-opioid receptor (Ki = 4.2 nM) and κ-opioid receptor (Ki = 2.3 nM).46 The addition of a hydroxyl group on the BC ring and replacement of the N-methyl group with a cyclobutylmethyl group afforded butorphanol (3),47,48 which was 10-fold more potent than morphine, and more importantly, the addiction side effect was greatly reduced. Butorphanol acts as a κ-opioid receptor H

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Figure 10. Structural simplification of dynemicin and the mechanism of dynemicin DNA damage.

aromatic ring, a basic tertiary amine, and a piperidine or piperidine-mimic group. 3.1.2. Structural Simplification of Schisandrin C: Discovery of Bicyclol. Schisandrin C (12, MW = 384), a NP isolated from the fruit of the traditional Chinese medicine Fructus Schizandrae, displays antihepatitis B virus (HBV) activity and significantly decreases transaminase levels.58 Initially, the chemical structure of schisandrin C was incorrectly assigned (13, Figure 4). Furthermore, a total synthesis of the wrong structure was performed. Interestingly, the intermediate bifendate (14) was found to possess potent activity in the decrease of aminotransferase levels.59 Compared with schisandrin C, bifendate lacks the seven-membered ring, and thus its synthetic accessibility is greatly improved. Importantly, bifendate retained the potent pharmacological activity of its parent compound. Bifendate has been widely used in the clinical treatment of patients with elevated aminotransferase levels, which is caused by viral hepatitis or drug-induced liver injury. However, its water solubility is poor due to its high melting point (180 °C),60 which is possibly a result of its symmetric structure and high lattice energy. To reduce the molecular symmetry, one carboxylic ester group was reduced to a hydroxymethyl group, which afforded bicyclol (15, MW = 390).61 As a result, the melting point of bicyclol was decreased to 138 °C.62 Compared with bifendate, bicyclol had improved solubility, greater in vivo absorption, better bioavailability, and biological activity.63 Pharmacologically, bicyclol displayed obvious antifibrotic and hepatoprotective effects against liver injury induced by CCl4 or other hepatotoxins in mice and rats.64 It also exhibited antihepatitis virus activity in duck viral hepatitis.64 Bicyclol has been approved for treating patients with elevated aminotransferase levels caused by chronic viral hepatitis in China since 2004.58,65 3.1.3. Structural Simplification of Myriocin: Discovery of Fingolimod. Myriocin (16, MW = 401), also known as antibiotic ISP-1, is a metabolite of the fungus Isaria sinclairii, and it has immunosuppressive activity.66 Although myriocin showed better in vitro and in vivo immunosuppressive activity than ciclosporin A, it was 100-fold more toxic and poorly soluble. Myriocin is a structural analogue of endogenous sphingosine-1-phosphate (S1P) and acts as an agonist of S1P receptors. It has a complex chemical structure that includes three chiral centers, one trans-double bond, and five polar groups (three hydroxyl groups, one carboxyl, and one amino

Figure 11. Structural simplification of neurotrophic sesquiterpenes.

Figure 12. Structural simplification of pyripyropene A.

morphine. Although methadone is a simple and highly flexible molecule, its stereo configuration is similar to that of pethidine (Figure 3). Similar to morphine, methadone is a potent μ receptor agonist.50 Moreover, methadone also acts as a Nmethyl-D-aspartate (NMDA) antagonist and serotonin reuptake inhibitor, which could enhance its analgesic properties.50 Currently, methadone is widely used for the treatment of morphine addiction because of its relatively low risk of addiction. The structural simplification of morphine highlights the importance of retaining the proper conformation and the key pharmacophore. Although simplified morphine derivatives have diverse chemical structures, they share similar conformations and common pharmacophores including an I

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Figure 13. Structural simplification of pladienolide B.

the basis of a systematic SAR study, derivatives with m and n values (in the side chain) of 2 and 8, respectively, displayed the most potent activity. Among these derivatives, fingolimod (20, MW = 307) was successfully developed in 2010 for treating patients with multiple sclerosis.69 3.1.4. Structural Simplification of Trichostatin A: Discovery of Vorinostat. Trichostatin A (TSA, 21, MW = 302), isolated from the actinomycete Streptomyces hygroscopicus, is a potent noncompetitive histone deacetylase (HDAC) inhibitor (Ki = 3.4 nM).70 It reversibly inhibited HDAC at nanomolar concentrations by chelating the zinc in the active site of HDAC with its hydroxamic acid group. SAR analysis revealed that two conjugated trans double bonds and the chiral center are not essential for the activity. Breslow et al. performed a structural simplification study of TSA by eliminating the conjugated double bonds and chiral center and retaining the hydroxamic acid group as the key pharmacophore (Figure 6A).71 The simplified analogue, vorinostat (22, MW = 264), can be easily synthesized, and it retained excellent HDAC inhibitory activity (HDAC1, IC50 = 0.04 μM).72 Crystal structures revealed that TSA and vorinostat adopted a similar binding mode in the active site of HDAC (Figure 6B,C).73 Vorinostat was approved in 2006 for the treatment of advanced primary cutaneous T-cell lymphoma.74 3.1.5. Structural Simplification of Halichondrin B: Discovery of Eribulin. Halichondrin B (23, Figure 7) is a large polyether macrolide (MW = 1110) that was isolated from the marine sponge Halichondria okadai Kadota.75 The marine macrolide showed excellent activity against B16 melanoma cells (IC50 = 0.093 ng/mL) and potent in vivo activity in inhibiting tumor growth in mice.76 Mechanism studies revealed that it acted as a tubulin-destabilizing agent and inhibited tubulin polymerization and microtubule assembly.77 Despite its promising biological activity, the limited supply of the NP from

Figure 14. Structural simplification of melicobisquinolinone B based on MCRs.

group). A SAR study indicated that the C-14 ketone group, C6 double bond, and C-4 hydroxyl group of myriocin were not essential for the activity, and the stereo configuration of the C3 hydroxyl group had little effect on the activity.66,67 On the basis of the SAR, Fujita et al. designed and synthesized simplified analogues (18) with a symmetric 2-alkyl-2-aminopropane-1,3-diol side chain to mimic the structure of the terminal group of sphingosine (17, Figure 5).68 Derivatives containing a side chain with 13−15 carbon atoms displayed higher activities than that of ciclosporin A. However, the molecular conformation became more complicated, which was caused by the flexibility of the alkyl side chain. To solve this problem, Fujita et al. replaced part of the side chain with a phenyl group to restrict the molecular conformations.66 Therefore, derivatives 19 were designed and synthesized. On J

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Figure 15. Structural simplification of campotothecin based on MCRs.

Table 7. In Vitro Antitumor Activity of Campotothecin and Simplified Analogue 81 (IC50, μM)a compounds

Hela

Jurkat

MCF-7

A549

LoVo

U373

SKMEL

PC3

81 campotothecin

0.17 1.3

0.05 0.09

0.45 6.0

0.61 0.20

0.29 0.008

0.10 0.033

0.23 0.047

0.19 0.48

a

Abbreviations: Hela, cervical cancer; Jurkat, human T-cell leukemia; LoVo, colon cancer; U373, human glioblastoma; SKMEL, melanoma; PC3, prostate cancer.

3.2.1. Structural Simplification of Staurosporine: Discovery of Ruboxistaurin and Enzastaurin. Staurosporine (25, Figure 8), an alkaloid originally isolated from cultures of Streptomyces sp. AM-2282, shows a wide range of biological activities including antitumor and neurotrophic potency.84,85 Staurosporine was validated as an inhibitor of protein kinase C (PKC), which is a family of serine/threonine-specific kinases that is composed of at least 12 isozymes or subtypes.86 Therapeutically, a selective PKC antagonist could treat a variety of diseases including diabetes and cancer.87,88 However, staurosporine had limited selectivity for both ATP-dependent kinases and individual PKC isozymes. The complex structure of staurosporine includes eight rings and four chiral centers, making its total synthesis challenging. Lilly’s research group reported the structural simplification of staurosporine and identified a novel class of macrocyclic bisindolylmaleimides (represented by ruboxistaurin, 26).89 The simplification process included opening the central benzene and tetrahydropyrane rings and oxidizing the pyrrolidone into maleimide. After the ring opening, ruboxistaurin contains only one chiral center and displayed good selectivity for PKC β. For example, compared with staurosporine, 26 exhibited better activity against PKC βI and βII with IC50 values of 0.0047 μM and 0.0059 μM, respectively. Moreover, its selectivity for inhibiting PKC α is significantly increased (Table 1). Ruboxistaurin mesylate was evaluated in the clinic for the treatment of diabetic retinopathy, but the phase III clinical trial of ruboxistaurin was terminated because of limited efficacy. In 2016, a phase I and II study for ruboxistaurin was conducted for treating adult patients with heart failure.90 Furthermore, Faul et al. identified a series of acyclic (N-azacycloalkyl) bisindolylmaleimides (represented by enzastaurin, 27).91 Enzastaurin displayed nanomolar activity against PKC βI and βII with an IC50 value of 0.03 μM. Meanwhile, it had good selectivity for PKC α. Enzastaurin was advanced into clinical

its marine source and its extremely complex structure are serious obstacles for its total synthesis and drug development. In 1992, Kishi et al. reported the first total synthesis of halichondrin B, but the synthetic route needed nearly 120 steps.78 Despite the length, the total synthesis provided enough material to support preclinical development. Interestingly, in an investigation of the bioactivities of the synthetic intermediates and analogues, the C1−C38 macrolide was found to show antitumor activity similar to that of the parent compound.79 Further investigations revealed that the unstable lactone moiety could be replaced by a non-hydrolyzable ester bioisostere, and the keto analogues displayed the best activity. As a result, a simplified analogue, named eribulin (24), was developed.80,81 Compared with halichondrin B, the structure of eribulin is greatly simplified (MW = 729). Additionally, the synthetic route was significantly shortened. In the crystal structure of tubulin in complex with eribulin, eribulin forms directly or water-mediated hydrogen bonds with residues Tyr224, Val177, and Asp179 within the binding pocket (Figure 7).82 Eribulin displayed superior efficacy over other antimitotics such as paclitaxel,81 and its mesylate derivative was approved by the FDA in 2010 for the treatment of patients with refractory metastatic breast cancer.83 3.2. Structural Simplification Leading to Clinical Candidates

In contrast to successful clinical drugs, candidate drugs derived from structural simplification of NPs are relatively limited. Herein only two examples of clinical candidates are introduced, in which reducing the number of rings and chiral centers is also used as the simplification strategy. The first example (simplification of staurosporine) illustrates structural simplification guided by different biological activity, while the second example (simplification of asperlicin) discusses pharmacophore inspired structural simplification. K

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Figure 16. Structural simplification of yohimbine by the SCONP scaffold tree.

gastrointestinal system.96,97 However, several limitations, such as its complicated structure, difficulties in total synthesis, limited SAR information, and poor oral bioavailability, have hampered the direct clinical application of asperlicin.98,99 Through a systematic structural analysis of asperlicin, Evans et al. found that the 1,4-benzodiazepine (BZD, 31) and Ltryptophan (L-Trp, 32) groups were the essential structural motifs (Figure 9).100 Moreover, the 5-phenyl-1,4-benzodiazepine scaffold is a privileged structure for the inhibition of Gprotein coupled receptors (GPCRs),101−103 which might be the pharmacophore that binds with CCK. Therefore, the 5phenyl-1,4-benzodiazepine scaffold was used as the lead structure for further modification. The right-hand side of asperlicin was an analogue of L-Trp, which is the key residue for the interaction of cholecystokinin with CCK. Therefore, a series of simplified derivatives (33) were designed by combining the BZD and L-Trp groups. After a systematic SAR study, devazepide (MK-329, 34) was discovered,104,105 and it displayed potent antagonistic activity against CCK with an IC50 value of 0.8 nM. Moreover, 34 showed good selectivity for the benzodiazepine receptor.100 Although a pilot clinical trial of devazepide in patients with advanced pancreatic cancer failed to demonstrate any impact on tumor progression,106 this

trials; however, its phase III clinical trials failed due to the poor efficacy for treating glioblastoma, breast and lung cancer.92 Now, clinical trials of enzastaurin are focused on treating tumor patients with specific biomarkers.93 In addition to its PKC inhibitory activity, staurosporine was also confirmed to be an effective Janus kinase 3 (JAK3) inhibitor with an IC50 value of 6 nM.84,94,95 The simplification of staurosporine led to a series of new simplified analogues with highly potent JAK3 inhibitory activity.95 Initially, Yang et al. replaced the amino-sugar group with an alkyl ring in which an attached hydroxymethyl group mimicked the methylamino fragment of the amino-sugar. SAR studies revealed that a suitable substituent at the C3 and/or C9 position could increase the JAK3 inhibitory activity. Therefore, further optimization focused on regioselective functionalization of the indolocarbazole unit. As a result, simplified analogues 28 (IC50 = 3 nM) and 29 (IC50 = 3 nM) were synthesized and demonstrated excellent inhibitory activity against JAK3.95 3.2.2. Structural Simplification of Asperlicin: Discovery of Devazepide. Asperlicin (30), a mycotoxin isolated from Aspergillus alliaceus,96 is a selective antagonist (IC50 = 1.4 μM) of pancreatic cholecystokinin receptors (CCK) with potential therapeutic effects in CCK-related disorders of the L

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Figure 17. BIOS libraries inspired by withanolide A and bioactive simplified analogues.

Figure 18. Structural simplification of podophyllotoxin (A) and the binding modes of podophyllotoxin (B, PDB: 1SA1), analogues 97 (C) and 98 (D) with tubulin. Molecular docking was used to reproduce the binding modes of analogues 97 and 98.

compound is widely used as a tool compound for the investigation of CCK receptors.

analysis of the case studies described in the following sections, reducing the number of rings and chiral centers is also the most commonly used simplification strategy, after which synthetic difficulty can be significantly reduced. Notably, most of the simplified compounds were only evaluated at the molecular and/or cellular level, and only two examples (i.e.,

3.3. Structural Simplification Leading to Preclinical Candidates or Lead Compounds

Currently, most examples in structural simplification of NPs are still at the stage of identifying new lead compounds. After M

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Figure 19. Structural simplification of taxuspine X.

Figure 20. Structural simplification of cortistatin A.

from the extracts of the marine organism Ecteinascidia turbinate.114 Trabectedin is a highly potent antitumor agent and has been approved as the first marine-derived antitumor drug for the treatment of soft tissue sarcoma and ovarian cancer. Mechanism study revealed trabectedin could bind to the minor groove of DNA, thus bending the DNA helix toward the major groove.115 Moreover, it interfered with cellular transcription-coupled nucleotide excision repair to induce cell death and cytotoxicity.115 With an aim to discover new trabectedin analogues with simpler chemical structures, better synthetic accessibility, and higher stability, Corey et al. performed a structural simplification of trabectedin in which the third isoquinoline ring was substituted with a phthalimide moiety (Table 2).116 Compared with trabectedin, structurally more simpler phthalascidin (36) displayed comparable or higher antitumor activity against A549 (lung cancer), HCT116 (colon cancer), and A375 (malignant melanoma) and PC (prostate cancer) cell lines. Moreover, the antiproliferative activity of phthalascidin (IC50 range: 0.1−1 nM) is better than those of several well-known natural antitumor agents (e.g., Taxol, camptothecin, adriamycin, and etoposide) by 1−3 orders of magnitude. Moreover, compound 36 could be easily synthesized from known synthetic intermediates (in six chemical steps) and displayed better stability than trabectedin which contains the unstable spiro 10-member lactonic ring. A mechanism study revealed that phthalascidin shared a similar

simplified erythrinane and largazole derivatives) reported the in vivo potency. The lack of in vivo PK/PD evaluations limits further development of these simplified NP derivatives. Moreover, the in vivo evaluations are also helpful to identify the problems to be overcome and guide further structural optimizations. Target identification is a bottleneck in NP-based drug discovery.10,107 In the following structural simplification examples, although targets of a large portion of NPs have been validated, the lack of binding mode information limited the efficiency to design simplified analogues. Thus, structural biology studies are highly required to clarify the key structural motifs for binding NPs with their targets and guide the rational simplification design. Also, the change of molecular targets has been observed in some cases (e.g., simplified bryostatin and campotothecin derivatives). Therefore, validation of the mechanisms is necessary to confirm whether the simplified compounds act on the same target as the parent NP. Recently, highly efficient and practical synthetic methods, such as multicomponent reactions (MCRs),108−110 FOS,111 DTS,112 and BIOS,113 have been applied to synthesize simplified NP analogues. Although successful examples are still limited, these new methods will contribute to improve the efficiency of structural simplification of NPs. 3.3.1. Structural Simplification by Reducing the Ring Number. 3.3.1.1. Structural Simplification of Trabectedin. Trabectedin (35, Table 2), also known as ecteinascidin743, is a bis-tetrahydroisoquinoline-fused alkaloid isolated N

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Figure 21. Structural simplification of bryostatin 1.

Figure 22. Structural simplification of cyclopamine 1.

Figure 23. Diverted total synthesis and simplification of carolacton-inspired analogues.

O

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Figure 24. Diverted total synthesis of promysalin-inspired analogues.

Figure 25. Structural simplification of chaetocin.

3.3.1.3. Structural Simplification of Sampangine. Invasive fungal infections (IFIs) are associated with high mortality in immune-compromised hosts. Despite the high mortality of IFIs, effective and safe antifungal agents are very rare. More importantly, increasing resistance is being developed to almost all the clinically available antifungal agents. Sampangine (41, Table 4), an azaoxoaporphine alkaloid extracted from the stem bark of Canangaodorat, displayed broad-spectrum in vitro antifungal activity.119 Further lead optimization and drug development were hampered because the aromatic tetracyclic derivatives had poor water solubility (kinetic solubility 12.6 μg/mL) and were inactive in vivo.120 To address these bottlenecks, our group performed a series of scaffold hopping and structural simplification studies, and identified a thiophene analogue, ZG-20 (42), with improved activity and water solubility (kinetic solubility 48 μg/mL, Table 4).121 After rings A and B were removed, simplified tricyclic analogue ZG-20-07 (43) and bicyclic analogue ZG-20−41 (44) displayed improved antifungal activities (Table 4) and water solubility. Moreover, they showed good in vivo antifungal potencies with low toxicities in a C. elegans−C. albicans infection model.122,123 Compounds 43 and 44, which were developed via a structural simplification, had several advantages over fluconazole, such as superior fungicidal activity, higher potency against fluconazoleresistant strains, and better inhibition of biofilm formation and yeast-to-hypha morphological transitions.122,123

mode of action to trabectedin and acted by inducing DNA− protein cross-linking.116 3.3.1.2. Structural Simplification of Erythrinane. Erythrinane (37, Table 3), a member of the Erythrina alkaloid family, is characterized by a unique tetracyclic spiroamine framework, and it was found to be a potent antagonist of nicotinic acetylcholine receptors (nAChRs).117 However, the limited availability of erythrinane and its analogues from natural sources hampers their broad application. In the pursuit of simpler and more synthetically accessible analogues, Crestey et al. performed a structural simplification of erythrinane in which the tetracyclic scaffold was simplified step by step to identify the groups essential to the nAChRs inhibitory activity (Table 3).118 First, the A-ring methoxyl group and the two double bonds in the A and B rings were sequentially deleted, resulting in tetracyclic derivatives 38, which showed retained affinity for a variety of nAChR subtypes. When the A ring was removed, tricyclic derivative 39 showed improved affinity for α4β2 (Ki = 5.5 μM). Notably, the selectivity of 39 for other subtypes was also significantly increased. Further deletion of the B ring gave bicyclic tetrahydroisoquinoline analogue 40, which displayed a submicromolar binding affinity toward α4β2 (Ki = 0.87 μM) with more than 300-fold selectivity over the other subtypes. In a mouse forced swim test, compound 38 showed an in vivo antidepressant-like effect at a dose of 30 mg/kg. P

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Figure 26. Structural simplification of largazole (A) and the binding mode of largazole thiol (B, PDB code: 3RQD) with HDAC8.

Figure 27. Structural simplification of lobatamide C.

with low toxicity to normal cells.124 It prevented cancer metastasis and angiogenesis, and was evaluated in phase II clinical trials in China.125,126 However, further clinical trial of

3.3.1.4. Structural Simplification of Gambogic Acid. Gambogic acid (GA, 45), the major component of gamboges resin, displayed potent in vitro and in vivo antitumor activity Q

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Figure 28. Structural simplification of sanglifehrin A (A) and the binding modes of sanglifehrin A (B, PDB code: 1YND), analogues 142 (C, PDB code: 1NMK), 143 (D, PDB code: 5T9U), 146 (E, PDB code: 5T9Z), 147 (F, PDB code: 5TA2), and 148 (G, PDB code: 5TA4) with cyclophilin A.

by step simplification of GA to obtain a series of analogues with a simplified planar region (Table 5).125 Compound 46, a simplified analogue obtained by removal of the A ring, displayed in vitro antitumor activity comparable or superior to that of GA.125 Mechanistic studies indicated that compound 46 was able to induce programmed cell death and arrest cell cycle growth in the G2/M phase as well as regulate apoptotic related proteins and cellular caspase-3 activity. The mode of

GA was terminated because of limited antitumor efficacy. The structure of GA can be divided into two fragments: a planar region that contains rings A, B, and C and the caged core D ring (4-oxa-tricyclo[4.3.1.03,7]dec-2-one) system. A preliminary SAR study revealed that the 4-oxa-tricyclo[4.3.1.03,7]dec2-one ring system was essential for the antitumor activity.125,127 To get more SAR information and improve the antitumor potency, You’s group performed a systematic step R

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Table 8. Biological Activities of Simplified Analogues of Sanglifehrin A compounds

TR-FRET Cyp A binding Kd (nM)

PPIase functional assay Ki (nM)

HCV genotype 1b replicon EC50 (nM)

143 144 145 146 147 148 149 cyclophilin A

25 65 2600 64 11 24 48 17

16 65 795 14 4 7 4.3 6.7

600 240 4500 320 36 87 620 170

Figure 30. Structural simplification of caprazamycin B.

Figure 31. Structural simplification of militarinone D.

bacteria strains than sanguinarine (Table 6). Mechanism studies revealed that these analogues exhibited strong cell division inhibitory activity and obvious inhibition on B. subtilis FtsZ polymerization, indicating that they inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. 3.3.1.6. Structural Simplification of Dynemicin. The violet dynemicin (52, Figure 10), a cyclic 10-membered enediyne NP isolated from the fermentation broth of Micromonospora chersina. M956-1,131,132 exhibited strong in vitro activity against Gram-positive bacteria and significant in vivo potency against Staphylococcus aureus Smith infection in mice (i.p., PD50 = 0.13 mg/kg) with low toxicity. In addition, dynemicin demonstrated highly potent antitumor activity against a variety of cancer cell lines and significantly prolonged the life span of mice with P388 leukemia or B16 melanoma.131,133 Structurally, dynemicin contains an anthraquinone and a 10-membered ring with a 1,5-diyn-3-ene bridge. The mechanism of its antitumor activity involves intercalation

Figure 29. Structural simplification of anguinomycin.

action of compound 46 was consistent with the apoptotic induction effects of GA. In contrast, compound 47, which was obtained both the A and B rings were removed, was substantially less effective. 3.3.1.5. Structural Simplification of Sanguinarine. Sanguinarine (48, Table 6) is a benzo[c]phenanthridine alkaloid which displayed moderate antibacterial activity against a broad range of Gram-positive bacteria.128 It was validated as a filamenting temperature-sensitive protein Z (FtsZ, an antibacterial target)129 inhibitor that can alter the Z-ring formation and function of FtsZ.130 To further improve the antibacterial activity, Ma et al. simplified the skeleton of sanguinarine to synthesize a series of 5-methyl-2-phenylphenanthridium derivatives (Table 6).128 Compounds 49, 50, and 51 displayed better activity against sensitive and resistant S

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Figure 32. Structural simplification of bistramide A (A) and the binding mode of bistramide A (B, PDB code: 2FXU) with monomeric actin.

rings of dynemicin and incorporated a phenylsulfone ethylene carbamate moiety on the nitrogen atom. The resulting simplified analogue, 54, was highly active with an IC50 value of 20 fM against Molt-4 T-cell leukemia cells.134 3.3.1.7. Structural Simplification of Merrilactone A. Sesquiterpenoid NPs, such as merrilactone A (55, Figure 11)137 and anislactone A/B (56),138 possess a variety of biological activities.139 Structurally, merrilactone A is a sesquiterpene dilactone consisting of two γ-lactones and an oxetane ring, and it displayed intriguing neurotrophic activity in primary cultures of fetal rat cortical neurons.137 Although nonpeptidic small molecules with neurotrophic activity are considered to have potential for the development of therapeutic agents against neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, the drug development of merrilactone A was hampered because of its structural complexity as well as the poor yields and high costs of obtaining it from its natural source.139 Thus, the structural simplification of merrilactone A was performed by Tiefenbacher’s group to reduce its complexity while maintaining its neurotrophic activity. By simplifying the scaffold of merrilactone A, analogues 57 and 58 showed neurite outgrowth activity comparable to that of the reference drug jiadifenolide.140 Compared with the 17−26 steps required for the total synthesis of merrilactone A, compounds 57 and 58 can be synthesized in just 6−8 steps with high yields from commercial materials.141,142 3.3.1.8. Structural Simplification of Pyripyropene A. Pyripyropene A (59, Figure 12), isolated from the culture broth of Aspergillus f umigatus strain FO-1289, is a strong and selective inhibitor of sterol O-acyltransferase 2 (SOAT2) (IC50 = 0.07 μM),143−145 which is an important target for the treatment of hypercholesterolemia and atherosclerosis.146,147 In the pursuit of new cholesterol-lowering or antiatherosclerotic agents, Nagamitsu’s group reported the first total synthesis

Figure 33. Structural simplification of withaferin A by FOS.

Figure 34. Structural simplification of rakicidin A.

of the anthraquinone core into DNA and triggering of a Bergman reaction, generating highly reactive benzenoid diradicals, causing DNA damage (Figure 10).134,135 Guided by the mechanism, structural simplification was focused on mimics of dihydroquinoline epoxides spanned by an enediyne bridge (red part in compound 52) while retaining the antitumor activity and reducing the molecular complexity. The simplest analogue, 53, was synthesized by Wender et al. in only seven steps and maintained the antitumor activity of the parent compound.135,136 Nicolaou et al. removed the A and B T

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Figure 35. Structural simplification of spongistatins.

IC50 = 1.5 μM).23,153 Furthermore, Burkart et al. reported C18−C19 cyclopropyl derivative 65, which displayed improved stability and effectively mimicked the apoptotic and splicing activity of PB.154 It showed potent inhibitory activity against HCT116 cell line (IC50 = 42.9 nM), which was slightly less active than PB (IC50 = 24.8 nM). The results indicated that the C18−C19 epoxide moiety was not essential for the spliceosome activity. Compound 66 lacking the 6-OH group demonstrated potent inhibitory activity against the mutant SF3B1 pancreatic cancer cell line (GI50 = 8.1 nM), high binding affinity to the SF3b complex (IC50 = 4.0 nM), and inhibition of pre-mRNA splicing.155 Moreover, NP herboxidiene (67, Figure 13) could be seen as a simplified analogue of PB, whose 12-member macrolide ring was replaced by the 6-member tetrahydropyran ring.156 Herboxidiene displayed potent inhibitory activity against several human cancer cell lines (e.g., Hela cell line, IC50 = 14.7 nM). However, analogue 68, a hybrid molecule from herboxidiene and PB, was totally inactive (IC50 > 20 μM), which highlighted the central role of the methyl substituent in the tetrahydropyran ring and the hydroxyl group in the side chain.156 3.3.1.10. Structural Simplification of Melicobisquinolinone B. Melicobisquinolinone B (69, Figure 14) containing the pyranoquinolone structural motif exhibited potent antitumor activities and was investigated as a potential anticancer agent.157−159 The MCRs have the advantages of environmental friendliness, atom economy, and efficient

of pyripyropene A in 2011. 148 Then, the structural simplification was performed to give new A ring-simplified pyripyropene A analogues based on the results of the SAR studies. Among these simplified analogues, 60 showed excellent SOAT2 inhibitory activity (IC50 = 0.07 μM) with high isozyme selectivity over SOAT1, and its activity was comparable to that of natural pyripyropene A.147 60 was considered to be the most potent and selective synthetic inhibitor of SOAT2 and an attractive candidate for further development. 3.3.1.9. Structural Simplification of Pladienolide B. Pladienolide B (PB, 61, Figure 13) contains a 12-member macrolide ring with an extended epoxide-containing side chain.149 It acted by targeting the SF3B1 subunit of spliceosome and displayed potent antiproliferative and tumor suppressive activity when assayed in both cell culture and xenograft models.149,150 To investigate the importance of the epoxide-containing side chain, Maier et al. reported a simplified analogue bearing a phenyl substituted side chain (compound 62).151 However, it was inactive up to 4 μg/mL in a cellular proliferation assay against L929 mouse fibroblasts. The results highlighted the central role of the epoxidecontaining side chain for binding. After removal of the 3hydroxy group and the methyl groups at positions 10, 16, 20, and 22 in PB, simplified derivative 63 was inactive against several human cancer cell lines at the concentration up to 20 μM.152 In contrast, the aryl analogue 64 with a truncated side chain displayed moderate antitumor activity (A549 cell line, U

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Figure 36. Structural simplification of spongistatins.

acts by the inhibition of topoisomerase I (Top1).160 The total synthesis of campotothecin requires more than 15 steps due to its five conjugated planar rings. The investigation of camptothecin analogues identified two clinically useful agents, topotecan161 and irinotecan,162 that can be employed for the treatment of colon and ovarian cancer, respectively.163 Magedov et al. developed a one-step multicomponent condensation of various aminoheterocycles (77), aldehydes (76), and 1,3-indanedione (78) that facilitated the synthesis of various heterofused indenopyridines (Figure 15).110 These analogues (79) mimicked the A−D rings of campotothecin, and the dihydropyridine moiety could be transformed to the planar indenopyridine skeleton (80) via an intracellular oxidation. These simplified derivatives displayed broadspectrum antitumor activity. For example, compound 81 showed better inhibitory activity toward HeLa, Jurkat, and MCF-7 cells than campotothecin (Table 7).110 Interestingly, mechanism studies revealed that these analogues inhibited topoisomerase II (Top2) instead of Top1. These results indicated that the structural simplification of NPs may result in a change in the molecular target. 3.3.1.12. Structural Simplification of Yohimbine. Yohimbine (82, Figure 16) is an indole alkaloid derived from the bark of the Pausinystalia yohimbe tree with diverse biological activities.164 It was identified as an inhibitor of

Table 9. Antitumor Activity of Simplified Spongistatin Derivatives (IC50, nM) human cancer cell line

paclitaxel

166

174

175

MIP101 colon HCT116 colon 1A9PTX22 1A9 A549

200 0.3 47 1 6

0.1 0.05 0.03 0.03 0.07

0.08 0.02 0.007 0.007 0.04

587 407 >632 >632 >632

construction of molecules in only one or two synthetic steps. Magedov et al. developed a three-component reaction of pyridine (70) with malononitrile (72) and various aromatic aldehydes (71) to efficiently construct a library of compounds with pyrano[3,2-c]pyridone and pyrano[3,2-c]quinolone scaffolds (73, Figure 14).109 Most derivatives displayed submicromolar or low micromolar inhibitory activities against HeLa cells. Generally, pyrano[3,2-c]quinolones were more potent than pyrano[3,2-c]pyridines.109 Compound 74 showed potent inhibitory activity against HeLa cells with a GI50 value of 47 nM and significantly induced the apoptosis of Jurkat cells at a concentration of 5 μM. Mechanistic studies revealed that these compounds induced cell cycle arrest in the G2/M phase and blocked in vitro tubulin polymerization. 3.3.1.11. Structural Simplification of Campotothecin. Campotothecin (75, Figure 15) is a classic antitumor NP that V

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Figure 37. Structural simplification of migrastatin (A) and the binding mode of analogue 185 with fascin (B, PDB code: 3O8K).

phosphatase Cdc25A by Waldmann’s group.41 The pentacyclic scaffold of yohimbine was sequentially truncated into simpler compounds by a chemistry-based rule165,166 called “structural classification of natural products” (SCONP).41 As a result, a scaffold tree of yohimbine was obtained in which complex scaffolds become smaller step by step (Figure 16A). The simpler scaffolds in the scaffold tree may retain the bioactivity of the more complex compounds, which can be used for structural simplification. For example, the simplified tetracyclic scaffold 85 showed similar phosphatase Cdc25A inhibitory activity (IC50 = 20.3 μM) to yohimbane (IC50 = 22.3 μM).167 In contrast, analogue 86 was inactive against Cdc25A and was identified as a mycobacterial protein tyrosine phosphatase B (MptpB) inhibitor.167 Moreover, analogue 87 showed potent activity against the HeLa cervical cancer cell line (IC50 = 0.8 μM) and arrested the cell cycle at the G2/M phase.168 In addition to the inhibitory activity against MptpB,41 additional simpler tetrahydrocarbazole (88) and indole (89) derivatives were inhibitors of vascular endothelial growth factor receptors 2 (VEGFR-2).169 The results also indicated that over simplification might lead to the change of the binding target. 3.3.1.13. Structural Simplification of Withanolide A. Withanolide A (90, Figure 17) is steroid-like NP with diverse bioactivities.170 The trans-hydrindane/dehydro-δ-lactone fragment was thought to be the essential pharmacophore. Waldmann’s group developed the concept of BIOS, which integrates computational and synthetic tools to design and synthesize bioactive simplified NP analogues.113,171 To reduce the structural complexity of withanolide A, an efficient BIOS method was developed for the synthesis of trans-hydrindane dehydro-δ-lactone derivatives (91).172 Cell-based assays indicated that four withanolide analogues act by inhibiting

Hedgehog (Hh) signaling. Among these analogues, compound 92 was proven to bind to the SMO protein (Ki = 57 nM) with low cytotoxicity. The same group further constructed a compound library of substituted δ-lactones 93.173 Several withanolides, particularly vinylogous urethane analogues, displayed significant potency in inhibiting the Wnt/β-catenin pathway. Compound 94 was the most potent withanolide (IC50 = 0.11 μM) and interfered with the Wnt pathway by a novel tankyrase-independent mechanism. Interestingly, its simplified analogue, 95, retained the ability to inhibit the Wnt reporter gene (IC50 = 4.5 μM), although it was 40-fold less active. The novel and potent inhibitors of the Hedgehog signaling pathway and the Wnt/β-catenin pathway were promising lead compounds for drug discovery. 3.3.2. Structural Simplification by Removing Chiral Centers. 3.3.2.1. Structural Simplification of Podophyllotoxin. Podophyllotoxin (96, Figure 18), a well-known NP isolated from the roots of Podophyllotoxin peltatum, displays good in vitro antitumor activity.174 However, the total synthesis of podophyllotoxin is challenging due to its complex structure. The C ring of podophyllotoxin contains four chiral centers, and the facile epimerization of the C-2 position converts the compound into its inactive cis-acetone isomer in vivo.175 The structural modification of podophyllotoxin was focused on its semisynthetic derivatives. Hitotsuyanagi et al. designed and synthesized structurally simplified podophyllotoxin analogues containing the 4-aza-2,3-dehydro-4-deoxypodophyllotoxin scaffold, which could be easily synthesized because of the elimination of the chiral centers.176 Interestingly, these derivatives retained the good antitumor activity of their parent compound.176 For example, compound 97 displayed potent antitumor activity against the P-388 leukemia W

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Table 10. Selected Examples of Structural Simplification of Complex NPs

X

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Table 10. continued

Y

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Table 10. continued

cell line with an IC50 value of 0.00182 μg/mL, which makes it 2-fold more potent than podophyllotoxin (IC50 = 0.0043 μg/

mL). Using multicomponent synthesis, Magedov et al. synthesized analogues bearing a dihydropyridine pyrazole Z

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scaffold.177 Compared with podophyllotoxin, the A ring and the chiral centers were removed. A one-step multicomponent reaction enabled a highly efficient construction of the library of analogues and elucidation of the SARs. These simplified derivatives displayed good in vitro antitumor activities. For example, compound 98 had an IC50 value of 0.02 μM and 0.01 μM against the HeLa and MCF-7 cancer cell line, respectively, which were comparable to that of podophyllotoxin. Moreover, it showed an antiapoptotic effect comparable to that of podophyllotoxin against the Jurkat leukemia cell line. Mechanism studies revealed that compound 98 inhibited tubulin polymerization and disrupted the formation of mitotic spindles in dividing cells at concentrations as low as 5 nM, which was similar to podophyllotoxin. Molecular docking results revealed analogues 97, 98, and podophyllotoxin adopted a similar binding mode with tubulin (Figure 18).177,178 3.3.2.2. Structural Simplification of Taxuspine X. Paclitaxel (Taxol) and its derivative docetaxel are widely used anticancer agents for the treatment of ovarian, breast, and lung cancer. These compounds have potent antitumor activity via binding to β-tubulin. However, broad clinical application resulted in significant multidrug resistance (MDR), which was a significant obstacle for the success of chemotherapy in different types of cancers.179,180 One major mechanism of MDR is the overexpression of P-glycoprotein (P-gp), a wellknown trans-membrane ABC transporter, which effluxes a variety of chemotherapeutic drugs out of tumor cells.180−182 Taxuspine X (99), a Taxol analogue that was isolated from the Japanese yew Taxus cuspidate, was proven to be a potent MDR reversing agent.183−185 However, 99 was isolated in very poor yields from the natural source, and the total synthesis was limited by intrinsic difficulties and high costs. To explore the biological potential of taxuspine analogues, Botta et al. performed structural simplification studies (Figure 19).186,187 Simplified diterpenoid 100 was synthesized through a ringclosing metathesis approach. However, its significant structural complexity still represents a synthetic challenge, partly due to the presence of six stereocenters. Therefore, further structural simplification was conducted to obtain additional simplified analogues 101 and 102. Compound 101, bearing a benzoyloxy moiety on C13 of the taxane skeleton, was proven to be an efficient P-gp inhibitor (IC50 = 7.2 μM). 3.3.2.3. Structural Simplification of Cortistatin A. Cortistatin A (103, Figure 20), a novel antiangiogenic steroidal alkaloid isolated from an Indonesian marine organism, showed potent and selective antitumor activity against human umbilical vein endothelial cells (HUVECs).188 Compound 103 also significantly inhibited in vitro migration and tubular formation of HUVECs induced by vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF).188 Therefore, this compound is expected to be a promising antiangiogenic lead compound. Kobayashi et al. designed and synthesized simplified analogues by reducing the number of chiral centers and removing a bridged ring (Figure 20).189,190 Although compound 104 (IC50 = 0.035 μM) was less active than cortistatin A in the inhibition of HUVECs, it showed potent in vivo antiangiogenic and antitumor activities by oral administration. After introduction of an amide side chain on the scaffold, acetamide analogue 105 displayed a highly potent activity against HUVECs (IC50 = 0.0026 μM) as well as an excellent selectivity for KB3−1 cells (IC50 = 8.2 μM).190

3.3.2.4. Structural Simplification of Bryostatin 1. Chikungunya virus (CHIKV) is an arbovirus of the Alphavirus genus that has been spreading rapidly.191 Currently, there is no effective therapy to treat CHIKV infections, and the only medications (i.e., the anti-inflammatory drugs) can be used to alleviate the symptoms. PKC modulators were reported to inhibit CHIKV virus-induced cell death, representing a promising therapeutic choice to treat CHIKV infection.192−194 Bryostatin 1 (106, Figure 21) is a marine NP bearing a polyacetate backbone which was originally isolated from the bryozoan Bugula neritina.195 It is a great challenge for the total synthesis of bryostatin 1 because of the complex scaffold (nearly 55 synthetic steps).196 Bryostatin 1 was proven to be a potent pan-conventional and novel PKC isoform modulator (PKC δ binding affinity Ki = 1.1 nM). However, it was inactive in inhibiting CHIKV virus-induced cell death.191 Wender’s group designed the simplified analogues of bryostatin 1 by removing several chiral centers (Figure 21).191 Compared with bryostatin 1, synthetic routes of simplified analogues 107 and 108 were significantly shortened (∼30 steps). Interestingly, compounds 107 and 108 displayed potent activity in the CHIKV cell protective assay with an EC50 value of 0.13 μM and 0.8 μM, respectively.191 Moreover, compound 108 displayed no observable toxicity (CC50 > 50 μM). In 2014, Wender et al. reported a new class of simplified analogues in which the complex A/B-ring system of bryostatin 1 was replaced with simple salicylate-derived fragments (109, Figure 21).197,198 These analogues retained potent affinity (nanomolar) for PKC isoforms, whereas the synthetic route was greatly shortened to 23−25 steps. Analogue 109 displayed good protective activity (EC50 = 1.4 μM) and lower toxicity (CC50 > 50 μM). SAR study of various substitutions attached to the hydroxyl group revealed that methoxyl analogue 110 displayed good protective activity and lower toxicity (CHIKV EC50 = 2.2 μM, CC50 > 50 μM). However, compound 110 displayed a lower affinity to PKC (PKCδ Ki = 1.0 μM), indicating that there might be a PKC-independent mechanism for evading CHIKV-mediated cell death. This structural simplification study provided a good starting point for the design of new drugs for the treatment of CHIKV infections. 3.3.2.5. Structural Simplification of Cyclopamine 1. The steroidal alkaloid cyclopamine 1 (111, Figure 22) was isolated from Veratrum californicum and proven to be responsible for craniofacial birth defects.199,200 Subsequently, mechanism studies revealed that cyclopamine 1 blocked the Sonic Hedgehog (SHH) signaling pathway by binding to 7transmembrane protein Smoothened (SMO).201,202 Despite its teratogenicity, cyclopamine 1 showed highly potent activity against a number of human cancers and holds great promise for cancer chemotherapy.203−205 However, its poor aqueous solubility and acid lability hampered its further development.206,207 To address these limitations, Dahmane et al. explored the SAR of cyclopamine 1 by structural simplification.207 First, replacement of the C-nor-D-homo steroidal system with the androstane ring and aromatization of rings A and F generated simplified analogue 112 as well as the C-17 epimer 114. The C-3 deoxy compound 113 was also prepared. Biological evaluations demonstrated that simplified analogues 112−114 showed comparable SHH inhibitory activities with improved metabolically stability.208 3.3.2.6. Structural Simplification of Carolacton. Carolacton (115, Figure 23) is a NP isolated from myxobacterium Sorangium cellulosum.209 It was unable to AA

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group.221 The macrocyclic depsipeptide subunit locates outside the binding pocket and forms mainly hydrophobic interaction with surrounding residues.221 Nan’s group performed a structural simplification of largazole in which the −CH2CONHCH2− group and the C7-methyl group were eliminated to afford ring-opened analogue 131 (Figure 26).222 Compared with largazole, analogue 131 displayed decreased HDAC1inhibitory activity, but it was more potent against HDAC3 and HDAC6. A typical HDAC inhibitor has three essential pharmacophoric features, namely, a recognition cap group, a hydrophobic linker, and a zinc-binding group (ZBG). Therefore, the long side chain of compound 131 was replaced with the classic hydroxamic acid ZBG to afford a series of analogues 132.222 Disappointingly, these hydroxamic acid analogues displayed significantly reduced HDAC1 inhibitory activity (IC50 values of 2.45−9.69 μM). Further structural simplification, including the replacement of the chiral L-valine moiety with a carbon chain linker, was conducted to afford analogue 133, which displayed significantly improved inhibitory activity.222 Furthermore, analogue 134, containing a 2,2′bisthiazole moiety instead of the 2,4′-bisthiazole moiety, showed a 2-fold increase in activity compared to that of compound 133. Further structure modification of 134 afforded analogue 135 via the introduction of a hydrophobic cyclopropyl group to the thiazole ring, and 135 displayed HDAC1 inhibitory activity (IC50 = 0.07 μM) comparable to that of lagazole.222 Moreover, analogue 135 displayed potent and broad-spectrum inhibitor activity against various HDAC isoforms except HDAC7 and HDAC9. The simplified structure of 135 has a smaller molecular weight and showed favorable pharmacokinetic profiles characterized by high Cmax (7.04 μg/ mL) and AUC0‑t (12.07 μg·h/mL) values and excellent absolute bioavailability (F% = 118.7%) in mice (20 mg/kg, P.O.).222 Moreover, this compound showed in vivo efficacy in ameliorating clinical symptoms of experimental autoimmune encephalomyelitis (EAE) mice when administered orally. The simplified largazole derivatives are currently under preclinical evaluation for the treatment of various tumors. 3.3.3.3. Structural Simplification of Lobatamide C. Lobatamide C (137, Figure 27) belongs to a unique class of NPs with a common benzolactone core structure and a highly unsaturated enamide side chain.223 This compound displayed highly potent inhibitory activities against the NCI’s 60 cell-line human tumor screen (mean panel GI50 values = 1.6 nM) along with unique cellular response profiles.223 Mechanism studies revealed that the salicylate enamide macrolides potently inhibited mammalian vacuolar-type (H+)-ATPases (V-ATPases), which are proton-translocating pumps ubiquitous in eukaryotic cells.224−226 To clarify the minimal pharmacophores required for V-ATPase inhibition, Porco et al. designed and synthesized acyclic lobatamide analogues via opening the lactone ring (Figure 27).227,228 Biological assays indicated that simplified salicylate enamide analogue 138 displayed potent inhibitory activity toward V-ATPase with an IC50 value of 0.1 μM.227 Analogue 139, with a steric prenyl substituent, showed slightly higher activity (IC50 = 60 nM).228 The results indicated that the simplification of lobatamide C was feasible and that acyclic salicylate enamide V-ATPase inhibitors required further optimization. 3.3.3.4. Structural Simplification of Sanglifehrin A. Sanglifehrin A (SFA, 140, Figure 28), an immunosuppressive NP isolated from Streptomyces sp. A92-308110,229,230 exhibited high affinity (Kd = 6.9 nM) to cyclophilin A and inhibited the

affect the viability of planktonic bacteria but effectively kills pathogen Streptococcus mutans biofilm cells at low nanomolar concentration.210,211 Earlier SAR work revealed that modifications of the 12-member macrolide ring were not tolerated.212,213 Thus, Wuest et al. applied DTS to synthesize 16 simplified carolacton-inspired analogues (Figure 23).214 1,3Disubstituted aryl motifs were rationally selected to mimic the trisubstituted olefin side chain. Among them, compound 120 inhibited the formation of biofilms at concentrations at the concentration of 63 μM, and compound 121 exhibited a similar effect on S. mutans biofilms at concentrations as low as 500 nM. The results highlighted that 1,3-disubstituted aryl motifs could be used as an bioisosteric substitution of the trisubstituted olefins, which significantly reduced the synthetic difficulty while maintaining the structural integrity. 3.3.2.7. Structural Simplification of Promysalin. Promysalin (122, Figure 24) is a NP produced by Pseudomonas putida, and displays potent inhibitory activity against Pseudomonas aeruginosa at nanomolar concentrations,215 while Gram-positive bacteria show no susceptibility to it.216 Promysalin acts by a unique mode of action that it could inhibit the production of pyoverdine (a siderophore) in P. putida KT2440, which can actively chelate Fe3+ for its end use in enzymatic processes and is essential for the growth of Pseudomonads. Wuest et al. synthesized 16 promysalin analogues utilizing DTS (Figure 24).217 Several analogues displayed comparable inhibitory activity against P. aeruginosa to promysalin. For example, the simplified analogue 126, obtained by removing the hydroxyl group in the side chain, displayed potent inhibitory activity against P. aeruginosa strains PAO1 and PA14 with an IC50 value of 5.8 μM and 0.035 μM, respectively. The results determined the key structural features responsible for bioactivity and highlighted the central role of the intramolecular hydrogen-bonding network for binding with iron. 3.3.3. Structural Simplification by Truncating Unnecessary Substructures. 3.3.3.1. Structural Simplification of Chaetocin. Chaetocin (127, Figure 25), a NP isolated from the genus Chaetomium, is the first reported inhibitor of protein lysine methyltransferase G9a (PKMT G9a).218 It is a dimer composed of symmetric structures that contain eight chiral centers. Due to the structural complexity and functional group density, the total synthesis of chaetocin is highly challenging. In the structural simplification of chaetocin, Fujishiro et al. synthesized monomeric derivatives to investigate the importance of the dimeric structure for the activity (Figure 25).219 Interestingly, monomeric derivative 128 was a more potent PKMT G9a inhibitor (IC50 = 3.3 μM) than chaetocin (IC50 = 7.2 μM). Further removal of the indole moiety of analogue 128 afforded structurally simplified bicyclic compound 129, which retained the PKMT G9a inhibitory activity (IC50 = 5.2 μM) of the parent compound. Compared with chaetocin, the structure of compound 129 was greatly simplified and its toxicity was also significantly lower. 3.3.3.2. Structural Simplification of Largazole. Largazole (130, Figure 26) is a depsipeptide NP that was isolated from cyanobacterium Symploca sp. by Luesch and co-workers in 2008.220 It displayed potent HDAC1 inhibitory activity with an IC 50 value of 0.0137 μM and exhibited potent antiproliferative activity and selectivity for cancer cells. In the crystal structure of HDAC8 in complex with largazole thiol (136, Figure 26B), the thiol side chain inserts into the binding pocket and chelates the zinc in the active site with its thiol AB

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3.3.3.5. Structural Simplification of Anguinomycin. The polyketide NPs of the leptomycin family have attracted substantial interest from chemists and biologists because of their highly complex structure and excellent antitumor activity.235,236 Unfortunately, drug development of leptomycin B (150, Figure 29) failed in phase I clinical trials due to toxicity to patients.237 In contrast, two related compounds, anguinomycins C and D (151 and 152), showed excellent antitumor activities at low nanomolar concentrations and induced apoptosis in pRB-inactivated tumor cells while only inducing growth arrest in normal cells.235,236 A mechanism study revealed that these antitumor antibiotics inhibited the nuclear export receptor chromosome region maintenance 1 (CRM1).238−240 Gademann et al. investigated the importance of the polyketide side chain for the antitumor potency. After the side chain was replaced with a simpler linear terpene, compound 153 displayed similar activity in blocking nucleocytoplasmic transport.241 Further reducing the length of the polyketide side chain led to the very simple analogue 154, which effectively blocked nuclear export at 25 nM.241 The simplicity, good synthetic accessibility, and excellent activity of compound 154 make it a particularly attractive candidate for further development. 3.3.3.6. Structural Simplification of Caprazamycin B. Caprazamycin B (CPZ-B, 155, Figure 30), a nucleoside NP extracted from the culture broth of the actinomycete Streptomyces sp. MK730−62F2,242 demonstrated excellent in vitro antimicrobial activity against both drug-susceptible and multidrug-resistant Mycobacterium tuberculosis strains with low toxicity to mice at single doses up to 200 mg/kg.242 CPZ-B was a new member of the 6′-N-alkyl-5′-β-O-aminoribosoyl-Cglycluridine class of antibiotics, which act by targeting phospho-MurNAc-pentapeptide translocase (MraY) to block the formation of lipid I and peptidoglycan biosynthesis.243−247 On the basis of its excellent biological properties, CPZ-B was expected to be a promising antibacterial drug candidate. However, the total synthesis of CPZ-B remains challenging. Only recently have Takemoto et al. reported a 23-step total synthesis for the related compound caprazamycin A.248 This fact, combined with its extremely poor water solubility, hampered the clinical development of this compound.249 Therefore, Matsuda et al. reported the rational simplification of CPZ-B through FOS.247 First, the diazepanone ring of CPZ-B was proven to be nonessential for the antibacterial activity. Then, the diazepanone and aminoribose units were replaced with an oxazolidine moiety to give oxazolidine analogue 156 (Figure 30). Biological evaluation revealed that compound 156 showed good antibacterial potency against drug-susceptible S. aureus, E. faecalis, and E. faecium and drug-resistant bacterial strains (e.g., MRSA and VRE strains) with MIC values ranging from 2 to 16 μg/mL.247 Compound 156 can be synthesized in just 12 steps, which makes it a good candidate for further development. 3.3.3.7. Structural Simplification of Militarinone D. A number of pyridone alkaloids with diverse bioactivities and pharmaceutical relevance have been isolated from entomopathogenic Deuteromycetes fungi. Among these compounds, militarinone D (157, Figure 31) was discovered from a mycelial extract of the entomopathogenic fungus Paecilomyces militaris. (RCEF 0095) and identified through activity-directed fractionation.250,251 Militarinone D showed potent neuritogenic activity in PC-12 cells and significantly induced neurite outgrowth in the absence of a nerve growth factor

peptidyl-prolyl cis−trans isomerase (PPIase) activity of cyclophilin A (Ki = 12.8 nM) in a cell-free assay.231 It was investigated as a potential treatment for hepatitis C virus (HCV). However, SFA has a complex molecular structure consisting of a 22-membered macrocycle bearing a nine-carbon tether at the 23 position terminated by a highly substituted spirobicyclic moiety, which poses a tremendous challenge for the synthesis of new analogues. The crystal structure of SFAcyclophilin A complex revealed that the 22-membered macrocycle scaffold formed a hydrogen bond network with residues Gln63, Arg55, His126, and Asn102 (Figure 28B).232 In contrast, the terminal substituted spirobicyclic moiety was oriented out of the binding domain, indicating that it was unnecessary for the binding activity.232 For the structural simplification of SFA, Wagner et al. performed the selective oxidative cleavage of the C26C27 exocyclic double bond to afford the spirolactam fragment and macrolide 141 (Figure 28).233 Biological assays indicated that macrolide 141 displayed potent binding affinity for cyclophilin (Kd = 29 nM), which was slightly less active than SFA, indicating the macrocyclic portion of SFA was the key fragment for the activity. Moreover, the removal of the C24 polyketide side chain eliminated the immunosuppressive activity. Further degradation studies afforded analogue 142, which has an allylic alcohol side chain, and it displayed improved binding affinity for cyclophilin (Kd = 5.7 nM). On the basis of analogue 142, Schultz et al. performed a further step-by-step structural simplification study (Figure 28, Table 8).234 After analyzing the cocrystal structure of 142 with cyclophilin A, they envisioned that the C23 and C14 side chains and the two hydroxyl groups might be unnecessary (Figure 28C).233 Therefore, the C23 and C14 side chains were removed, and the two hydroxyls were methylated to afford simplified analogue 143. This compound displayed potent binding affinity for cyclophilin A (Kd = 25 nM) and submicromolar antiviral activity in the HCV replicon cellular assay (EC50 = 600 nM). Similar to 142, analogue 143 retained the hydrogen bonding interaction with residues Arg55, Gln63, Asn102, and His126 (Figure 28D).234 Furthermore, the C14 to C17 stereocenters were investigated using analogues 144− 145, which were synthesized in only a few steps. Biological assays indicated that the chiral centers at C16 and C17 were not essential for the activity. Subsequent replacement of the C18−C21 diene unit with a styryl group led to potent analogues 146 and 147. Analogue 147 displayed the most potent binding affinity for cyclophilin A (Kd = 11 nM) and sub-micromolar antiviral activity in the HCV replicon cellular assay (EC50 = 36 nM). The crystal structure of analogue 147 in complex with cyclophilin A displayed a novel binding mode in which the m-tyrosine (m-Tyr) residue was displaced into the solvent (Figure 28F).234 On the basis of this observation, they further simplified the scaffold and replaced the m-Tyr with an alanine to afford analogues 148 and 149. Analogue 148 displayed an excellent binding affinity for cyclophilin A (Kd = 24 nM) with potent cellular activity (EC50 = 87 nM), confirming that the m-Tyr residue was unnecessary in these new analogues. The binding mode of compound 148 was similar to that of SFA, whose macrocycle moiety formed hydrogen bonds with residues Asn102, Arg55, and Gln63 (Figure 28G).234 After removal of the C14 to C17 stereocenters of compound 148, analogue 149 only showed a 2-fold decrease in binding affinity, and its cellular activity was retained. AC

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(NGF).251−253 In 2011, Gademann et al. reported a unified approach for the stereoselective total synthesis of pyridine alkaloids and evaluated their neuritogenic activities in a standardized assay with PC-12 cells.254 The results revealed that neither the side chain length nor the absolute configuration was the essential pharmacophore. Therefore, Gademann’s group synthesized truncated analogue 158 by deleting the side chain, and this compound showed neurite outgrowth activity comparable to that of militarinone D at 20 μM.255 3.3.3.8. Structural Simplification of Bistramide A. Bistramide A (159, Figure 32) is a marine-derived NP isolated from the ascidian Lissoclinum bistratum.256−258 In addition to highly potent antitumor activity against A549 lung cancer cell lines, bistramide A was also confirmed to alter the voltage dependence of muscle twitch tension and inhibit Na+ conductance.259,260 Initially, bistramide A was thought to selectively activate PKC δ.261 However, Kozmin et al. proved that actin was the primary target of bistramide A.261,262 Structurally, bistramide A can be divided into three parts, namely, C(19)−C(38) lipophilic subunit A, C(13)−C(18) hydrophilic subunit B, and C(1)−C(13) reactive subunit C (Figure 32A).263 The X-ray crystal structure of the actinbistramide A complex revealed that subunits A and B spanned the entire deep binding cleft of actin through an network of hydrogen bonds and van der Waals interactions (Figure 32B).264 In contrast, subunit C was oriented out of the binding domain and faced to the solvent. Subunit C was proved to be unnecessary for the binding affinity and could be truncated.263,265 Thus, simplified analogue 160 was designed, which simultaneously retained the G-actin affinity and reduced the structural complexity of the parent compound.263 3.3.3.9. Structural Simplification of Withaferin A. The withanolides constitute a class of NPs characterized by an ergostane skeleton with a modified side chain in which carbons 22 and 26 are oxidized to form a δ-lactone.170 To date, over 600 members of this family have been isolated and characterized, and they have shown a broad range of biological activities including anti-inflammatory, antitumor, antimicrobial, and immunoregulatory activities as well as antifeedant and insecticidal activity.170,266 Withaferin A (161, Figure 33) was the first withanolide analogue isolated from Withania somnifera Dun (Solanaceae) by Lavie in 1965.267 The compound was reported to trigger apoptosis and largely suppress cell migration/invasion in MDA-MB-231 human breast cancer cells depending on the inhibition of STAT3 phosphorylation.268 Withacnistin (162, Figure 33), a C18-functionalized derivative of withaferin A, was also identified as a potent STAT3 inhibitor and induced regression in breast tumor cells.268,269 Considering their potent inhibitory activities against STAT3, withaferin A and withacnistin were investigated as potential lead compounds for antitumor drug discovery. The FOS approach was applied to synthesize simplified withaferin A analogues with maintained or improved biological activity.270 After truncating of the δ-lactone side chain, compound 163 showed STAT3 inhibitory activity (more than 50% inhibition of STAT3 phosphorylation at 1 μM) comparable to that of compound 161 in MDA-MB-231 breast cancer cell lines. 3.3.3.10. Structural Simplification of Rakicidin A. Tumor hypoxia is a common feature of most tumors and is highly correlated to poor prognosis of cancer patients owing to its multiple contributions to chemo-resistance, radio-resistance,

and metastasis.271,272 Rakicidin A (164, Figure 34) is a macrocyclic depsipeptide isolated from culture broth of Micromonospora sp. strain R385-2.273 In 2011, Ashihara’s group demonstrated that rakicidin A exhibited selective growth inhibitory activity against hypoxic cancer cells and inhibited the proliferation of imatinib-resistant, hypoxia-adapted chronic myelogenous leukemia (HA-CML) cells by inducing apoptosis.274 Structurally, rakicidin A is a cyclic depsipeptide consisting of 4-amino-penta-2,4-dienoic acid (APD, red in Figure 34), 3-hydroxy-2,4,16-trimethylheptadecanoic acid, sarcosine, and β-hydroxyasparagine (β-HOAsn) moieties. This compound belongs to the APD-containing cyclolipodepsipeptide (APD-CLD) class of NPs with five chiral centers.275 Due to its structural complexity and unique biological activity, rakicidin A is of particular interest for both synthetic and medicinal studies. Chen et al. reported the first total synthesis of rakicidin A and determined that the absolute configuration of rakicidin A is 2S,3S,14S,15S,16R.276 SAR studies revealed that the APD functionality was essential for the biological activities of rakicidin A.276−279 Guided by the SAR, Poulsen et al. synthesized simplified analogue 165 by pruning the βHOAsn side chain and the C14 and C16 methyl groups, and this derivative showed potent and selective growth inhibition under hypoxic conditions with a GI50 value of 352 nM.279 Although the potency was 10-fold lower, compound 165 showed better hypoxic selectivity (>67-fold) than rakicidin A. 3.3.3.11. Structural Simplification of Spongistatins. The spongipyran NPs, such as spongistatin 1 (166, altohyrtin A, Figure 35) and spongistatin 2 (167, altohyrtin C, Figure 35), are a unique family of bis(spiroacetal) macrolides which were isolated from marine sponges in the early 1990s.280−283 They displayed exceptional cytotoxicity against a wide range of human cancer cell lines, acting by interfering with tubulin polymerization.284 Spongistatin 1 had an average IC50 of 0.13 nM against the panel of 60 cancer cell lines, which was thought to be the most potent antiproliferative agent ever discovered.285 Although it shows great promise in cancer chemotherapy, the extreme scarcity of natural supply and synthetic difficulty have halted its further preclinical development. In order to obtain SAR and identify the spongipyran pharmacophore, several groups devoted their efforts to simplify this highly complex NP. Smith et al. reported two simplified analogues (compounds 168 and 169) bearing the F ring and the C44−C51 triene side-chain.286 However, these analogues only displayed micromolar inhibitory activity against several human cancer cell lines. Furthermore, the same group synthesized the AB-spiroacetal spongistatin derivatives 170 and 171.287 Neither of them had significant cytotoxic or antitubulin activity. Smith et al. synthesized two diminutive derivatives of spongistatin 1 (172 and 173, Figure 35).285 Analogue 172 displayed no significant cytotoxic activity (IC50 > 1 μM). In contrast analogue 173 displayed potent cytotoxic activity against U937 (IC50 = 60 nM) and MDA-MB-435 (IC50 = 83 nM). A less drastic simplification of spongistatin 1 was performed by Paterson et al.288 After dehydration at E-ring C35 position, compound 174 (Figure 36) showed enhanced cytotoxicity at the low picomolar level (Table 9), whereas truncation of the side-chain at C46 (compound 175, Figure 36) resulted in an obvious decrease of the activity (Table 9).288 The SAR revealed that E-ring modification could be tolerated instead of F-ring side-chain truncation. Furthermore, Wagner et al. synthesized several structurally simplified analogues containing AD

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only part of the spongistatin structure.289 However, truncation of C1−C28 (176 and 177) and replacement of the two spiroketals and their associated functionality by a simple alkane linker (lactone 178) led to loss of the activity. Similarly, replacing C, D rings or E, F rings by the alkane linker (179 and 180) also resulted in weak cytotoxicity (Figure 36). 3.3.3.12. Structural Simplification of Migrastatin. Tumor metastasis is one of the main causes of death in cancer patients. Migrastatin (181, Figure 37), a novel 14-membered lactone isolated from Streptomyces sp. MK-929−43F1, showed moderate antimetastatic activity (IC50 = 29 μM) against 4T1 mouse breast tumor cells.290,291 Despite the modest potency, Danishefsky and co-workers envisioned that migrastatin could be used as a lead compound to discover more potent antimetastatic and antiangiogenic agents. They reported the first total synthesis of migrastatin and then performed structural simplification studies using the DTS approach (Figure 37).292−295 After removal of the glutarimide side chain, simplified analogues 183 and 184 were 1000-fold more potent than migrastatin. These compounds significantly inhibited cell migration in 4T1 mouse breast cancer cells with IC50 values of 22 nM and 24 nM, respectively. Interestingly, these analogues did not show any cytotoxic or antiproliferative activity up to 20 μM.292 On the basis of analogue 183, further structural simplification was performed by modifying the ester group. Analogues 185 and 186 retained potent antimetastatic activity in MDA-MB-435 breast cancer cells with an IC50 value of 0.10 μM and 0.37 μM, respectively. Moreover, 186 showed good in vivo potency by significantly reducing the metastasized MDA231 cells (87%) in a pretreated mice group. It could not attenuate tumor growth, which indicated the inhibition was not related to cytotoxicity.295 To elucidate its mechanism of action, Chen et al. demonstrated that migrastatin analogues targeted actin-bundling protein fascin to block tumor metastasis using an affinity protein purification approach (Figure 37B).296 3.3.4. Recent Examples of Structural Simplification. Besides the case studies described above, examples of structurally simplified NPs reported in recent years are summarized in Table 10.

Besides DOS, DTS, and FOS, the development of new highly efficient synthesis methods,111,309 such as chemical or molecular editing310 and dynamic strategic bond analysis,311 will provide a deep understanding of SAR and biological functions of complex NPs, and lay an important foundation for structural simplification. These types of approaches are particularly useful in the development of antibacterial NPs, which require three-dimensionality to retain the activity.312,313 They offer a new opportunity to solve the difficulty in synthesizing complex structures and their simplified analogues. Moreover, new technologies are still highly desirable for improving the efficiency of structural simplification. In particular, the BIOS strategy employs biologically relevant structural information encoded in complex NPs to guide the simplification of NP structures.171 Computational tools for the fragmentation of NPs enable hierarchical structuring, visualization, and analysis of complex structures and bioactivity data, and the identification of simplified scaffolds with desirable activities. The resulting NP fragments have been proven to be a rich source of bioactive molecules.4 Ideally, structural simplification should identify less complicated molecules that retain the biological activity of the parent compound. However, simplified molecules were often less active than the lead compound at the molecular or cellular level. Thus, the success of structural simplification needs to be evaluated in terms of the balance between the synthetic accessibility, in vitro activity, in vivo potency, physicochemical properties, PK profiles, and so on. For most simplified molecules, reoptimization is required to improve the efficacy and drug-likeness. More importantly, reductions in structural complexity will lead to simplified analogues with new bioactivities and new targets. Target identification by chemical biology approaches is important for drug development. With the advancement of synthetic, computational, and biological approaches, structural simplification will play an increasingly important role in drug discovery and contribute to improving the efficiency and success rate of drug development.

AUTHOR INFORMATION Corresponding Author

*Phone/Fax: +86 21 81871239. E-mail: [email protected]. cn.

4. CONCLUSIONS AND PERSPECTIVES The design of “low-fat” drug-like molecules by structural simplification represents a powerful strategy in drug discovery.25−27 Structural simplification is particularly useful in NPsbased drug development because NPs are challenging for direct drug development because of their complex structures, abundant chiral centers, difficult total syntheses, and unfavorable ADMET profiles. The structural simplification of NPs has yielded several marketed drugs highlighting its utility in drug development. Recently, numerous NPs with extremely complex structures, particularly marine NPs, have been shown to possess highly potent biological activities. These NPs usually have a MW greater than 1000 and more than 5 chiral centers, which pose great challenges in total synthesis and drug development. Structural simplification of these extremely complex NPs is highly desirable. Another important area for structural simplification is the development of new antibacterial agents, which require three-dimensionality, but complex structures are difficult to synthesize and commercialize. Although progress has been made, successful examples of structural simplification are rather limited, and more medicinal chemistry efforts need to be devoted in this important field.

ORCID

Shengzheng Wang: 0000-0002-2383-2673 Chunquan Sheng: 0000-0001-9489-804X Author Contributions #

S.W. and G.D. contributed equally to this perspective.

Notes

The authors declare no competing financial interest. Biographies Shengzheng Wang received his bachelor’s degree in pharmacy (2009) and Ph.D. in medicinal chemistry (2014) from Second Military Medical University. Since 2014, he has been a lecturer in the Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University. His research interests include antitumor drug discovery and organocatalysis. Guoqiang Dong received his bachelor’s degree in pharmacy (2008) and Ph.D. in medicinal chemistry (2013) from Second Military Medical University. Since 2013, he has been a lecturer in the Department of Medicinal Chemistry, School of Pharmacy, Second AE

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bFGF V-ATPases SFA HCV FtsZ CHIKV CRM1 CPZ-B MraY NGF HA-CML APD β-HOAsn APD-CLD SOAT SHH SMO PB Top MptpB

Military Medical University. His current research is focused on the modification and scaffold hopping of natural products and multitargeting antitumor drugs. Chunquan Sheng received his bachelor’s degree in pharmacy (2000) and Ph.D. in medicinal chemistry (2005) from Second Military Medical University, after which he worked as a faculty member in the same university. From 2014 to 2015, he worked as a visiting scholar at Department of Chemistry and Chemical Biology in University of New Mexico, USA. He is currently Professor and Director of Department of Medicinal Chemistry and the Vice Dean of School of Pharmacy, Second Military Medical University. Professor Sheng’s research interests mainly include rational drug design and natural productsinspired drug discovery focusing on antifungal and antitumor agents. He was supported by several talent programs in China including National Outstanding Young Scholarship (NSFC) and Young Chang Jiang Scholar (MOE).

basic fibroblast growth factor vacuolar-type (H+)-ATPases Sanglifehrin A hepatitis C virus filamenting temperature-sensitive protein Z Chikungunya virus chromosome region maintenance 1 caprazamycin B phospho-MurNAc-pentapeptide translocase nerve growth factor hypoxia-adapted chronic myelogenous leukemia 4-amino-penta-2,4-dienoic acid β-hydroxyasparagine APD-containing cyclolipodepsipeptide sterol O-acyltransferase sonic hedgehog smoothened pladienolide topoisomerase Mycobacterium tuberculosis protein tyrosine phosphatases B hedgehog

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grants 81725020 to C.S. and 21602252 to S.W.), the National Key R&D Program of China (2017YFA0506000 to C.S.), and the Hong Kong Scholars Program (XJ201713 to S.W.).

REFERENCES

ABBREVIATIONS NP natural product FDA U.S. Food and Drug Administration ADMET absorption, distribution, metabolism, excretion, metabolism, and toxicity RO5 Lipinski’s rule of five PK pharmacokinetic PD pharmacodynamic SAR structure−activity relationship DOS diversity-oriented synthesis DTS diverted total synthesis BIOS biology-oriented synthesis FOS function-oriented synthesis BGC biosynthetic gene cluster MW molecular weight LE ligand efficiency NMDA N-methyl-D-aspartate HBV hepatitis B virus S1P sphingosine-1-phosphate TSA trichostatin A HDAC histone deacetylase PKC protein kinase C JAK Janus kinase CCK cholecystokinin receptors BZD 1,4-benzodiazepine L-Trp L-tryptophan GPCR G-protein coupled receptor MCR multicomponent reaction nAChR nicotinic acetylcholine receptor PKMT protein lysine methyltransferase ZBG zinc-binding group EAE experimental autoimmune encephalomyelitis IFI invasive fungal infection GA gambogic acid MDR multidrug resistance P-gp P-glycoprotein HUVEC human umbilical vein endothelial cell VEGF vascular endothelial growth factor

(1) Cragg, G. M.; Newman, D. J. Natural products: a continuing source of novel drug leads. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 3670−3695. (2) Butler, M. S.; Robertson, A. A.; Cooper, M. A. Natural product and natural product derived drugs in clinical trials. Nat. Prod. Rep. 2014, 31, 1612−1661. (3) Harvey, A. L.; Edrada-Ebel, R.; Quinn, R. J. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discovery 2015, 14, 111−129. (4) Crane, E. A.; Gademann, K. Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis. Angew. Chem., Int. Ed. 2016, 55, 3882−3902. (5) Xiao, Z.; Morris-Natschke, S. L.; Lee, K. H. Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates. Med. Res. Rev. 2016, 36, 32−91. (6) Shen, B. A. New Golden Age of Natural Products Drug Discovery. Cell 2015, 163, 1297−1300. (7) Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629−661. (8) Kato, N.; Takahashi, S.; Nogawa, T.; Saito, T.; Osada, H. Construction of a microbial natural product library for chemical biology studies. Curr. Opin. Chem. Biol. 2012, 16, 101−108. (9) Hong, J. Role of natural product diversity in chemical biology. Curr. Opin. Chem. Biol. 2011, 15, 350−354. (10) Kakeya, H. Natural products-prompted chemical biology: phenotypic screening and a new platform for target identification. Nat. Prod. Rep. 2016, 33, 648−654. (11) Pascolutti, M.; Quinn, R. J. Natural products as lead structures: chemical transformations to create lead-like libraries. Drug Discovery Today 2014, 19, 215−221. (12) Eberhardt, L.; Kumar, K.; Waldmann, H. Exploring and exploiting biologically relevant chemical space. Curr. Drug Targets 2011, 12, 1531−1546. (13) Breinbauer, R.; Vetter, I. R.; Waldmann, H. From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. Angew. Chem., Int. Ed. 2002, 41, 2878−2890. (14) Kellenberger, E.; Hofmann, A.; Quinn, R. J. Similar interactions of natural products with biosynthetic enzymes and therapeutic targets could explain why nature produces such a large proportion of existing drugs. Nat. Prod. Rep. 2011, 28, 1483−1492. (15) Nicolaou, K. C.; Hale, C. R.; Nilewski, C.; Ioannidou, H. A. Constructing molecular complexity and diversity: total synthesis of

Hh

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DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

natural products of biological and medicinal importance. Chem. Soc. Rev. 2012, 41, 5185−5238. (16) Feher, M.; Schmidt, J. M. Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J. Chem. Inf. Comput. Sci. 2003, 43, 218−227. (17) Henkel, T.; Brunne, R. M.; Muller, H.; Reichel, F. Statistical Investigation into the Structural Complementarity of Natural Products and Synthetic Compounds. Angew. Chem., Int. Ed. 1999, 38, 643−647. (18) Rodrigues, T.; Reker, D.; Schneider, P.; Schneider, G. Counting on natural products for drug design. Nat. Chem. 2016, 8, 531−541. (19) Koehn, F. E.; Carter, G. T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discovery 2005, 4, 206− 220. (20) Patridge, E.; Gareiss, P.; Kinch, M. S.; Hoyer, D. An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discovery Today 2016, 21, 204−207. (21) Yao, H.; Liu, J.; Xu, S.; Zhu, Z.; Xu, J. The structural modification of natural products for novel drug discovery. Expert Opin. Drug Discovery 2017, 12, 121−140. (22) Chen, J.; Li, W.; Yao, H.; Xu, J. Insights into drug discovery from natural products through structural modification. Fitoterapia 2015, 103, 231−241. (23) Maier, M. E. Design and synthesis of analogues of natural products. Org. Biomol. Chem. 2015, 13, 5302−5343. (24) Guo, Z. The modification of natural products for medical use. Acta Pharm. Sin. B 2017, 7, 119−136. (25) Hann, M. M. Molecular obesity, potency and other addictions in drug discovery. MedChemComm 2011, 2, 349−355. (26) Hann, M. M.; Keseru, G. M. Finding the sweet spot: the role of nature and nurture in medicinal chemistry. Nat. Rev. Drug Discovery 2012, 11, 355−365. (27) Mignani, S.; Huber, S.; Tomas, H.; Rodrigues, J.; Majoral, J. P. Compound high-quality criteria: a new vision to guide the development of drugs, current situation. Drug Discovery Today 2016, 21, 573−584. (28) Polanski, J.; Bogocz, J.; Tkocz, A. The analysis of the market success of FDA approvals by probing top 100 bestselling drugs. J. Comput.-Aided Mol. Des. 2016, 30, 381−389. (29) Bottcher, T. An Additive Definition of Molecular Complexity. J. Chem. Inf. Model. 2016, 56, 462−470. (30) Hann, M. M.; Leach, A. R.; Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci. 2001, 41, 856−864. (31) Mendez-Lucio, O.; Medina-Franco, J. L. The many roles of molecular complexity in drug discovery. Drug Discovery Today 2017, 22, 120−126. (32) Schneider, G.; Neidhart, W.; Giller, T.; Schmid, G. ’ScaffoldHopping’ by topological pharmacophore search: A contribution to virtual screening. Angew. Chem., Int. Ed. 1999, 38, 2894−2896. (33) Bohm, H. J.; Flohr, A.; Stahl, M. Scaffold hopping. Drug Discovery Today: Technol. 2004, 1, 217−224. (34) Sun, H.; Tawa, G.; Wallqvist, A. Classification of scaffoldhopping approaches. Drug Discovery Today 2012, 17, 310−324. (35) Pan, S.; Zhang, H.; Wang, C.; Yao, S. C.; Yao, S. Q. Target identification of natural products and bioactive compounds using affinity-based probes. Nat. Prod. Rep. 2016, 33, 612−620. (36) Farha, M. A.; Brown, E. D. Strategies for target identification of antimicrobial natural products. Nat. Prod. Rep. 2016, 33, 668−680. (37) Frantz, S. Better antibiotics through chemistry. Nat. Rev. Drug Discovery 2004, 3, 900−901. (38) O’Shea, R.; Moser, H. E. Physicochemical properties of antibacterial compounds: implications for drug discovery. J. Med. Chem. 2008, 51, 2871−2878. (39) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 2001, 46, 3−26.

(40) Davis, T. D.; Gerry, C. J.; Tan, D. S. General platform for systematic quantitative evaluation of small-molecule permeability in bacteria. ACS Chem. Biol. 2014, 9, 2535−2544. (41) Noren-Muller, A.; Reis-Correa, I., Jr.; Prinz, H.; Rosenbaum, C.; Saxena, K.; Schwalbe, H. J.; Vestweber, D.; Cagna, G.; Schunk, S.; Schwarz, O.; Schiewe, H.; Waldmann, H. Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 10606−10611. (42) Cerri, A.; Gobbini, M. Simplified digitalis-like compounds acting on Na(+), K(+)-ATPase. J. Enzyme Inhib. Med. Chem. 2003, 18, 289−295. (43) Eguchi, M. Recent advances in selective opioid receptor agonists and antagonists. Med. Res. Rev. 2004, 24, 182−212. (44) Blakemore, P. R.; White, J. D. Morphine, the Proteus of organic molecules. Chem. Commun. 2002, 11, 1159−1168. (45) Corbett, A. D.; Paterson, S. J.; Kosterlitz, H. W. Selectivity of Ligands for Opioid Receptors. In Opioids; Herz, A.; Akil, H.; Simon, E. J., Eds.; Springer: Berlin, 1993; pp 645−679. (46) Gudin, J.; Fudin, J.; Nalamachu, S. Levorphanol use: past, present and future. Postgrad. Med. 2016, 128, 46−53. (47) Heel, R. C.; Brogden, R. N.; Speight, T. M.; Avery, G. S. Butorphanol: a review of its pharmacological properties and therapeutic efficacy. Drugs 1978, 16, 473−505. (48) Commiskey, S.; Fan, L. W.; Ho, I. K.; Rockhold, R. W. Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J. Pharmacol. Sci. 2005, 98, 109−116. (49) Gharagozlou, P.; Hashemi, E.; DeLorey, T. M.; Clark, J. D.; Lameh, J. Pharmacological profiles of opioid ligands at kappa opioid receptors. BMC Pharmacol. 2006, 6, 3. (50) Aarnes, T. K.; Muir, W. W. Chapter 26 - Pain Assessment and Management. In Small Animal Pediatrics; Peterson, M. E.; Kutzler, M. A., Eds.; W.B. Saunders: Saint Louis, 2011; pp 220−232. (51) Prezzavento, O.; Arena, E.; Sánchez-Fernández, C.; Turnaturi, R.; Parenti, C.; Marrazzo, A.; Catalano, R.; Amata, E.; Pasquinucci, L.; Cobos, E. J. (+)-and (−)-Phenazocine enantiomers: Evaluation of their dual opioid agonist/σ1 antagonist properties and antinociceptive effects. Eur. J. Med. Chem. 2017, 125, 603−610. (52) Levine, J. D.; Gordon, N. C. Synergism between the analgesic actions of morphine and pentazocine. Pain 1988, 33, 369−372. (53) Woolfe, G.; Macdonald, A. D. The evaluation of the analgesic action of pethidine hydrochloride (demerol). J. Pharmacol. Exp. Ther. 1944, 80, 300−307. (54) Ziering, A.; Lee, J. Piperidine derivatives; 1,3-dialkyl-4-aryl-4acyloxypiperidines. J. Org. Chem. 1947, 12, 911−914. (55) Van Bever, W. F. M.; Niemegeers, C. J. E.; Janssen, P. A. J. Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide and N-[3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl]-N-phenylpropanamide. J. Med. Chem. 1974, 17, 1047−1051. (56) Barnett, C. J. Modification of methadone synthesis process step. U.S. Patent US4048211A, 1977. (57) King, J. A.; Meltzer, R. I.; Doczi, J. The Synthesis of Some Fluorene Derivatives1. J. Am. Chem. Soc. 1955, 77, 2217−2223. (58) Liu, G. T. Bicyclol: a novel drug for treating chronic viral hepatitis B and C. Med. Chem. 2009, 5, 29−43. (59) Liu, G. T. Therapeutic effects of biphenyl dimethyl dicarboxylate (DDB) on chronic viral hepatitis B. Proc. Chin. Acad. Med. Sci. Peking Union Med. Coll. 1987, 2, 228−233. (60) Nie, J.; Yang, D.; Hu, K.; Lu, Y. Study on four polymorphs of bifendate based on X-ray crystallography. Acta Pharm. Sin. B 2016, 6, 234−242. (61) Liu, G. T. The anti-virus and hepatoprotective effect of bicyclol and its mechanism of action. Chin. J. New Drugs 2001, 10, 325−327. (62) Zhou, P.; Huang, L.; Zhang, Z.; Wang, L.; Huo, S.; Lei, Z. Simple method for the preparation of bicyclol from bifendate. Chin. Patent CN103724317A, 2014. (63) Yuan, H.; Ma, Q.; Ye, L.; Piao, G. The Traditional Medicine and Modern Medicine from Natural Products. Molecules 2016, 21, 559. AG

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(64) Sun, H.; Yu, L.; Wei, H.; Liu, G. A novel antihepatitis drug, bicyclol, prevents liver carcinogenesis in diethylnitrosamine-initiated and phenobarbital-promoted mice tumor model. J. Biomed. Biotechnol. 2012, 2012, 584728. (65) Bao, X. Q.; Liu, G. T. Bicyclol: a novel antihepatitis drug with hepatic heat shock protein 27/70-inducing activity and cytoprotective effects in mice. Cell Stress Chaperones 2008, 13, 347−355. (66) Fujita, T.; Hirose, R.; Hamamichi, N.; Kitao, Y.; Sasaki, S.; Yoneta, M.; Chiba, K. 2-Substituted 2-aminoethanol: Minimum essential structure for immunosuppressive activity of ISP-I (Myriocin). Bioorg. Med. Chem. Lett. 1995, 5, 1857−1860. (67) Sasaki, S.; Hashimoto, R.; Kiuchi, M.; Inoue, K.; Ikumoto, T.; Hirose, R.; Chiba, K.; Hoshino, Y.; Okumoto, T.; Fujita, T. Fungal metabolites. Part 14. Novel potent immunosuppressants, mycestericins, produced by Mycelia sterilia. J. Antibiot. 1994, 47, 420−433. (68) Fujita, T.; Yoneta, M.; Hirose, R.; Sasaki, S.; Inoue, K.; Kiuchi, M.; Hirase, S.; Adachi, K.; Arita, M.; Chiba, K. Simple compounds, 2alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity. Bioorg. Med. Chem. Lett. 1995, 5, 847−852. (69) Thomas, K.; Proschmann, U.; Ziemssen, T. Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis. Expert Opin. Pharmacother. 2017, 18, 1649−1660. (70) Yoshida, M.; Horinouchi, S.; Beppu, T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. BioEssays 1995, 17, 423−430. (71) Stowell, J. C.; Huot, R. I.; Van Voast, L. The synthesis of Nhydroxy-N’-phenyloctanediamide and its inhibitory effect on proliferation of AXC rat prostate cancer cells. J. Med. Chem. 1995, 38, 1411−1413. (72) Huang, Y.; Dong, G.; Li, H.; Liu, N.; Zhang, W.; Sheng, C. Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) Dual Inhibitors as a Novel Strategy for the Combinational Treatment of Leukemia and Invasive Fungal Infections. J. Med. Chem. 2018, 61, 6056−6074. (73) Finnin, M. S.; Donigian, J. R.; Cohen, A.; Richon, V. M.; Rifkind, R. A.; Marks, P. A.; Breslow, R.; Pavletich, N. P. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999, 401, 188−193. (74) Mann, B. S.; Johnson, J. R.; Cohen, M. H.; Justice, R.; Pazdur, R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007, 12, 1247− 1252. (75) Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. Norhalichondrin A: an antitumor polyether macrolide from a marine sponge. J. Am. Chem. Soc. 1985, 107, 4796−4798. (76) Hirata, Y.; Uemura, D. Halichondrins - antitumor polyether macrolides from a marine sponge. Pure Appl. Chem. 1986, 58, 701− 710. (77) Bai, R. L.; Paull, K. D.; Herald, C. L.; Malspeis, L.; Pettit, G. R.; Hamel, E. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulinbased mechanism of action by analysis of differential cytotoxicity data. J. Biol. Chem. 1991, 266, 15882−15889. (78) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc. 1992, 114, 3162−3164. (79) Jackson, K. L.; Henderson, J. A.; Phillips, A. J. The halichondrins and E7389. Chem. Rev. 2009, 109, 3044−3079. (80) Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singer, L. A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay, L.; Towle, M. J.; Salvato, K. A.; Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.; Yu, M. J. Macrocyclic ketone analogues of halichondrin B. Bioorg. Med. Chem. Lett. 2004, 14, 5551−5554. (81) Towle, M. J.; Salvato, K. A.; Budrow, J.; Wels, B. F.; Kuznetsov, G.; Aalfs, K. K.; Welsh, S.; Zheng, W.; Seletsky, B. M.; Palme, M. H.; Habgood, G. J.; Singer, L. A.; Dipietro, L. V.; Wang, Y.; Chen, J. J.; Quincy, D. A.; Davis, A.; Yoshimatsu, K.; Kishi, Y.; Yu, M. J.;

Littlefield, B. A. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res. 2001, 61, 1013−1021. (82) Doodhi, H.; Prota, A. E.; Rodriguez-Garcia, R.; Xiao, H.; Custar, D. W.; Bargsten, K.; Katrukha, E. A.; Hilbert, M.; Hua, S.; Jiang, K.; Grigoriev, I.; Yang, C. P.; Cox, D.; Horwitz, S. B.; Kapitein, L. C.; Akhmanova, A.; Steinmetz, M. O. Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes. Curr. Biol. 2016, 26, 1713−1721. (83) Donoghue, M.; Lemery, S. J.; Yuan, W.; He, K.; Sridhara, R.; Shord, S.; Zhao, H.; Marathe, A.; Kotch, L.; Jee, J.; Wang, Y.; Zhou, L.; Adams, W. M.; Jarral, V.; Pilaro, A.; Lostritto, R.; Gootenberg, J. E.; Keegan, P.; Pazdur, R. Eribulin mesylate for the treatment of patients with refractory metastatic breast cancer: use of a ″physician’s choice″ control arm in a randomized approval trial. Clin. Cancer Res. 2012, 18, 1496−1505. (84) Omura, S.; Sasaki, Y.; Iwai, Y.; Takeshima, H. Staurosporine, a potentially important gift from a microorganism. J. Antibiot. 1995, 48, 535−548. (85) Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchiya, H.; Takahashi, Y.; Asuma, R. A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J. Antibiot. 1977, 30, 275−282. (86) Hug, H.; Sarre, T. F. Protein kinase C isoenzymes: divergence in signal transduction? Biochem. J. 1993, 291, 329−343. (87) Jirousek, M. R.; Goekjian, P. G. Protein kinase C inhibitors as novel anticancer drugs. Expert Opin. Invest. Drugs 2001, 10, 2117− 2140. (88) van Gijn, R.; Zuidema, X.; Bult, A.; Beijnen, J. H. Protein kinase C as a target for new anti-cancer agents. J. Oncol. Pharm. Pract. 1999, 5, 166−178. (89) Jirousek, M. R.; Gillig, J. R.; Gonzalez, C. M.; Heath, W. F.; McDonald, J. H., 3rd; Neel, D. A.; Rito, C. J.; Singh, U.; Stramm, L. E.; Melikian-Badalian, A.; Baevsky, M.; Ballas, L. M.; Hall, S. E.; Winneroski, L. L.; Faul, M. M. (S)-13-[(dimethylamino)methyl]10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta. J. Med. Chem. 1996, 39, 2664−2671. (90) https://clinicaltrials.gov/, clinical trial identifier: NCT02769611. (91) Faul, M. M.; Gillig, J. R.; Jirousek, M. R.; Ballas, L. M.; Schotten, T.; Kahl, A.; Mohr, M. Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCbeta. Bioorg. Med. Chem. Lett. 2003, 13, 1857−1859. (92) Crump, M.; Leppa, S.; Fayad, L.; Lee, J. J.; Di Rocco, A.; Ogura, M.; Hagberg, H.; Schnell, F.; Rifkin, R.; Mackensen, A.; Offner, F.; Pinter-Brown, L.; Smith, S.; Tobinai, K.; Yeh, S. P.; Hsi, E. D.; Nguyen, T.; Shi, P.; Hahka-Kemppinen, M.; Thornton, D.; Lin, B.; Kahl, B.; Schmitz, N.; Savage, K. J.; Habermann, T. Randomized, Double-Blind, Phase III Trial of Enzastaurin Versus Placebo in Patients Achieving Remission After First-Line Therapy for High-Risk Diffuse Large B-Cell Lymphoma. J. Clin. Oncol. 2016, 34, 2484−2492. (93) https://clinicaltrials.gov/, clinical trial identifier: NCT03263026. (94) Fiorucci, G.; Percario, Z. A.; Marcolin, C.; Coccia, E. M.; Affabris, E.; Romeo, G. Inhibition of protein phosphorylation modulates expression of the Jak family protein tyrosine kinases. J. Virol. 1995, 69, 5833−5837. (95) Yang, S. M.; Malaviya, R.; Wilson, L. J.; Argentieri, R.; Chen, X.; Yang, C.; Wang, B.; Cavender, D.; Murray, W. V. Simplified staurosporine analogs as potent JAK3 inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 326−331. (96) Chang, R.; Lotti, V.; Monaghan, R.; Birnbaum, J.; Stapley, E.; Goetz, M.; Albers-Schonberg, G.; Patchett, A.; Liesch, J.; Hensens, O.; et al. A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus. Science 1985, 230, 177−179. AH

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(97) Zucker, K. A.; Adrian, T. E.; Zdon, M. J.; Ballantyne, G. H.; Modlin, I. M. Asperlicin: a unique nonpeptide cholecystokinin antagonist. Surgery 1987, 102, 163−170. (98) Lotti, V. J.; Cerino, D. J.; Kling, P. J.; Chang, R. S. A new simple mouse model for the in vivo evaluation of cholecystokinin (CCK) antagonists: comparative potencies and durations of action of nonpeptide antagonists. Life Sci. 1986, 39, 1631−1638. (99) Bock, M. G.; DiPardo, R. M.; Rittle, K. E.; Evans, B. E.; Freidinger, R. M.; Veber, D. F.; Chang, R. S.; Chen, T. B.; Keegan, M. E.; Lotti, V. J. Cholecystokinin antagonists. Synthesis of asperlicin analogues with improved potency and water solubility. J. Med. Chem. 1986, 29, 1941−1945. (100) Evans, B. E.; Bock, M. G.; Rittle, K. E.; DiPardo, R. M.; Whitter, W. L.; Veber, D. F.; Anderson, P. S.; Freidinger, R. M. Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin. Proc. Natl. Acad. Sci. U. S. A. 1986, 83, 4918−4922. (101) Huang, X. P.; Karpiak, J.; Kroeze, W. K.; Zhu, H.; Chen, X.; Moy, S. S.; Saddoris, K. A.; Nikolova, V. D.; Farrell, M. S.; Wang, S.; et al. Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 2015, 527, 477−483. (102) Spencer, J.; Rathnam, R. P.; Chowdhry, B. Z. 1,4Benzodiazepin-2-ones in medicinal chemistry. Future Med. Chem. 2010, 2, 1441−1449. (103) Gao, F.; Sexton, P. M.; Christopoulos, A.; Miller, L. J. Benzodiazepine ligands can act as allosteric modulators of the Type 1 cholecystokinin receptor. Bioorg. Med. Chem. Lett. 2008, 18, 4401− 4404. (104) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Gould, N. P.; Lundell, G. F.; Homnick, C. F. Design of nonpeptidal ligands for a peptide receptor: cholecystokinin antagonists. J. Med. Chem. 1987, 30, 1229−1239. (105) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S.; et al. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235−2246. (106) Abbruzzese, J. L.; Gholson, C. F.; Daugherty, K.; Larson, E.; DuBrow, R.; Berlin, R.; Levin, B. A pilot clinical trial of the cholecystokinin receptor antagonist MK-329 in patients with advanced pancreatic cancer. Pancreas 1992, 7, 165−171. (107) Su, Y.; Ge, J.; Zhu, B.; Zheng, Y. G.; Zhu, Q.; Yao, S. Q. Target identification of biologically active small molecules via in situ methods. Curr. Opin. Chem. Biol. 2013, 17, 768−775. (108) Weber, L. The application of multi-component reactions in drug discovery. Curr. Med. Chem. 2002, 9, 2085−2093. (109) Magedov, I. V.; Manpadi, M.; Ogasawara, M. A.; Dhawan, A. S.; Rogelj, S.; Van Slambrouck, S.; Steelant, W. F.; Evdokimov, N. M.; Uglinskii, P. Y.; Elias, E. M.; Knee, E. J.; Tongwa, P.; Antipin, M. Y.; Kornienko, A. Structural simplification of bioactive natural products with multicomponent synthesis. 2. antiproliferative and antitubulin activities of pyrano[3,2-c]pyridones and pyrano[3,2-c]quinolones. J. Med. Chem. 2008, 51, 2561−2570. (110) Evdokimov, N. M.; Van Slambrouck, S.; Heffeter, P.; Tu, L.; Le Calve, B.; Lamoral-Theys, D.; Hooten, C. J.; Uglinskii, P. Y.; Rogelj, S.; Kiss, R.; Steelant, W. F.; Berger, W.; Yang, J. J.; Bologa, C. G.; Kornienko, A.; Magedov, I. V. Structural simplification of bioactive natural products with multicomponent synthesis. 3. Fused uracil-containing heterocycles as novel topoisomerase-targeting agents. J. Med. Chem. 2011, 54, 2012−2021. (111) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res. 2008, 41, 40−49. (112) Szpilman, A. M.; Carreira, E. M. Probing the biology of natural products: molecular editing by diverted total synthesis. Angew. Chem., Int. Ed. 2010, 49, 9592−9628. (113) Wetzel, S.; Bon, R. S.; Kumar, K.; Waldmann, H. Biologyoriented synthesis. Angew. Chem., Int. Ed. 2011, 50, 10800−10826.

(114) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumor agents from the Caribbean tunicate Ecteinascidin turbinata. J. Org. Chem. 1990, 55, 4512−4515. (115) Abraham, I.; El Sayed, K.; Chen, Z. S.; Guo, H. Current status on marine products with reversal effect on cancer multidrug resistance. Mar. Drugs 2012, 10, 2312−2321. (116) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743. Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 3496−3501. (117) Iturriagavásquez, P.; Carbone, A.; Garcíabeltrán, O.; Livingstone, P. D.; Biggin, P. C.; Cassels, B. K.; Wonnacott, S.; Zapatatorres, G.; Bermudez, I. Molecular determinants for competitive inhibition of alpha4beta2 nicotinic acetylcholine receptors. Mol. Pharmacol. 2010, 78, 366−375. (118) Crestey, F.; Jensen, A. A.; Borch, M.; Andreasen, J. T.; Andersen, J.; Balle, T.; Kristensen, J. L. Design, synthesis, and biological evaluation of erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists. J. Med. Chem. 2013, 56, 9673−9682. (119) Rao, J. U. M.; Giri, G. S.; Hanumaiah, T.; Rao, K. V. J. Sampangine, a New Alkaloid from Cananga odorata. J. Nat. Prod. 1986, 49, 346−347. (120) Peterson, J. R.; Zjawiony, J. K.; Liu, S.; Hufford, C. D.; Clark, A. M.; Rogers, R. D. Copyrine alkaloids: synthesis, spectroscopic characterization, and antimycotic/antimycobacterial activity of A- and B-ring-functionalized sampangines. J. Med. Chem. 1992, 35, 4069− 4077. (121) Jiang, Z.; Liu, N.; Dong, G.; Jiang, Y.; Liu, Y.; He, X.; Huang, Y.; He, S.; Chen, W.; Li, Z.; Yao, J.; Miao, Z.; Zhang, W.; Sheng, C. Scaffold hopping of sampangine: discovery of potent antifungal lead compound against Aspergillus fumigatus and Cryptococcus neoformans. Bioorg. Med. Chem. Lett. 2014, 24, 4090−4094. (122) Jiang, Z.; Liu, N.; Hu, D.; Dong, G.; Miao, Z.; Yao, J.; He, H.; Jiang, Y.; Zhang, W.; Wang, Y.; Sheng, C. The discovery of novel antifungal scaffolds by structural simplification of the natural product sampangine. Chem. Commun. 2015, 51, 14648−14651. (123) Liu, N.; Zhong, H.; Tu, J.; Jiang, Z.; Jiang, Y.; Li, J.; Zhang, W.; Wang, Y.; Sheng, C.; Jiang, Y.; Jiang, Y. Discovery of simplified sampangine derivatives as novel fungal biofilm inhibitors. Eur. J. Med. Chem. 2018, 143, 1510−1523. (124) Han, Q. B.; Xu, H. X. Caged Garcinia xanthones: development since 1937. Curr. Med. Chem. 2009, 16, 3775−3796. (125) Wang, X.; Lu, N.; Yang, Q.; Gong, D.; Lin, C.; Zhang, S.; Xi, M.; Gao, Y.; Wei, L.; Guo, Q.; You, Q. Studies on chemical modification and biology of a natural product, gambogic acid (III): determination of the essential pharmacophore for biological activity. Eur. J. Med. Chem. 2011, 46, 1280−1290. (126) Chi, Y.; Zhan, X. K.; Yu, H.; Xie, G. R.; Wang, Z. Z.; Xiao, W.; Wang, Y. G.; Xiong, F. X.; Hu, J. F.; Yang, L.; Cui, C. X.; Wang, J. W. An open-labeled, randomized, multicenter phase IIa study of gambogic acid injection for advanced malignant tumors. Chin. Med. J. 2013, 126, 1642−1646. (127) Sun, H.; Chen, F.; Wang, X.; Liu, Z.; Yang, Q.; Zhang, X.; Zhu, J.; Qiang, L.; Guo, Q.; You, Q. Studies on gambogic acid (IV): Exploring structure−activity relationship with IκB kinase-beta (IKKβ). Eur. J. Med. Chem. 2012, 51, 110−123. (128) Liu, J.; Ma, R.; Bi, F.; Zhang, F.; Hu, C.; Venter, H.; Semple, S. J.; Ma, S. Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine. Bioorg. Med. Chem. Lett. 2018, 28, 1825−1831. (129) Lock, R. L.; Harry, E. J. Cell-division inhibitors: new insights for future antibiotics. Nat. Rev. Drug Discovery 2008, 7, 324−338. (130) Beuria, T. K.; Santra, M. K.; Panda, D. Sanguinarine blocks cytokinesis in bacteria by inhibiting FtsZ assembly and bundling. Biochemistry 2005, 44, 16584−16593. AI

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

as a target of the antitumor natural product pladienolide. Nat. Chem. Biol. 2007, 3, 570−575. (151) Müller, S.; Mayer, T.; Sasse, F.; Maier, M. E. Synthesis of a Pladienolide B Analogue with the Fully Functionalized Core Structure. Org. Lett. 2011, 13, 3940−3943. (152) Gundluru, M. K.; Pourpak, A.; Cui, X.; Morris, S. W.; Webb, T. R. Design, synthesis and initial biological evaluation of a novel pladienolide analog scaffold. MedChemComm 2011, 2, 904−908. (153) Kumar, V. P.; Chandrasekhar, S. Enantioselective Synthesis of Pladienolide B and Truncated Analogues as New Anticancer Agents. Org. Lett. 2013, 15, 3610−3613. (154) Villa, R.; Kashyap, M. K.; Kumar, D.; Kipps, T. J.; Castro, J. E.; La Clair, J. J.; Burkart, M. D. Stabilized cyclopropane analogs of the splicing inhibitor FD-895. J. Med. Chem. 2013, 56, 6576−6582. (155) Arai, K.; Buonamici, S.; Chan, B.; Corson, L.; Endo, A.; Gerard, B.; Hao, M. H.; Karr, C.; Kira, K.; Lee, L.; Liu, X.; Lowe, J. T.; Luo, T.; Marcaurelle, L. A.; Mizui, Y.; Nevalainen, M.; O’Shea, M. W.; Park, E. S.; Perino, S. A.; Prajapati, S.; Shan, M.; Smith, P. G.; Tivitmahaisoon, P.; Wang, J. Y.; Warmuth, M.; Wu, K. M.; Yu, L.; Zhang, H.; Zheng, G. Z.; Keaney, G. F. Total synthesis of 6deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 cancer cell line. Org. Lett. 2014, 16, 5560−5563. (156) Lagisetti, C.; Yermolina, M. V.; Sharma, L. K.; Palacios, G.; Prigaro, B. J.; Webb, T. R. Pre-mRNA splicing-modulatory pharmacophores: the total synthesis of herboxidiene, a pladienolideherboxidiene hybrid analog and related derivatives. ACS Chem. Biol. 2014, 9, 643−648. (157) Mcbrien, K. D.; Gao, Q.; Huang, S.; Klohr, S. E.; Wang, R. R.; Pirnik, D. M.; Neddermann, K. M.; Bursuker, I.; Kadow, K. F.; Leet, J. E. Fusaricide, a new cytotoxic N-hydroxypyridone from Fusarium sp. J. Nat. Prod. 1996, 59, 1151−1153. (158) Kamperdick, C.; Van, N. H.; Sung, T. V.; Adam, G. Bisquinolinone alkaloids from Melicope ptelefolia. Phytochemistry 1999, 50, 177−181. (159) Chen, I. S.; Wu, S. J.; Tsai, I. L. Chemical and bioactive constituents from Zanthoxylum simulans. J. Nat. Prod. 1994, 57, 1206−1211. (160) Hsiang, Y. H.; Hertzberg, R.; Hecht, S.; Liu, L. F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem. 1985, 260, 14873−14878. (161) Pommier, Y. DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition. Chem. Rev. 2009, 109, 2894−2902. (162) Xu, Y.; Her, C. Inhibition of Topoisomerase (DNA) I (TOP1): DNA Damage Repair and Anticancer Therapy. Biomolecules 2015, 5, 1652−1670. (163) Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat. Rev. Cancer 2006, 6, 789−802. (164) Tam, S. W.; Worcel, M.; Wyllie, M. Yohimbine: a clinical review. Pharmacol. Ther. 2001, 91, 215−243. (165) Koch, M. A.; Schuffenhauer, A.; Scheck, M.; Wetzel, S.; Casaulta, M.; Odermatt, A.; Ertl, P.; Waldmann, H. Charting biologically relevant chemical space: a structural classification of natural products (SCONP). Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 17272−17277. (166) Schuffenhauer, A.; Ertl, P.; Roggo, S.; Wetzel, S.; Koch, M. A.; Waldmann, H. The scaffold tree–visualization of the scaffold universe by hierarchical scaffold classification. J. Chem. Inf. Model. 2007, 47, 47−58. (167) Correa, I. R., Jr.; Noren-Muller, A.; Ambrosi, H. D.; Jakupovic, S.; Saxena, K.; Schwalbe, H.; Kaiser, M.; Waldmann, H. Identification of inhibitors for mycobacterial protein tyrosine phosphatase B (MptpB) by biology-oriented synthesis (BIOS). Chem. - Asian J. 2007, 2, 1109−1126. (168) Wehner, F.; Noren-Muller, A.; Muller, O.; Reis-Correa, I., Jr.; Giannis, A.; Waldmann, H. Indoloquinolizidine derivatives as novel and potent apoptosis inducers and cell-cycle blockers. ChemBioChem 2008, 9, 401−405. (169) Rosenbaum, C.; Baumhof, P.; Mazitschek, R.; Muller, O.; Giannis, A.; Waldmann, H. Synthesis and biological evaluation of an

(131) Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H.; VanDuyne, G. D.; Clardy, J. Dynemicin A, a novel antibiotic with the anthraquinone and 1,5-diyn3-ene subunit. J. Antibiot. 1989, 42, 1449−1452. (132) Lynch, V. M.; Fairhurst, R. A.; Iliadis, T. N.; Magnus, P.; Davis, B. E. Two [7.3.1]Azabicyclo-z-3-ene-1,5-diyne Analogues of Dynemicin A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1995, 51, 782−786. (133) Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Chemistry and biology of natural and designed enediynes. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 5881−5888. (134) Nicolaou, K. C.; Dai, W. M.; Tsay, S. C.; Estevez, V. A.; Wrasidlo, W. Designed enediynes: a new class of DNA-cleaving molecules with potent and selective anticancer activity. Science 1992, 256, 1172−1178. (135) Wender, P. A.; Zercher, C. K. Studies on DNA-cleaving agents: synthesis of a functional dynemicin analogue. J. Am. Chem. Soc. 1991, 113, 2311−2313. (136) Nicolaou, K. C.; Smith, A. L. Molecular design, chemical synthesis, and biological action of enediynes. Acc. Chem. Res. 1992, 25, 497−503. (137) Huang, J.-m.; Yokoyama, R.; Yang, C.-s.; Fukuyama, Y. Merrilactone A, a novel neurotrophic sesquiterpene dilactone from Illicium merrillianum. Tetrahedron Lett. 2000, 41, 6111−6114. (138) Kouno, I.; Mori, K.; Kawano, N.; Sato, S. Structure of anislactone A; a new skeletal type of sesquiterpene from the pericarps of Illicium anisatum. Tetrahedron Lett. 1989, 30, 7451−7452. (139) Shi, L.; Meyer, K.; Greaney, M. F. Synthesis of (±)-merrilactone A and (±)-anislactone A. Angew. Chem., Int. Ed. 2010, 49, 9250−9253. (140) Richers, J.; Pothig, A.; Herdtweck, E.; Sippel, C.; Hausch, F.; Tiefenbacher, K. Synthesis and Neurotrophic Activity Studies of Illicium Sesquiterpene Natural Product Analogues. Chem. - Eur. J. 2017, 23, 3178−3183. (141) Chen, J.; Gao, P.; Yu, F.; Yang, Y.; Zhu, S.; Zhai, H. Total synthesis of (±)-merrilactone A. Angew. Chem., Int. Ed. 2012, 51, 5897−5899. (142) Birman, V. B.; Danishefsky, S. J. The total synthesis of (±)-merrilactone A. J. Am. Chem. Soc. 2002, 124, 2080−2081. (143) Omura, S.; Tomoda, H.; Kim, Y. K.; Nishida, H. Pyripyropenes, highly potent inhibitors of acyl-CoA:cholesterol acyltransferase produced by Aspergillus fumigatus. J. Antibiot. 1993, 46, 1168−1169. (144) Lada, A. T.; Davis, M.; Kent, C.; Chapman, J.; Tomoda, H.; Omura, S.; Rudel, L. L. Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness. J. Lipid Res. 2004, 45, 378−386. (145) Ohshiro, T.; Rudel, L. L.; Omura, S.; Tomoda, H. Selectivity of microbial acyl-CoA: cholesterol acyltransferase inhibitors toward isozymes. J. Antibiot. 2007, 60, 43−51. (146) Roth, B. D. ACAT inhibitors: evolution from cholesterolabsorption inhibitors to antiatherosclerotic agents. Drug Discovery Today 1998, 3, 19−25. (147) Ohtawa, M.; Arima, S.; Ichida, N.; Terayama, T.; Ohno, H.; Yamazaki, T.; Ohshiro, T.; Sato, N.; Omura, S.; Tomoda, H.; Nagamitsu, T. Design and Synthesis of A-Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors. ChemMedChem 2018, 13, 411−421. (148) Odani, A.; Ishihara, K.; Ohtawa, M.; Tomoda, H.; Omura, S.; Nagamitsu, T. Total synthesis of pyripyropene A. Tetrahedron 2011, 67, 8195−8203. (149) Mizui, Y.; Sakai, T.; Iwata, M.; Uenaka, T.; Okamoto, K.; Shimizu, H.; Yamori, T.; Yoshimatsu, K.; Asada, M.; Uenaka, T. Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. III. In vitro and in vivo antitumor activities. J. Antibiot. 2004, 57, 188−196. (150) Kotake, Y.; Sagane, K.; Owa, T.; Mimori-Kiyosue, Y.; Shimizu, H.; Uesugi, M.; Ishihama, Y.; Iwata, M.; Mizui, Y. Splicing factor SF3b AJ

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

indomethacin library reveals a new class of angiogenesis-related kinase inhibitors. Angew. Chem., Int. Ed. 2004, 43, 224−228. (170) Chen, L. X.; He, H.; Qiu, F. Natural withanolides: an overview. Nat. Prod. Rep. 2011, 28, 705−740. (171) van Hattum, H.; Waldmann, H. Biology-oriented synthesis: harnessing the power of evolution. J. Am. Chem. Soc. 2014, 136, 11853−11859. (172) Svenda, J.; Sheremet, M.; Kremer, L.; Maier, L.; Bauer, J. O.; Strohmann, C.; Ziegler, S.; Kumar, K.; Waldmann, H. Biologyoriented synthesis of a withanolide-inspired compound collection reveals novel modulators of hedgehog signaling. Angew. Chem., Int. Ed. 2015, 54, 5596−5602. (173) Sheremet, M.; Kapoor, S.; Schroder, P.; Kumar, K.; Ziegler, S.; Waldmann, H. Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling. ChemBioChem 2017, 18, 1797−1806. (174) Giri, A.; Narasu, M. L. Production of podophyllotoxin from Podophyllum hexandrum: a potential natural product for clinically useful anticancer drugs. Cytotechnology 2000, 34, 17−26. (175) Rönquist-Nii, Y.; Eksborg, S.; Axelson, M.; Harmenberg, J.; Beck, O. Determination of picropodophyllin and its isomer podophyllotoxin in human serum samples with electrospray ionization of hexylamine adducts by liquid chromatography−tandem mass spectrometry. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2011, 879, 326−334. (176) Hitotsuyanagi, Y.; Fukuyo, M.; Tsuda, K.; Kobayashi, M.; Ozeki, A.; Itokawa, H.; Takeya, K. 4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: simple aza-podophyllotoxin analogues possessing potent cytotoxicity. Bioorg. Med. Chem. Lett. 2000, 10, 315−317. (177) Magedov, I. V.; Frolova, L.; Manpadi, M.; Bhoga, U.; Tang, H.; Evdokimov, N. M.; George, O.; Georgiou, K. H.; Renner, S.; Getlik, M.; Kinnibrugh, T. L.; Fernandes, M. A.; Van slambrouck, S.; Steelant, W. F.; Shuster, C. B.; Rogelj, S.; van Otterlo, W. A.; Kornienko, A. Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis. J. Med. Chem. 2011, 54, 4234−4246. (178) Ravelli, R. B.; Gigant, B.; Curmi, P. A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature 2004, 428, 198−202. (179) Galletti, E.; Magnani, M.; Renzulli, M. L.; Botta, M. Paclitaxel and docetaxel resistance: molecular mechanisms and development of new generation taxanes. ChemMedChem 2007, 2, 920−942. (180) Teodori, E.; Dei, S.; Martelli, C.; Scapecchi, S.; Gualtieri, F. The functions and structure of ABC transporters: implications for the design of new inhibitors of Pgp and MRP1 to control multidrug resistance (MDR). Curr. Drug Targets 2006, 7, 893−909. (181) Leslie, E. M.; Deeley, R. G.; Cole, S. P. C. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol. 2005, 204, 216−237. (182) Perez-Tomas, R. Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr. Med. Chem. 2006, 13, 1859−1876. (183) Zamir, L. O.; Zhou, Z. H.; Caron, G.; Nedea, M. E.; Sauriol, F.; Mamer, O. Isolation of a putative biogenetic taxane precursor from Taxus canadensis needles. J. Chem. Soc., Chem. Commun. 1995, 26, 529−530. (184) Begley, M. J.; Jackson, C. B.; Pattenden, G. Investigation of transannular cyclisations of verticillanes to the taxane ring system. Tetrahedron Lett. 1985, 26, 3397−3400. (185) Hosoyama, H.; Inubushi, A.; Katsui, T.; Shigemori, H.; Kobayashi, J. i. Taxuspines U, V, and W, new taxane and related diterpenoids from the Japanese yew Taxus cuspidata. Tetrahedron 1996, 52, 13145−13150. (186) Castagnolo, D.; Contemori, L.; Maccari, G.; Avramova, S. I.; Neri, A.; Sgaragli, G.; Botta, M. From taxuspine x to structurally

simplified taxanes with remarkable p-glycoprotein inhibitory activity. ACS Med. Chem. Lett. 2010, 1, 416−421. (187) Avramova, S. I.; Galletti, E.; Renzulli, M. L.; Giorgi, G.; Sgaragli, G.; Alderighi, D.; Ghiron, C.; Corelli, F.; Radi, M.; Botta, M. Synthesis of an original oxygenated taxuspine X analogue: a versatile ″non-natural″ natural product with remarkable P-gp modulating activity. ChemMedChem 2008, 3, 745−748. (188) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.; Kobayashi, M. Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex. J. Am. Chem. Soc. 2006, 128, 3148−3149. (189) Kotoku, N.; Sumii, Y.; Hayashi, T.; Tamura, S.; Kawachi, T.; Shiomura, S.; Arai, M.; Kobayashi, M. Creation of readily accessible and orally active analogue of cortistatin a. ACS Med. Chem. Lett. 2012, 3, 673−677. (190) Kotoku, N.; Ito, A.; Shibuya, S.; Mizuno, K.; Takeshima, A.; Nogata, M.; Kobayashi, M. Short-step synthesis and structure-activity relationship of cortistatin A analogs. Tetrahedron 2017, 73, 1342− 1349. (191) Staveness, D.; Abdelnabi, R.; Near, K. E.; Nakagawa, Y.; Neyts, J.; Delang, L.; Leyssen, P.; Wender, P. A. Inhibition of Chikungunya Virus-Induced Cell Death by Salicylate-Derived Bryostatin Analogues Provides Additional Evidence for a PKCIndependent Pathway. J. Nat. Prod. 2016, 79, 680−684. (192) Bourjot, M.; Delang, L.; Nguyen, V. H.; Neyts, J.; Gueritte, F.; Leyssen, P.; Litaudon, M. Prostratin and 12-O-tetradecanoylphorbol 13-acetate are potent and selective inhibitors of Chikungunya virus replication. J. Nat. Prod. 2012, 75, 2183−2187. (193) Nothias-Scaglia, L. F.; Pannecouque, C.; Renucci, F.; Delang, L.; Neyts, J.; Roussi, F.; Costa, J.; Leyssen, P.; Litaudon, M.; Paolini, J. Antiviral Activity of Diterpene Esters on Chikungunya Virus and HIV Replication. J. Nat. Prod. 2015, 78, 1277−1283. (194) Gupta, D. K.; Kaur, P.; Leong, S. T.; Tan, L. T.; Prinsep, M. R.; Chu, J. J. Anti-Chikungunya viral activities of aplysiatoxin-related compounds from the marine cyanobacterium Trichodesmium erythraeum. Mar. Drugs 2014, 12, 115−127. (195) Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold, E.; Clardy, J. Isolation and structure of bryostatin 1. J. Am. Chem. Soc. 1982, 104, 6846−6848. (196) Keck, G. E.; Poudel, Y. B.; Cummins, T. J.; Rudra, A.; Covel, J. A. Total synthesis of bryostatin 1. J. Am. Chem. Soc. 2011, 133, 744− 747. (197) Wender, P. A.; Nakagawa, Y.; Near, K. E.; Staveness, D. Computer-guided design, synthesis, and protein kinase C affinity of a new salicylate-based class of bryostatin analogs. Org. Lett. 2014, 16, 5136−5139. (198) Wender, P. A.; Staveness, D. Improved protein kinase C affinity through final step diversification of a simplified salicylatederived bryostatin analog scaffold. Org. Lett. 2014, 16, 5140−5143. (199) Binns, W.; James, L. F.; Keeler, R. F.; Balls, L. D. Effects of teratogenic agents in range plants. Cancer Res. 1968, 28, 2323−2326. (200) Keeler, R. F.; Binns, W. Teratogenic compounds of Veratrum californicum (Durand). II. Production of ovine fetal cyclopia by fractions and alkaloid preparations. Can. J. Biochem. 1966, 44, 829− 838. (201) Cooper, M. K.; Porter, J. A.; Young, K. E.; Beachy, P. A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 1998, 280, 1603−1607. (202) Chen, J. K.; Taipale, J.; Cooper, M. K.; Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002, 16, 2743−2748. (203) Berman, D. M.; Karhadkar, S. S.; Hallahan, A. R.; Pritchard, J. I.; Eberhart, C. G.; Watkins, D. N.; Chen, J. K.; Cooper, M. K.; Taipale, J.; Olson, J. M.; Beachy, P. A. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002, 297, 1559− 1561. (204) Dahmane, N.; Sanchez, P.; Gitton, Y.; Palma, V.; Sun, T.; Beyna, M.; Weiner, H.; Ruiz i Altaba, A. The Sonic Hedgehog-Gli AK

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

pathway regulates dorsal brain growth and tumorigenesis. Development 2001, 128, 5201−5212. (205) Sanchez, P.; Ruiz i Altaba, A. In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech. Dev. 2005, 122, 223−230. (206) Keeler, R. F. Teratogenic compounds in Veratrum californicum (Durand) IX. Structure-activity relation. Teratology 1970, 3, 169−173. (207) Winkler, J. D.; Isaacs, A.; Holderbaum, L.; Tatard, V.; Dahmane, N. Design and synthesis of inhibitors of Hedgehog signaling based on the alkaloid cyclopamine. Org. Lett. 2009, 11, 2824−2827. (208) Isaacs, A. K.; Xiang, C.; Baubet, V.; Dahmane, N.; Winkler, J. D. Studies directed toward the elucidation of the pharmacophore of steroid-based Sonic Hedgehog signaling inhibitors. Org. Lett. 2011, 13, 5140−5143. (209) Jansen, R.; Irschik, H.; Huch, V.; Schummer, D.; Steinmetz, H.; Bock, M.; Schmidt, T.; Kirschning, A.; Müller, R. Carolacton − A Macrolide Ketocarbonic Acid that Reduces Biofilm Formation by the Caries- and Endocarditis-Associated Bacterium Streptococcus mutans. Eur. J. Org. Chem. 2010, 2010, 1284−1289. (210) Kunze, B.; Reck, M.; Dötsch, A.; Lemme, A.; Schummer, D.; Irschik, H.; Steinmetz, H.; Wagner-Döbler, I. Damage of Streptococcus mutans biofilms by carolacton, a secondary metabolite from the myxobacterium Sorangium cellulosum. BMC Microbiol. 2010, 10, 199. (211) Reck, M.; Rutz, K.; Kunze, B.; Tomasch, J.; Surapaneni, S. K.; Schulz, S.; Wagner-Dobler, I. The biofilm inhibitor carolacton disturbs membrane integrity and cell division of Streptococcus mutans through the serine/threonine protein kinase PknB. J. Bacteriol. 2011, 193, 5692−5706. (212) Schmidt, T.; Kirschning, A. Total Synthesis of Carolacton, a Highly Potent Biofilm Inhibitor. Angew. Chem., Int. Ed. 2012, 51, 1063−1066. (213) Stumpp, N.; Premnath, P.; Schmidt, T.; Ammermann, J.; Dräger, G.; Reck, M.; Jansen, R.; Stiesch, M.; Wagner-Döbler, I.; Kirschning, A. Synthesis of new carolacton derivatives and their activity against biofilms of oral bacteria. Org. Biomol. Chem. 2015, 13, 5765−5774. (214) Solinski, A. E.; Koval, A. B.; Brzozowski, R. S.; Morrison, K. R.; Fraboni, A. J.; Carson, C. E.; Eshraghi, A. R.; Zhou, G.; Quivey, R. G.; Voelz, V. A.; Buttaro, B. A.; Wuest, W. M. Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms. J. Am. Chem. Soc. 2017, 139, 7188−7191. (215) Steele, A. D.; Knouse, K. W.; Keohane, C. E.; Wuest, W. M. Total synthesis and biological investigation of (−)-promysalin. J. Am. Chem. Soc. 2015, 137, 7314−7317. (216) Li, W.; Estrada-de los Santos, P.; Matthijs, S.; Xie, G. L.; Busson, R.; Cornelis, P.; Rozenski, J.; De Mot, R. Promysalin, a salicylate-containing Pseudomonas putida antibiotic, promotes surface colonization and selectively targets other Pseudomonas. Chem. Biol. 2011, 18, 1320−1330. (217) Steele, A. D.; Keohane, C. E.; Knouse, K. W.; Rossiter, S. E.; Williams, S. J.; Wuest, W. M. Diverted Total Synthesis of Promysalin Analogs Demonstrates That an Iron-Binding Motif Is Responsible for Its Narrow-Spectrum Antibacterial Activity. J. Am. Chem. Soc. 2016, 138, 5833−5836. (218) Greiner, D.; Bonaldi, T.; Eskeland, R.; Roemer, E.; Imhof, A. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3−9. Nat. Chem. Biol. 2005, 1, 143−145. (219) Fujishiro, S.; Dodo, K.; Iwasa, E.; Teng, Y.; Sohtome, Y.; Hamashima, Y.; Ito, A.; Yoshida, M.; Sodeoka, M. Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: reducing cytotoxicity by structural simplification. Bioorg. Med. Chem. Lett. 2013, 23, 733−736. (220) Taori, K.; Paul, V. J.; Luesch, H. Structure and activity of largazole, a potent antiproliferative agent from the Floridian marine

cyanobacterium Symploca sp. J. Am. Chem. Soc. 2008, 130, 1806− 1807. (221) Cole, K. E.; Dowling, D. P.; Boone, M. A.; Phillips, A. J.; Christianson, D. W. Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. J. Am. Chem. Soc. 2011, 133, 12474−12477. (222) Chen, F.; Chai, H.; Su, M. B.; Zhang, Y. M.; Li, J.; Xie, X.; Nan, F. J. Potent and orally efficacious bisthiazole-based histone deacetylase inhibitors. ACS Med. Chem. Lett. 2014, 5, 628−633. (223) McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina, J. H.; Laakso, J.; Ireland, C. M.; Murray, L.; Capon, R. J.; Boyd, M. R. The Lobatamides, Novel Cytotoxic Macrolides from Southwestern Pacific Tunicates. J. Org. Chem. 1998, 63, 7805−7810. (224) Nishi, T.; Forgac, M. The vacuolar (H+)-ATPases  nature’s most versatile proton pumps. Nat. Rev. Mol. Cell Biol. 2002, 3, 94− 103. (225) Changelian, P. S.; Flanagan, M. E.; Ball, D. J.; Kent, C. R.; Magnuson, K. S.; Martin, W. H.; Rizzuti, B. J.; Sawyer, P. S.; Perry, B. D.; Brissette, W. H.; McCurdy, S. P.; Kudlacz, E. M.; Conklyn, M. J.; Elliott, E. A.; Koslov, E. R.; Fisher, M. B.; Strelevitz, T. J.; Yoon, K.; Whipple, D. A.; Sun, J.; Munchhof, M. J.; Doty, J. L.; Casavant, J. M.; Blumenkopf, T. A.; Hines, M.; Brown, M. F.; Lillie, B. M.; Subramanyam, C.; Shang-Poa, C.; Milici, A. J.; Beckius, G. E.; Moyer, J. D.; Su, C.; Woodworth, T. G.; Gaweco, A. S.; Beals, C. R.; Littman, B. H.; Fisher, D. A.; Smith, J. F.; Zagouras, P.; Magna, H. A.; Saltarelli, M. J.; Johnson, K. S.; Nelms, L. F.; Des Etages, S. G.; Hayes, L. S.; Kawabata, T. T.; Finco-Kent, D.; Baker, D. L.; Larson, M.; Si, M. S.; Paniagua, R.; Higgins, J.; Holm, B.; Reitz, B.; Zhou, Y. J.; Morris, R. E.; O’Shea, J. J.; Borie, D. C. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 2003, 302, 875−878. (226) Boyd, M. R.; Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J. W.; Hayakawa, Y.; Beutler, J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E. J. Discovery of a novel antitumor benzolactone enamide class that selectively inhibits mammalian vacuolar-type (H+)-atpases. J. Pharmacol. Exp. Ther. 2001, 297, 114−120. (227) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. Synthesis and V-ATPase inhibition of simplified lobatamide analogues. Org. Lett. 2002, 4, 3103−3106. (228) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A. Total synthesis, stereochemical assignment, preparation of simplified analogues, and V-ATPase inhibition studies. J. Am. Chem. Soc. 2003, 125, 7889−7901. (229) Fehr, T.; Kallen, J.; Oberer, L.; Sanglier, J. J.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92−308110. II. Structure elucidation, stereochemistry and physico-chemical properties. J. Antibiot. 1999, 52, 474−479. (230) Sanglier, J. J.; Quesniaux, V.; Fehr, T.; Hofmann, H.; Mahnke, M.; Memmert, K.; Schuler, W.; Zenke, G.; Gschwind, L.; Maurer, C.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92−308110. I. Taxonomy, fermentation, isolation and biological activity. J. Antibiot. 1999, 52, 466−473. (231) Zenke, G.; Strittmatter, U.; Fuchs, S.; Quesniaux, V. F. J.; Brinkmann, V.; Schuler, W.; Zurini, M.; Enz, A.; Billich, A.; Sanglier, J. J.; Fehr, T. Sanglifehrin A, a novel cyclophilin-binding compound showing immuno suppressive activity with a new mechanism of action. J. Immunol. 2001, 166, 7165−7171. (232) Kallen, J.; Sedrani, R.; Zenke, G.; Wagner, J. Structure of human cyclophilin A in complex with the novel immunosuppressant sanglifehrin A at 1.6 A resolution. J. Biol. Chem. 2005, 280, 21965− 21971. (233) Sedrani, R.; Kallen, J.; Martin Cabrejas, L. M.; Papageorgiou, C. D.; Senia, F.; Rohrbach, S.; Wagner, D.; Thai, B.; Jutzi Eme, A. M.; France, J.; Oberer, L.; Rihs, G.; Zenke, G.; Wagner, J. Sanglifehrincyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data. J. Am. Chem. Soc. 2003, 125, 3849−3859. AL

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

(234) Steadman, V. A.; Pettit, S. B.; Poullennec, K. G.; Lazarides, L.; Keats, A. J.; Dean, D. K.; Stanway, S. J.; Austin, C. A.; Sanvoisin, J. A.; Watt, G. M.; Fliri, H. G.; Liclican, A. C.; Jin, D. B.; Wong, M. H.; Leavitt, S. A.; Lee, Y. J.; Tian, Y.; Frey, C. R.; Appleby, T. C.; Schmitz, U.; Jansa, P.; Mackman, R. L.; Schultz, B. E. Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A. J. Med. Chem. 2017, 60, 1000−1017. (235) Hayakawa, Y.; Adachi, K.; Komeshima, N. New antitumor antibiotics, anguinomycins A and B. J. Antibiot. 1987, 40, 1349−1352. (236) Hayakawa, Y.; Sohda, K. Y.; Shin-Ya, K.; Hidaka, T.; Seto, H. Anguinomycins C and D, new antitumor antibiotics with selective cytotoxicity against transformed cells. J. Antibiot. 1995, 48, 954−961. (237) Newlands, E. S.; Rustin, G. J.; Brampton, M. H. Phase I trial of elactocin. Br. J. Cancer 1996, 74, 648−649. (238) Sun, Q.; Carrasco, Y. P.; Hu, Y.; Guo, X.; Mirzaei, H.; Macmillan, J.; Chook, Y. M. Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 1303−1308. (239) Bonazzi, S.; Guttinger, S.; Zemp, I.; Kutay, U.; Gademann, K. Total synthesis, configuration, and biological evaluation of anguinomycin C. Angew. Chem., Int. Ed. 2007, 46, 8707−8710. (240) Kudo, N.; Wolff, B.; Sekimoto, T.; Schreiner, E. P.; Yoneda, Y.; Yanagida, M.; Horinouchi, S.; Yoshida, M. Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1. Exp. Cell Res. 1998, 242, 540−547. (241) Bonazzi, S.; Eidam, O.; Guttinger, S.; Wach, J. Y.; Zemp, I.; Kutay, U.; Gademann, K. Anguinomycins and derivatives: total syntheses, modeling, and biological evaluation of the inhibition of nucleocytoplasmic transport. J. Am. Chem. Soc. 2010, 132, 1432− 1442. (242) Igarashi, M.; Nakagawa, N.; Doi, N.; Hattori, S.; Naganawa, H.; Hamada, M. Caprazamycin B, a novel anti-tuberculosis antibiotic, from Streptomyces sp. J. Antibiot. 2003, 56, 580−583. (243) Bugg, T. D.; Lloyd, A. J.; Roper, D. I. Phospho-MurNAcpentapeptide translocase (MraY) as a target for antibacterial agents and antibacterial proteins. Infect. Disord.: Drug Targets 2006, 6, 85− 106. (244) Bouhss, A.; Mengin-Lecreulx, D.; Le Beller, D.; Van Heijenoort, J. Topological analysis of the MraY protein catalysing the first membrane step of peptidoglycan synthesis. Mol. Microbiol. 1999, 34, 576−585. (245) Bouhss, A.; Trunkfield, A. E.; Bugg, T. D.; Mengin-Lecreulx, D. The biosynthesis of peptidoglycan lipid-linked intermediates. FEMS Microbiol. Rev. 2008, 32, 208−233. (246) Al-Dabbagh, B.; Henry, X.; El Ghachi, M.; Auger, G.; Blanot, D.; Parquet, C.; Mengin-Lecreulx, D.; Bouhss, A. Active site mapping of MraY, a member of the polyprenyl-phosphate N-acetylhexosamine 1-phosphate transferase superfamily, catalyzing the first membrane step of peptidoglycan biosynthesis. Biochemistry 2008, 47, 8919− 8928. (247) Ii, K.; Ichikawa, S.; Al-Dabbagh, B.; Bouhss, A.; Matsuda, A. Function-oriented synthesis of simplified caprazamycins: discovery of oxazolidine-containing uridine derivatives as antibacterial agents against drug-resistant bacteria. J. Med. Chem. 2010, 53, 3793−3813. (248) Nakamura, H.; Tsukano, C.; Yasui, M.; Yokouchi, S.; Igarashi, M.; Takemoto, Y. Total synthesis of (−)-caprazamycin A. Angew. Chem., Int. Ed. 2015, 54, 3136−3139. (249) Takahashi, Y.; Igarashi, M.; Miyake, T.; Soutome, H.; Ishikawa, K.; Komatsuki, Y.; Koyama, Y.; Nakagawa, N.; Hattori, S.; Inoue, K.; Doi, N.; Akamatsu, Y. Novel semisynthetic antibiotics from caprazamycins A-G: caprazene derivatives and their antibacterial activity. J. Antibiot. 2013, 66, 171−178. (250) Schmidt, K.; Gunther, W.; Stoyanova, S.; Schubert, B.; Li, Z.; Hamburger, M. Militarinone A, a neurotrophic pyridone alkaloid from Paecilomyces militaris. Org. Lett. 2002, 4, 197−199. (251) Schmidt, K.; Riese, U.; Li, Z.; Hamburger, M. Novel tetramic acids and pyridone alkaloids, militarinones B, C, and D, from the insect pathogenic fungus Paecilomyces militaris. J. Nat. Prod. 2003, 66, 378−383.

(252) Cheng, Y.; Schneider, B.; Riese, U.; Schubert, B.; Li, Z.; Hamburger, M. Farinosones A-C, neurotrophic alkaloidal metabolites from the entomogenous deuteromycete Paecilomyces farinosus. J. Nat. Prod. 2004, 67, 1854−1858. (253) Isaka, M.; Chinthanom, P.; Supothina, S.; Tobwor, P.; HywelJones, N. L. Pyridone and tetramic acid alkaloids from the spider pathogenic fungus Torrubiella sp. BCC 2165. J. Nat. Prod. 2010, 73, 2057−2060. (254) Jessen, H. J.; Schumacher, A.; Shaw, T.; Pfaltz, A.; Gademann, K. A unified approach for the stereoselective total synthesis of pyridone alkaloids and their neuritogenic activity. Angew. Chem., Int. Ed. 2011, 50, 4222−4226. (255) Schmid, F.; Jessen, H. J.; Burch, P.; Gademann, K. Truncated militarinone fragments identified by total chemical synthesis induce neurite outgrowth. MedChemComm 2013, 4, 135−139. (256) Degnan, B. M.; Hawkins, C. J.; Lavin, M. F.; McCaffrey, E. J.; Parry, D. L.; Watters, D. J. Novel cytotoxic compounds from the ascidian Lissoclinum bistratum. J. Med. Chem. 1989, 32, 1354−1359. (257) Gouiffès, D.; Moreau, S.; Helbecque, N.; Bernier, J. L.; Hénichart, J. P.; Barbin, Y.; Laurent, D.; Verbist, J. F. Proton Nuclear Magnetic Study of Bistramide A, a new cytotoxic drug isolated from Lissoclinum Bistratum Sluiter. Tetrahedron 1988, 44, 451−459. (258) Biard, J. F.; Roussakis, C.; Kornprobst, J. M.; Gouiffes-Barbin, D.; Verbist, J. F.; Cotelle, P.; Foster, M. P.; Ireland, C. M.; Debitus, C. Bistramides A, B, C, D, and K: a new class of bioactive cyclic polyethers from Lissoclinum bistratum. J. Nat. Prod. 1994, 57, 1336− 1345. (259) Sauviat, M. P.; Verbist, J. F. Alteration of the voltagedependence of the twitch tension in frog skeletal muscle fibres by a polyether, Bistramide A. Gen. Physiol. Biophys. 1993, 12, 465−471. (260) Sauviat, M. P.; Gouiffes-Barbin, D.; Ecault, E.; Verbist, J. F. Blockade of sodium channels by Bistramide A in voltage-clamped frog skeletal muscle fibres. Biochim. Biophys. Acta, Biomembr. 1992, 1103, 109−114. (261) Griffiths, G.; Garrone, B.; Deacon, E.; Owen, P.; Pongracz, J.; Mead, G.; Bradwell, A.; Watters, D.; Lord, J. The polyether bistratene A activates protein kinase C-delta and induces growth arrest in HL60 cells. Biochem. Biophys. Res. Commun. 1996, 222, 802−808. (262) Statsuk, A. V.; Bai, R.; Baryza, J. L.; Verma, V. A.; Hamel, E.; Wender, P. A.; Kozmin, S. A. Actin is the primary cellular receptor of bistramide A. Nat. Chem. Biol. 2005, 1, 383−388. (263) Rizvi, S. A.; Liu, S.; Chen, Z.; Skau, C.; Pytynia, M.; Kovar, D. R.; Chmura, S. J.; Kozmin, S. A. Rationally simplified bistramide analog reversibly targets actin polymerization and inhibits cancer progression in vitro and in vivo. J. Am. Chem. Soc. 2010, 132, 7288− 7290. (264) Rizvi, S. A.; Tereshko, V.; Kossiakoff, A. A.; Kozmin, S. A. Structure of bistramide A-actin complex at a 1.35 angstroms resolution. J. Am. Chem. Soc. 2006, 128, 3882−3883. (265) Rizvi, S. A.; Courson, D. S.; Keller, V. A.; Rock, R. S.; Kozmin, S. A. The dual mode of action of bistramide A entails severing of filamentous actin and covalent protein modification. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 4088−4092. (266) Misico, R. I.; Nicotra, V. E.; Oberti, J. C.; Barboza, G.; Gil, R. R.; Burton, G. Withanolides and related steroids. Prog. Chem. Org. Nat. Prod. 2011, 94, 127−229. (267) Lavie, D.; Glotter, E.; Shvo, Y. Constituents of Withania somnifera Dun. III. The Side Chain of Withaferin A. J. Org. Chem. 1965, 30, 1774−1778. (268) Lee, J.; Hahm, E. R.; Singh, S. V. Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells. Carcinogenesis 2010, 31, 1991−1998. (269) Kupchan, S. M.; Anderson, W. K.; Bollinger, P.; Doskotch, R. W.; Smith, R. M.; Saenz-Renauld, J. A.; Schnoes, H. K.; Burlingame, A. L.; Smith, D. H. Tumor inhibitors. XXXIX. Active principles of Acnistus arborescens. Isolation and structural and spectral studies of withaferin A and withacnistin. J. Org. Chem. 1969, 34, 3858−3866. AM

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

evaluation of a spongistatin AB-spiroketal analogue. Bioorg. Med. Chem. Lett. 2002, 12, 2039−2042. (288) Paterson, I.; Aceña, J. L.; Bach, J.; Chen, D. Y. K.; Coster, M. J. Synthesis and biological evaluation of spongistatin/altohyrtin analogues: E-ring dehydration and C46 side-chain truncation. Chem. Commun. 2003, 3, 462−463. (289) Wagner, C. E.; Wang, Q.; Melamed, A.; Fairchild, C. R.; Wild, R.; Heathcock, C. H. Synthesis and biological evaluation of analogs of altohyrtin C (spongistatin 2). Tetrahedron 2008, 64, 124−136. (290) Nakae, K.; Yoshimoto, Y.; Sawa, T.; Homma, Y.; Hamada, M.; Takeuch, T.; Imoto, M. Migrastatin, a new inhibitor of tumor cell migration from Streptomyces sp. MK929−43F1. Taxonomy, fermentation, isolation and biological activities. J. Antibiot. 2000, 53, 1130−1136. (291) Nakae, K.; Yoshimoto, Y.; Ueda, M.; Sawa, T.; Takahashi, Y.; Naganawa, H.; Takeuchi, T.; Imoto, M. Migrastatin, a novel 14membered lactone from Streptomyces sp. MK929−43F1. J. Antibiot. 2000, 53, 1228−1230. (292) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X. Y.; Danishefsky, S. J. Discovery of potent cell migration inhibitors through total synthesis: lessons from structure-activity studies of (+)-migrastatin. J. Am. Chem. Soc. 2004, 126, 1038−1040. (293) Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. The total synthesis of (+)-migrastatin. J. Am. Chem. Soc. 2003, 125, 6042−6043. (294) Shan, D.; Chen, L.; Njardarson, J. T.; Gaul, C.; Ma, X.; Danishefsky, S. J.; Huang, X. Y. Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 3772−3776. (295) Oskarsson, T.; Nagorny, P.; Krauss, I. J.; Perez, L.; Mandal, M.; Yang, G.; Ouerfelli, O.; Xiao, D.; Moore, M. A.; Massague, J.; Danishefsky, S. J. Diverted total synthesis leads to the generation of promising cell-migration inhibitors for treatment of tumor metastasis: in vivo and mechanistic studies on the migrastatin core ether analog. J. Am. Chem. Soc. 2010, 132, 3224−3228. (296) Chen, L.; Yang, S.; Jakoncic, J.; Zhang, J. J.; Huang, X. Y. Migrastatin analogues target fascin to block tumour metastasis. Nature 2010, 464, 1062−1066. (297) Tichenor, M. S.; MacMillan, K. S.; Stover, J. S.; Wolkenberg, S. E.; Pavani, M. G.; Zanella, L.; Zaid, A. N.; Spalluto, G.; Rayl, T. J.; Hwang, I.; Baraldi, P. G.; Boger, D. L. Rational design, synthesis, and evaluation of key analogues of CC-1065 and the duocarmycins. J. Am. Chem. Soc. 2007, 129, 14092−14099. (298) MacMillan, K. S.; Lajiness, J. P.; Cara, C. L.; Romagnoli, R.; Robertson, W. M.; Hwang, I.; Baraldi, P. G.; Boger, D. L. Synthesis and evaluation of a thio analogue of duocarmycin SA. Bioorg. Med. Chem. Lett. 2009, 19, 6962−6965. (299) Rujirawanich, J.; Kim, S.; Ma, A. J.; Butler, J. R.; Wang, Y.; Wang, C.; Rosen, M.; Posner, B.; Nijhawan, D.; Ready, J. M. Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives. J. Am. Chem. Soc. 2016, 138, 10561−10570. (300) Schnermann, M. J.; Beaudry, C. M.; Egorova, A. V.; Polishchuk, R. S.; Sutterlin, C.; Overman, L. E. Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 6158−6163. (301) Chen, L.; Riaz Ahmed, K. B.; Huang, P.; Jin, Z. Design, synthesis, and biological evaluation of truncated superstolide A. Angew. Chem., Int. Ed. 2013, 52, 3446−3449. (302) Just-Baringo, X.; Bruno, P.; Pitart, C.; Vila, J.; Albericio, F.; Alvarez, M. Dissecting the structure of thiopeptides: assessment of thiazoline and tail moieties of baringolin and antibacterial activity optimization. J. Med. Chem. 2014, 57, 4185−4195. (303) Sohoel, H.; Liljefors, T.; Ley, S. V.; Oliver, S. F.; Antonello, A.; Smith, M. D.; Olsen, C. E.; Isaacs, J. T.; Christensen, S. B. Total synthesis of two novel subpicomolar sarco/endoplasmatic reticulum Ca2+-ATPase inhibitors designed by an analysis of the binding site of thapsigargin. J. Med. Chem. 2005, 48, 7005−7011. (304) Alonso, E.; Fuwa, H.; Vale, C.; Suga, Y.; Goto, T.; Konno, Y.; Sasaki, M.; LaFerla, F. M.; Vieytes, M. R.; Gimenez-Llort, L.; Botana,

(270) Tahara, T.; Streit, U.; Pelish, H. E.; Shair, M. D. STAT3 Inhibitory Activity of Structurally Simplified Withaferin A Analogues. Org. Lett. 2017, 19, 1538−1541. (271) Yamazaki, Y.; Kunimoto, S.; Ikeda, D. Rakicidin A: a hypoxiaselective cytotoxin. Biol. Pharm. Bull. 2007, 30, 261−265. (272) Wilson, W. R.; Hay, M. P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 2011, 11, 393−410. (273) McBrien, K. D.; Berry, R. L.; Lowe, S. E.; Neddermann, K. M.; Bursuker, I.; Huang, S.; Klohr, S. E.; Leet, J. E. Rakicidins, new cytotoxic lipopeptides from Micromonospora sp. fermentation, isolation and characterization. J. Antibiot. 1995, 48, 1446−1452. (274) Takeuchi, M.; Ashihara, E.; Yamazaki, Y.; Kimura, S.; Nakagawa, Y.; Tanaka, R.; Yao, H.; Nagao, R.; Hayashi, Y.; Hirai, H.; Maekawa, T. Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells. Cancer Sci. 2011, 102, 591− 596. (275) Tsakos, M.; Jacobsen, K. M.; Yu, W.; Villadsen, N. L.; Poulsen, T. B. The Rakicidin Family of Anticancer Natural Products − Synthetic Strategies towards a New Class of Hypoxia-Selective Cytotoxins. Synlett 2016, 27, 1898−1906. (276) Sang, F.; Li, D.; Sun, X.; Cao, X.; Wang, L.; Sun, J.; Sun, B.; Wu, L.; Yang, G.; Chu, X.; Wang, J.; Dong, C.; Geng, Y.; Jiang, H.; Long, H.; Chen, S.; Wang, G.; Zhang, S.; Zhang, Q.; Chen, Y. Total synthesis and determination of the absolute configuration of rakicidin A. J. Am. Chem. Soc. 2014, 136, 15787−15791. (277) Chen, J.; Li, J.; Wu, L.; Geng, Y.; Yu, J.; Chong, C.; Wang, M.; Gao, Y.; Bai, C.; Ding, Y.; Chen, Y.; Zhang, Q. Syntheses and antipancreatic cancer activities of rakicidin A analogues. Eur. J. Med. Chem. 2018, 151, 601−627. (278) Oku, N.; Matoba, S.; Yamazaki, Y. M.; Shimasaki, R.; Miyanaga, S.; Igarashi, Y. Complete stereochemistry and preliminary structure-activity relationship of rakicidin A, a hypoxia-selective cytotoxin from Micromonospora sp. J. Nat. Prod. 2014, 77, 2561− 2565. (279) Tsakos, M.; Clement, L. L.; Schaffert, E. S.; Olsen, F. N.; Rupiani, S.; Djurhuus, R.; Yu, W.; Jacobsen, K. M.; Villadsen, N. L.; Poulsen, T. B. Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue. Angew. Chem., Int. Ed. 2016, 55, 1030−1035. (280) Pettit, G. R.; Chicacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.; Schmidt, J. M.; Hooper, J. N. A. Antineoplastic agents. 257. Isolation and structure of spongistatin 1. J. Org. Chem. 1993, 58, 1302−1304. (281) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. Isolation and structure of the remarkable human cancer cell growth inhibitors spongistatins 2 and 3 from an eastern indian ocean Spongia sp. J. Chem. Soc., Chem. Commun. 1993, 1166−1168. (282) Fusetani, N.; Shinoda, K.; Matsunaga, S. Bioactive marine metabolites. 48. Cinachyrolide A: a potent cytotoxic macrolide possessing two spiro ketals from marine sponge Cinachyra sp. J. Am. Chem. Soc. 1993, 115, 3977−3981. (283) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara, N.; Sasaki, T.; Kitagawa, I. Altohyrtin A, a potent anti-tumor macrolide from the Okinawan marine sponge Hyrtios altum. Tetrahedron Lett. 1993, 34, 2795−2798. (284) Bai, R.; Cichacz, Z. A.; Herald, C. L.; Pettit, G. R.; Hamel, E. Spongistatin 1, a highly cytotoxic, sponge-derived, marine natural product that inhibits mitosis, microtubule assembly, and the binding of vinblastine to tubulin. Mol. Pharmacol. 1993, 44, 757−766. (285) Smith, A. B., 3rd; Risatti, C. A.; Atasoylu, O.; Bennett, C. S.; Liu, J.; Cheng, H.; TenDyke, K.; Xu, Q. Design, synthesis, and biological evaluation of diminutive forms of (+)-spongistatin 1: lessons learned. J. Am. Chem. Soc. 2011, 133, 14042−14053. (286) Smith, A. B.; Lin, Q.; Pettit, G. R.; Chapuis, J.-C.; Schmidt, J. M. Synthesis and in vitro cancer cell growth inhibitory activity of monocyclic model compounds containing spongistatin triene sidechains. Bioorg. Med. Chem. Lett. 1998, 8, 567−568. (287) Smith, A. B.; Corbett, R. M.; Pettit, G. R.; Chapuis, J.-C.; Schmidt, J. M.; Hamel, E.; Jung, M. K. Synthesis and biological AN

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

L. M. Design and synthesis of skeletal analogues of gambierol: attenuation of amyloid-beta and tau pathology with voltage-gated potassium channel and N-methyl-D-aspartate receptor implications. J. Am. Chem. Soc. 2012, 134, 7467−7479. (305) Zheng, S.; Laraia, L.; O'Connor, C. J.; Sorrell, D.; Tan, Y. S.; Xu, Z.; Venkitaraman, A. R.; Wu, W.; Spring, D. R. Synthesis and biological profiling of tellimagrandin I and analogues reveals that the medium ring can significantly modulate biological activity. Org. Biomol. Chem. 2012, 10, 2590−2593. (306) Peng, W.; Tang, P.; Hu, X.; Liu, J. O.; Yu, B. Synthesis of the A,B-ring-truncated OSW saponin analogs and their antitumor activities. Bioorg. Med. Chem. Lett. 2007, 17, 5506−5509. (307) Bauer, W.; Briner, U.; Doepfner, W.; Haller, R.; Huguenin, R.; Marbach, P.; Petcher, T. J.; Pless, J. Pless. SMS 201−995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 1982, 31, 1133−1140. (308) Veber, D. F.; Freidlinger, R. M.; Perlow, D. S.; Paleveda, W. J., Jr.; Holly, F. W.; Strachan, R. G.; Nutt, R. F.; Arison, B. H.; Homnick, C.; Randall, W. C.; Glitzer, M. S.; Saperstein, R.; Hirschmann, R. A potent cyclic hexapeptide analogue of somatostatin. Nature 1981, 292, 55−58. (309) Wender, P. A.; Quiroz, R. V.; Stevens, M. C. Function through synthesis-informed design. Acc. Chem. Res. 2015, 48, 752−760. (310) Wilson, R. M.; Danishefsky, S. J. Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. J. Org. Chem. 2006, 71, 8329−8351. (311) Roach, J. J.; Sasano, Y.; Schmid, C. L.; Zaidi, S.; Katritch, V.; Stevens, R. C.; Bohn, L. M.; Shenvi, R. A. Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent kappa-OR Agonist. ACS Cent. Sci. 2017, 3, 1329−1336. (312) von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.; Habich, D. Antibacterial natural products in medicinal chemistry– exodus or revival? Angew. Chem., Int. Ed. 2006, 45, 5072−5129. (313) Brown, D. G.; Lister, T.; May-Dracka, T. L. New natural products as new leads for antibacterial drug discovery. Bioorg. Med. Chem. Lett. 2014, 24, 413−418.

AO

DOI: 10.1021/acs.chemrev.8b00504 Chem. Rev. XXXX, XXX, XXX−XXX