Total Synthesis in Search of Potent AntibodyâDrug Conjugate

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

pubs.acs.org/accounts

Total Synthesis in Search of Potent Antibody−Drug Conjugate Payloads. From the Fundamentals to the Translational Kyriacos C. Nicolaou* and Stephan Rigol

Downloaded via UNIV OF SOUTH DAKOTA on December 21, 2018 at 16:10:37 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Department of Chemistry, BioScience Research Collaborative, Rice University, 6100 Main Street, Houston, Texas 77005, United States

CONSPECTUS: The emergence and evolution of antibody−drug conjugates (ADCs) as targeted cancer therapies in recent years is a living example of the “magic bullet” concept of Paul Ehrlich, introduced by him more than a century ago. Consisting of three components, the antibody serving as the delivery system, the payload drug that kills the cancer cell, and the chemical linker through which the payload is attached to the antibody, ADCs represent a currently hotly pursued paradigm of targeted cancer therapies. While the needed monoclonal antibody falls in the domains of biology and biochemistry, the potent payload and the linker belong to the realm of chemistry. Naturally occurring molecules and their derivatives endowed with high cytotoxic properties have proven to be useful payloads for the first approved ADCs (i.e., Mylotarg, Adcetris, Kadcyla, and Besponsa). The latest approaches and intensifying activities in this new paradigm of cancer therapy demands a variety of payloads with different mechanisms of action in order to address the medical needs for the various types of cancers, challenging synthetic organic chemists to enrich the library of potential payloads. Total synthesis of natural and designed molecules not only provides a powerful avenue to replicate rare naturally occurring compounds in the laboratory but also offers a unique opportunity to rationally design and synthesize analogues thereof for biological evaluation and optimization of ADC payloads. In this Account, we describe our efforts in this area highlighting a number of total synthesis endeavors through which we rendered scarce naturally occurring molecules readily available for biological evaluations and, most importantly, employed the developed synthetic strategies and methods to construct, otherwise unavailable or difficult to reach, designed analogues of these molecules. Specifically, we summarize the total syntheses of natural and designed molecules of the calicheamicin, uncialamycin, tubulysin, trioxacarcin, epothilone, shishijimicin, namenamicin, thailanstatin, and disorazole families of compounds and demonstrate how these studies led to the discovery of analogues of higher potencies, yet some of them possessing lower complexities than their parent compounds as potential ADC payloads. The highlighted examples showcase the continuing impact of total synthesis of natural products and their analogues on modern medicine, including the so-called biologics and should prove useful and inspirational in advancing both the fields of total synthesis and biomedical research and the drug discovery and development process.

■

INTRODUCTION Among the current frontiers in cancer research is the antibody− drug conjugates (ADCs) field. This paradigm of targeted cancer therapy was introduced into clinical use at the dawn of the 21st century. Its inception, however, goes back more than a century. It was Paul Ehrlich who introduced the concept of the “magic bullet”,1 an idea that remained dormant but inspirational, waiting for advances in biology and chemistry to occur before gathering momentum. ADCs are made up of three essential components, the antibody serving as the delivery system, the payload cytotoxic agent whose role is to attack and destroy the © XXXX American Chemical Society

cancer cell, and the linker, which joins the payload to its carrier and then releases it inside the cancer cell by rupturing. In loose terms, an antibody−drug conjugate can be compared to a “laserguided missile” whose aim is to target and destroy the enemy position with precision and no collateral damage. Just like the latter, it took sophisticated science and technology to develop such targeted therapies, and improvements are certainly needed to make them more efficacious and safer. The first antibody− Received: October 24, 2018

A

DOI: 10.1021/acs.accounts.8b00537 Acc. Chem. Res. XXXX, XXX, XXX−XXX

Article

Accounts of Chemical Research

Figure 1. Select cytotoxic natural products synthesized in the Nicolaou laboratories as lead compounds for analogue design, synthesis, and biological evaluation in search of payloads for antibody−drug conjugates (ADCs).

cleavage, tubulin binding, spliceosome inhibition, etc.). This paradigm transforms an otherwise unselective cytotoxic agent into a selective antitumor agent, thereby constituting a targeted cancer therapy. This approach may also be successfully extended beyond cancer therapies to treat more effectively other diseases, for example, bacterial infections through antibody−antibiotic conjugates as recently demonstrated in mice.3 Thus, as biology was advancing and analytical techniques were improving, antibodies were first recognized as proteins, and then their structures were elucidated. The next decisive advance was the production of monoclonal antibodies that led to their human tolerated versions allowing them to be used as therapeutics.4 In the meantime, advances in natural products isolation and structural elucidation led to the discovery of myriad bioactive natural products, among which were numerous cytotoxic agents.5 In addition, synthetic organic chemists were making strides in their science of replicating Nature’s molecules in the laboratory and synthesizing their own designed molecules with increasing complexity and higher efficiency.6 From such cytotoxic compounds, natural or designed, emerged the first clinically used anticancer drugs. With their efficacy based on the fact that cancer cells replicate faster than normal cells, the early cytotoxic cancer drugs included cisplatin, cyclophosphamide, the Vinca alkaloids, and Taxol. Despite their popularity, these drugs suffered from side effects, a recognition that led to further advances resulting in a new generation of more selective and targeted cancer therapies that left healthy cells less affected. Among them are the angiogenesis inhibitors that exploit the fact that tumors rely on the generation of new blood vessels for their

drug conjugate approved for clinical use was Mylotarg. Carrying N-acetyl calicheamicin γI1 as payload and introduced in 2000 by Lederle Laboratories, Mylotarg was later passed to Wyeth, and then to Pfizer through acquisitions. It was withdrawn in 2010, only to be reapproved by the FDA under the same name but with a new administration regiment. Employing the same payload (N-acetyl calicheamicin γI1) but a different antibody, Besponsa is the newest ADC to be approved by the FDA (2017, Pfizer). With an auristatin derivative as its payload, Adcetris was introduced by Seattle Genetics for clinical use in 2011, while Kadcyla, equipped with a maytansinoid payload, was marketed by Genentech-Roche in 2013. Impressively there are currently almost 100 ADCs in clinical trials for various cancer indications,2 reflecting the intense research and development efforts in this field. Ahead of its time, Ehrlich’s idea of a “magic bullet” as a chemotherapy became a reality after major advances in immunology and organic synthesis. To construct such a biochemical “laser-guided missile” and equip it with a cancer killer molecule took decades of steady progress in these disciplines whose merging was essential for success. This scenario is made possible by the fact that cancer cells carry on their surfaces certain biomarkers, antigens that can be targeted by monoclonal antibodies. Equipped with appended cytotoxic payloads through chemical linkers such antibodies can bind to the surfaces of cancer cells and, through endocytosis, be internalized into the cell where they can be dismantled within the lysosome releasing their payload, which then damages the cell through its particular mechanism of action (e.g., DNA B


Article

Accounts of Chemical Research Scheme 1. Total Synthesis of Calicheamicin γI1

growth, while normal tissues not as much, thereby surviving the onslaught of the drug. Other examples of molecular targeting cancer therapies aim to interrupt signal transduction pathways

that induce cancer growth, such as the use of small molecule inhibitors of tyrosine kinases and the inhibition of the proteasome that blocks angiogenesis and hence tumor growth. C


Article


Figure 2. Attachment of calicheamicin θI1 (38) to an antiganglioside antibody to form an ADC with a totally synthetic payload (1994, 1998).

with a mesmerizing mechanism of action, one whose central event involved a Bergman cycloaromatization reaction.9 This event is triggered by glutathione-mediated cleavage of the methyl trisulfide unit of the molecule to a thiol group, whose intramolecular attack on the nearby six-membered ring Michael acceptor thereby erases the double bond, the locking device of the enediyne moiety. This structural change allows the two acetylenic moieties of the ten-membered enediyne system to come closer together for interaction, which unleashes the Bergman reaction leading to a benzenoid diradical whose proximal location within the minor groove of double stranded DNA enables it to abstract H atoms from either or both strands, an occurrence that leads to single and double strand DNA cuts, respectively, amounting to a lethal blow to the cell. All in all, calicheamicin γI1 presented a formidable, and yet tantalizing, synthetic challenge from the moment of its unearthing in the 1980s. This challenge was met in our laboratories in 1992 with the first total synthesis of calicheamicin γI1.10 Scheme 1A summarizes this synthesis as communicated in 199210 and described in full articles in 199311 with a number of improvements. Notable highlights in this synthesis are (a) the [3 + 2] nitrile oxide cycloaddition reaction used to cast the cyclohexenone precursor of the bicyclic enediyne domain (27 → 28 → 29), (b) the forging of the 10-membered cyclic enediyne structural motif (32 → 33), (c) the easily induced required inversion of a hydroxy group through an intramolecular attack of an ester moiety on a mesylate to form a γ-lactone (33 → 34), (d) the [3,3]-sigmatropic rearrangement of an allylic thioester to install stereoselectively the required sulfur moiety (17 → 18), (e) the formation of the stable thioester bond (18+23 → 24), and (f) the stereoselective coupling of the pentacyclic carbohydrate/benzenoid segment with the enediyne domain to form the skeleton of the target molecule (25 + 35 → 36) as shown in Scheme 1A. The synthesis of the bicyclic enediyne domain of calicheamicin γI1 (and common to several other enediyne antitumor antibiotics) was streamlined and significantly improved later as discussed below for the synthesis of its cousin molecules shishijimicin A (10) and namenamicin (11, Figure 1). Most importantly, employing the developed synthetic strategies and tactics, we synthesized the designed thioacetate

Further advances in immunology and biochemistry led to new insights and technologies resulting in the production of recombinant monoclonal antibodies and the recognition of biomarkers on the surface of cells. Humanized monoclonal antibodies became available and soon thereafter some were approved for clinical use. Hercepin (trastuzumab) was approved by FDA in 1998 as a cancer therapy to treat HER-positive breast cancer patients. And two years later, in 2000, Mylotarg was introduced as a targeted therapy for acute myelogenous leukemia (AML). This historic milestone heralded the beginning of the “magic bullet” era of ADCs in reality. The milestone represented by Mylotarg depended heavily on the discovery of calicheamicin γI1 (1, Figure 1), the N-acetyl derivative of which became the payload attached to this antibody−drug conjugate. Calicheamicin γI1 was discovered by scientists at Lederle laboratories in the late 1980s and was brought to our attention in 1987,7 before its structure was published in 1988,8 through personal communication. For us, it was also the beginning of our interest in the ADC payloads, which started in the 1990s and climaxed in the 2010s with the syntheses of several other lead natural products and their analogues as potential ADC payloads. This collection of often scarce, naturally occurring molecules endowed with powerful cytotoxicities included, besides calicheamicin γI1 (1), uncialamycin (2), the tubulysins (e.g., 3), the trioxacarcins (e.g., 4 and 5), the epothilones (e.g., B, 6), the thailanstatins (e.g., 7), the disorazoles A1 and B1 (8 and 9), shishijimicin A (10), and namenamicin (11, see Figure 1 for structures), and their analogues. Below we highlight the total syntheses of select members of these families of compounds and include some of the most potent analogues we designed, synthesized, and tested in collaboration with our industrial partners.

■

CALICHEAMICIN γI1 With its molecular weight of 1368 Da, six different types of atoms (C, H, O, N, S, and I), numerous stereogenic sites, and unusual structural motifs (e.g., a strained 10-membered enediyne ring, several glycosidic bonds, a dihydrooxime bridge, a thioester linkage, and a methyltrisulfide moiety) and a hexasubstituted benzene ring, calicheamicin γI1 (1) is endowed D


Article

Accounts of Chemical Research analogue of calicheamicin γI1 in which the “MeSSS” moiety was replaced with an “AcS” group (see calicheamicin θI1, 38, Scheme 1B) and found it to be equally potent, if not more, than the parent natural product.12 In a collaborative effort with the Reisfeld group at The Scripps Research Institute and in order to demonstrate the potential of calicheamicin γI1 and its analogues as payloads for ADCs, we conjugated calicheamicin θI1 (38), through its basic nitrogen group, to an antiganglioside GD2 antibody, producing one of the first antibody−drug conjugates of the enediyne class that demonstrated impressive suppression of growth and dissemination of liver metastasis in a syngeneic model of murine neuroblastoma (see Figure 2). Published in 1998,13 this demonstration preceded the approval of Mylotarg by two years and demonstrated the potential of potent cytotoxic natural products and their analogues as payloads for antibody− drug conjugates as targeted cancer therapies.

Scheme 2. Total Synthesis of Uncialamycin

■

UNCIALAMYCIN The naturally occurring, but extremely scarce, uncialamycin enediyne antitumor antibiotic (2) was isolated from a marine organism in a mere 300 μg and reported in 2005.14 Its structural elucidation left, besides its absolute configuration, one of its five stereogenic centers (i.e., C26, see Scheme 2A) unassigned. The small amounts of material isolated allowed antibacterial assays to be performed revealing phenomenal potencies against a number of bacterial strains.14 No antitumor or DNA-cleaving properties were reported at the time, although they were expected given the presence of the 10-membered ring enediyne structural motif embedded within the molecule. It was clear to us that uncialamycin and its analogues had considerable potential as powerful cytotoxic agents, most likely as suitable antibody−drug conjugate payloads, rather than as a drug-alone therapy. A venture to prepare it in the laboratory through total synthesis would not only provide us with the opportunity to decipher its complete molecular structure, including its absolute stereochemistry, but also to evaluate its cytotoxicity against tumor cells and study its mechanism of action, presumed to involve singleand double-strand DNA cleavage by analogy to calicheamicin γI1 (1) and the other enediyne antitumor antibiotics. Eagerly undertaken in 2006, our studies on uncialamycin continue to this day as they proved both challenging and fruitful. Reported in 2007,15 our first total synthesis rendered both racemic (26S)and (26R)-uncialamycins, and led to the identification of the (26R)-uncialamycin, whose structure was confirmed by X-ray crystallographic analysis, as the true structure of the naturally occurring molecule. Our second and asymmetric total synthesis of uncialamycin, reported in 2008,16 delivered enantioselectively each of the two epimeric target molecules, naturally occurring (26R)-uncialamycin (2) as highlighted in Scheme 2A and its diastereoisomer (26S)-uncialamycin.15 Using enantiomerically pure uncialamycin (2), we confirmed its potent DNA-cleaving properties (both single- and double-strand cuts) as well as its faster rate of DNA cleavage in the presence of glutathione.15 The ability of glutathione to reduce the anthraquinone moiety of uncialamycin to its dihydroquinone counterpart, a transformation that initiates the cascade leading to the Bergman cycloaromatization responsible for the DNA cleavage, explains the acceleration of DNA cleavage in the presence of the latter. We also demonstrated the extreme potencies of synthetic uncialamycin against a number of drug-resistant bacterial strains, and most importantly its cytotoxicities against certain cancer cell lines.17 The complete structural elucidation and initial biological evaluation of uncialamycin set the stage for further inves-

tigations. By 2016, we developed and reported a new and improved process for the synthesis of the natural product (2, see Scheme 2A)17 and applied it to the construction of an array of designed analogues from which we identified even more potent uncialamycins than the parent compound (e.g., 52 and 53, Scheme 2B).17 Equipped with appropriate handles for linker attachment, these molecules are suitable candidates as potential payloads for antibody−drug conjugates. Notable discoveries in this endeavor are (a) the new synthetic method developed for the construction of substituted anthraquinones involving methoxyamino semiquinones and cyanophthalides,17,18 and (b) the potency-enhancing properties of a basic amine functionality attached onto the anthraquinone domain of uncialamycin.17 A number of these uncialamycin analogues are currently under development in the pharmaceutical industry. E


Article


■

TUBULYSINS The tubulysins comprise a class of naturally occurring molecules with potent antitumor properties exerted through a mechanism involving microtubule depolymerization and breakdown of the mitotic spindle.19 With their potential in cancer therapies, these compounds stimulated considerable interest among biologists and chemists alike. Our interest in the tubulysins arose from our desire to search for suitable antibody−drug conjugate payloads and resulted in the total syntheses of the naturally occurring tubulysins V20 and U20a−f,21 and pretubulysin D,20a,b,22 as well as of numerous designed analogues starting with the highly potent N14-desacetoxytubulysin H (3).20a,b Summarized in Scheme 3A, the total synthesis of the latter exemplifies one of our approaches to this class of compounds that features a C−H activation reaction23 to forge the crucial C−C bond linking the thiazole moiety with the acetyl-bearing segment of the molecule. Involving the C−H bond between the two heteroatoms of the thiazole ring and the carbonyl moiety of the aldehyde building

block, this novel transformation induced by PhI(OCOCF3)2 proceeds through the generation of a carbon-centered radical and an iminium species followed by their coupling (54 + 55 → 56, Scheme 3A). Complemented by other synthetic tactics and methods, this synthetic strategy resulted in the generation of well over one hundred tubulysin analogues, from which a number of highly potent and suitably substituted compounds emerged as candidates for further development along the path toward ADC cancer therapies (e.g., 64 and 65, Scheme 3B).20b Such efforts are currently in progress.

■

TRIOXACARCINS Possessing novel molecular architectures and endowed with powerful antitumor properties, the trioxacarcins attracted significant interest from synthetic organic chemists in recent years.24 Our studies in this area25 led to the total synthesis of the naturally occurring trioxacarcins DC-45-A2, DC-45-A1, A (4), D, and C (5) (see Scheme 4A), as well as C7″-epi-trioxacarcin C, the latter as part of an effort to decipher its full molecular structure, since it was ambiguous with regards to the C7″stereochemical configuration at the time. Our original total synthesis25a,b was subsequently streamlined, improved, and applied to the construction of numerous analogues, some of which exhibited higher potencies than their more complex parent natural products.25c Scheme 4A highlights our recently improved syntheses25c of these targeted natural trioxacarcins through a divergent route, from common intermediate 72. Among the most notable features of these syntheses were (a) the Lewis acid-induced epoxyketone rearrangement/ring closure to cast the novel polyoxygenated 2,7-dioxabicyclo[2.2.1]heptane domain of the molecule (71 → 72, Scheme 4A) and (b) the use of the gold-induced glycosylation reactions employed to install stereoselectively the carbohydrate units into the targeted structures.25b,c Shown in Scheme 4B are two highly active, and yet structurally simpler, trioxacarcin analogues (i.e., 75 and 76)25c that provide inspiration and deserve further improvement and development as payloads for antibody−drug conjugates.

Scheme 3. Total Synthesis of N14-Desacetoxytubulysin H

■

EPOTHILONES Emerging in the 1990s,26 the epothilones are a family of natural products endowed with potent antitumor activities that became a rich playground for synthetic and semisynthetic efforts resulting in not only the total syntheses of several of the naturally occurring compounds27 but also myriad designed analogues for biological investigations.28 However, only one anticancer drug from this family, ixabepilone (Ixempra, BMS), received approval for clinical use as anticancer drug to date, with the many failures attributed to unacceptable side effects. In an effort to increase their cytotoxicity potencies and therefore make them suitable as ADC payloads, we became interested in preparing the aziridine counterpart of epothilone B (6, Scheme 5A) and related analogues through the recently introduced onestep Ess−Kü rti−Falck method29 from the corresponding epothilone D (6a, Scheme 5A), the latter being readily available from the more abundant epothilone B (6) through deoxygenation of the epoxide moiety.30 Our successful implementation of this strategy and its version that starts from epothilone B (6) and proceeds through intermediates 80 as shown in Scheme 5B allowed us to prepare dozens of analogues of epothilone B and variations of it in which the epoxide moiety was replaced, stereoselectively, with a free or N-substituted aziridine structural motif.30 Through the employed, rather unique for this case, F


Article

Accounts of Chemical Research Scheme 4. Total Synthesis of Trioxacarcins A and C

Scheme 5. Total Synthesis of Epothilone B

candidates or lead compounds for drug discovery and development purposes, primarily due to their strong binding to and inhibition of the spliceosome, the complex cellular machinery responsible for the splicing of premessenger ribonucleic acid to mRNA.31 Proceeding through excision of introns and religation of exons, this process has been recognized as controlling metabolism, angiogenesis, cancer cell proliferation, and metastasis and therefore became a biological target for inhibition as a means to combat cancer, through the development of appropriate small molecules for cancer therapies as single drug, combination, or antibody−drug conjugate targeted therapy. Our recent efforts in this area resulted in the total syntheses of thailanstatins A (7, Scheme 6A), B, and C, spliceostatin D, and numerous designed analogues for biological evaluation.32 As a prelude to these syntheses, we developed a series of stereoselective methods for the construction of tetrasubstituted dihydro- and tetrahydropyrans32b that may find applications in other synthetic organic and medicinal chemistry endeavors beyond our studies. Scheme 6A summarizes the synthetic strategies and methods employed to construct these natural and designed molecules as exemplified by the total syntheses of thailanstatin A (7)32a,b and its methyl ester (97).32a,c Scheme 7B depicts a select number of synthesized

aziridination method, we were able to improve the potencies of the epothilones down to low picomolar IC50 values, making a number of them attractive as potential candidates for antibody− drug conjugate payloads (e.g., 83a and 83b, Scheme 5C).30 Efforts along these lines are currently in progress.

■

THAILANSTATINS The thailanstatin family of naturally occurring molecules and related natural products have recently attracted considerable interest in academia and industry as potential cancer drug G


Article


Amano lipase PS as building blocks from which to reach both desired enantiomers [(+)-108 (43% ee) → (+)-108 (>95% ee) and (−)-109 (>95% ee), for the purpose of determining which of the two represented the true structure of disorazole B1], (b) the Stille coupling for the formation of 114 from 112 and 113 and the Suzuki coupling employing 2-hydroxy oxaborine 102 (102 + 104 → 105), (c) the Yamaguchi esterifications (105 + 115 → 116, 117 + 115 → 118), and (d) the macrolactonizations (116 → 8, 118 → 9) for the final ring closure employed in these constructions. It was particularly rewarding to be able to synthesize both diastereoisomers of the symmetrical bis-epoxide disorazole B1 structure, and decipher its full molecular structure as the one depicted in Scheme 7 (9, 6S,8R,23S,25R).35 Employing the developed synthetic strategies and technologies, we already synthesized a number of designed analogues of disorazoles A1 and B1, two of which are shown in Scheme 7B (i.e., 119 and 120).36 Further synthetic and biological studies are currently in progress aiming to design, synthesize, and biologically evaluate additional designed analogues within the disorazole family for the purposes of discovering potential ADC payloads.

Scheme 6. Total Synthesis of Thailanstatin A

■

SHISHIJIMICIN A

Isolated from a marine species, shishijimicin A (10) boasts as the most potent enediyne antitumor antibiotic isolated from Nature thus far.37 It possesses in its structure the same enediyne domain as calicheamicin γI1 (1), the flagship of this family of natural products. Its extreme potency coupled with its scarcity prompted us to undertake its total synthesis (as part of our program directed toward ADC payloads). Our specific aims included the improvement of our original synthesis of the enediyne segment of the molecule that we employed in our first total synthesis of shishijimicin A38 and earlier in the synthesis of calicheamicin γI1 (1),10a,11 and to design and synthesize simpler and hopefully highly potent analogues of shishijimicin A (10) for conversion to linker drugs and thence their attachment to appropriate tumor-associated antibodies. Scheme 8A summarizes our recently reported improved synthetic route to shishijimicin A (10),39 including improvements for the enediyne domain, which is common to calicheamicin γI1 and other enediyne antitumor antibiotics such as namenamicin (11), whose total synthesis will also be highlighted below. Notable among the improvements39 of the synthesis of the enediyne domain are (a) the optimization of the intramolecular [3 + 2] cycloaddition of oxime 27 to form desired product 29 (27 → 28 ≡ 28a → 29, 91% vs 51% yield in our original work38), (b) the direct, high yielding one-step cyclization of enediyne aldehyde 32 to cyclic enediyne 34 [LiHMDS, LaCl3·2LiCl, THF, −78 °C (85%) as opposed to the three-step procedure (43%) previously employed38], and (c) the presumed biomimetic approach to the construction of the carboline moiety of the molecule (124 + 125 → 126, Scheme 8A). In addition to the total synthesis of the natural product, we also designed and synthesized a series of shishijimicin A analogues, whose biological evaluation revealed a number of extremely potent cytotoxic compounds (e.g., 129, 130, Scheme 8B) with some possessing significantly simpler structures than the natural product (e.g., 130, Scheme 8B).39

thailanstatin analogues (e.g., 98 and 99) with higher potencies (i.e., picomolar IC50 values) than those of any of the naturally occurring compounds of this family of natural products.32b

■

DISORAZOLES A1 AND B1 Being the most potent of the disorazoles,33 disorazole A1 (8, Scheme 7A) represents a family of naturally occurring cytotoxic agents whose potential as payloads of antibody−drug conjugates has been recognized as a consequence of their high potencies and mechanism of action, the latter involving interference with microtubule dynamics. On the other hand, disorazole B1 (9, Scheme 7A) was reported with incomplete structural assignment and no biological data.34 Attracted by the potency of disorazole A1 and the multifaceted challenge presented by disorazole B1, we initiated their total syntheses as part of our forays to discover and develop payloads for ADCs.35 Scheme 7A summarizes the total syntheses of disorazoles A1 (8) and B1 (9) and the full structural elucidation of the latter. Highlights include (a) the Sharpless epoxidation of stannane conjugated vinyl allylic alcohol 107, followed by the enzymatic resolution of the resulting mixture of epoxides [(+)-108 and (−)-108] with

■

NAMENAMICIN Originally isolated from a marine organism collected around the Fijian island of Namenalada in 1996 by the Ireland group,40 namenamicin (11) was rediscovered in 2003 by Fusetani et al.37 H


Article

Accounts of Chemical Research Scheme 7. Total Synthesis of Disorazoles A1 and B1

decipher the absolute configuration of the molecule, including the stereochemical configuration at C7′, which remained unassigned despite the two reported isolations of the natural product.37,40 In addition, the synthesis of this rare compound would make it and its analogues readily available for further biological investigations. Indeed, our recent success in synthesizing both C7′-diastereoisomers of namenamicin [(7′R)-and (7′S)-namenamicin, 148 and 11, respectively, Scheme 9]

and shown to be active against certain cancer cells at low picomolar IC50 values.37 Although namenamicin lacks the carboline structural motif of shishijimicin A, the structural resemblance of the two molecules is obvious. Namenamicin’s high potency and potential as a candidate or lead compound for antibody−drug conjugate payloads coupled with a remaining ambiguity in its molecular structure prompted our interest in its total synthesis. Accomplishment of the latter was expected to I


Article

Accounts of Chemical Research Scheme 8. Total Synthesis of Shishijimicin A

Scheme 9. Total Synthesis of Namenamicin

achieved both goals, the identification of the true structure of the molecule as the (7′S)-namenamicin (11) and the rendering of

the natural product and potentially its analogues available for biological investigations.41 Scheme 9 outlines the total synthesis of (7′R)- and (7′S)-namenamicins (148 and 11) featuring a number of interesting synthetic maneuvers.41 Notable among them are (a) the novel pathway through which the required monomethylthio glycosyl donor (136) was constructed from the tris-methylthio compound 132 via bis-methylthio derivative 134 through a sequence involving intermediate 133 (semipinacol rearrangement) and (b) the various gold-induced glycosylation reactions employed to meet the required, but J


Article

Accounts of Chemical Research Notes

challenging within the context of the target molecule, stereochemical demands of the glycoside bonds.41 The developed synthetic strategies and methods should serve to generate a library of designed namenamicin analogues for further studies aiming to define structure−activity relationships (SARs) within this family of compounds, from which further appropriate forays may lead to promising potential payloads for ADCs.

The authors declare no competing financial interest. Biographies K. C. Nicolaou, born in Cyprus and educated in the U.K. and U.S.A., holds the Harry C. and Olga K. Wiess Chair in Natural Sciences at Rice University. The impact of his work in chemistry, biology, and medicine flows from his contributions to chemical synthesis as described in almost 800 publications. His commitment to chemical education is reflected in his books Classics in Total Synthesis series and Molecules That Changed the World, as well as his training of hundreds of graduate students and postdoctoral fellows.

■

CONCLUSION Ever since its emergence in the early part of the 19th century from an experiment by Friedrich Wöhler that went astray, the unintended synthesis of the one-carbon containing molecule of urea,42 organic synthesis kept improving steadily to its present sharp state of the art, rivalling in some instances biosynthesis, the force of Nature responsible for life on Earth. Its purpose has also been evolving in different directions. The early intentions of total synthesis were to demonstrate and improve the state of the art at the time and to confirm the structure of the targeted natural product. After gathering momentum, total synthesis found applications in the synthesis and manufacturing of important products such as in the dye and pharmaceutical industries, both of which it helped to establish. Later, it became an art as exemplified so vividly in the total syntheses of R. B. Woodward. If Woodward practiced synthesis as an art, E. J. Corey brought logic to it and turned it into science through his influential theoretical and methodological contributions. It was during the Corey era that practitioners of the art and science of total synthesis in academia started to look for applications to biology and medicine. These efforts significantly intensified with the advent of chemical biology in the 1990s and continue steadily to add value to endeavors in total synthesis. The described research in this Account exemplifies the trend in total synthesis of moving from the fundamentals to the translational without losing its identity and advancement for its own sake.43 The latter is extremely important to keep in mind, for its impact on biology and medicine as well as other disciplines, such as nanotechnology and materials science, will always depend on its continuous advancement to new levels of performance and reach in terms of efficiency and molecular complexity and diversity.43 The examples highlighted herein demonstrate the applications of total synthesis of rare natural products and their analogues to biology and medicine, while at the same time contributing to its own advancement through strategy design and method development. It is also comforting to think that the described work represents and points to a renaissance in natural products chemistry, for it demonstrates powerful and unique applications in biology and medicine and underscores the need for further research, in both the isolation and total synthesis of natural products, many of which are still waiting to be discovered from the ocean, the soil, and the forest, if not the human body. The chemistry summarized herein sets the stage for further developments to occur in the antibody−drug conjugates (ADCs) frontier field in targeted and personalized cancer therapies.

■

Stephan Rigol studied chemistry at Leipzig University in Germany where he received his doctoral degree after carrying out research in the field of synthetic organic and medicinal chemistry under the guidance of Athanassios Giannis. He then moved to the United States to join the group of K. C. Nicolaou at Rice University where he is currently conducting research in the field of natural products chemistry as a postdoctoral fellow.

■

ACKNOWLEDGMENTS K.C.N. thanks his students and postdoctoral fellows who contributed decisively to the achievements described in this Account and whose names appear in the references. We are grateful to the National Institutes of Health (USA), the Cancer Prevention & Research Institute of Texas (CPRIT), The Welch Foundation (grant C-1819), Bristol-Myers Squibb, and AbbVie Stemcentrx for their generous support of our research.

■

REFERENCES

(1) Ehrlich, P. Beiträge zur experimentellen Pathologie und Chemotherapie; Akademische Verlagsgesellschaft: Leipzig, 1909; pp 165−202. (2) Beck, A.; Goetsch, L.; Dumontet, C.; Corvaïa, N. Strategies and Challenges for the Next Generation of Antibody−Drug Conjugates. Nat. Rev. Drug Discovery 2017, 16, 315−337. (3) Lehar, S. M.; Pillow, T.; Xu, M.; Staben, L.; Kajihara, K. K.; Vandlen, R.; DePalatis, L.; Raab, H.; Hazenbos, W. L.; Morisaki, J. H.; Kim, J.; Park, S.; Darwish, M.; Lee, B. C.; Hernandez, H.; Loyet, K. M.; Lupardus, P.; Fong, R.; Yan, D.; Chalouni, C.; Luis, E.; Khalfin, Y.; Plise, E.; Cheong, J.; Lyssikatos, J. P.; Strandh, M.; Koefoed, K.; Andersen, P. S.; Flygare, J. A.; Wah Tan, M.; Brown, E. J.; Mariathasan, S. Novel Antibody-Antibiotic Conjugate Eliminates Intracellular S. aureus. Nature 2015, 527, 323−328. (4) Köhler, G.; Milstein, C. Continuous Cultures of Fused Cells Secreting Antibody of Predefined Specificity. Nature 1975, 256, 495− 497. (5) (a) Butler, M. S. The Role of Natural Product Chemistry in Drug Discovery. J. Nat. Prod. 2004, 67, 2141−2153. (b) Sarker, S. D.; Nahar, L. Natural Products Isolation; Humana Press: Totowa, NJ, 2012. (6) Nicolaou, K. C. Organic Synthesis: The Art and Science of Replicating the Molecules of Living Nature and Creating Others Like Them in the Laboratory. Proc. R. Soc. London, Ser. A 2014, 470, 20130690. (7) Nicolaou, K. C. The Battle of Calicheamicin γI1. Angew. Chem., Int. Ed. Engl. 1993, 32, 1377−1385. (8) (a) Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.; Morton, G. O.; Borders, D. B. Calichemicins, a Novel Family of Antitumor Antibiotics. 1. Chemistry and Partial Structure of Calichemicin γI1. J. Am. Chem. Soc. 1987, 109, 3464−3466. (b) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G. O.; McGahren, W. J.; Borders, D. B. Calichemicins, a Novel Family of Antitumor Antibiotics. 2. Chemistry and Structure of Calichemicin γI1. J. Am. Chem. Soc. 1987, 109, 3466−3468. (9) Bergman, R. G. Reactive 1,4-Dehydroaromatics. Acc. Chem. Res. 1973, 6, 25−31.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kyriacos C. Nicolaou: 0000-0001-5332-2511 Stephan Rigol: 0000-0003-2470-3512 K


Article

Accounts of Chemical Research (10) (a) Nicolaou, K. C.; Hummel, C. W.; Pitsinos, E. N.; Nakada, M.; Smith, A. L.; Shibayama, K.; Saimoto, H. Total Synthesis of Calicheamicin γ1I. J. Am. Chem. Soc. 1992, 114, 10082−10084. (b) Halcomb, R. L.; Boyer, S. H.; Wittman, M. D.; Olson, S. H.; Denhart, D. J.; Liu, K. K. C.; Danishefsky, S. J. Studies Related to the Carbohydrate Sectors of Esperamicin and Calicheamicin: Definition of the Stability Limits of the Esperamicin Domain and Fashioning of a Glycosyl Donor from the Calicheamicin Domain. J. Am. Chem. Soc. 1995, 117, 5720−5749. (c) Hitchcock, S. A.; Chu-Moyer, M. Y.; Boyer, S. H.; Olson, S. H.; Danishefsky, S. J. A Remarkable Glycosidation Reaction: The Total Synthesis of Calicheamicin γI1. J. Am. Chem. Soc. 1995, 117, 5750−5756. (11) (a) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C. Total Synthesis of Calicheamicin γI1 1. Synthesis of the Oligosaccharide Fragment. J. Am. Chem. Soc. 1993, 115, 7593−7611. (b) Smith, A. L.; Pitsinos, E. N.; Hwang, C. K.; Mizuno, Y.; Saimoto, H.; Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. Total Synthesis of Calicheamicin γI1 2. Development of an Enantioselective Route to (−)-Calicheamicinone. J. Am. Chem. Soc. 1993, 115, 7612−7624. (c) Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama, K.; Pitsinos, E. N.; Saimoto, H.; Mizuno, Y.; Baldenius, K. U.; Smith, A. L. Total Synthesis of Calicheamicin 3. The Final Stages. J. Am. Chem. Soc. 1993, 115, 7625−7635. (12) Nicolaou, K. C.; Li, T.; Nakada, M.; Hummel, C. W.; Hiatt, A.; Wrasidlo, W. Calicheamicin θI1: A Rationally Designed Molecule with Extremely Potent and Selective DNA Cleaving Properties and Apoptosis Inducing Activity. Angew. Chem., Int. Ed. Engl. 1994, 33, 183−186. (13) Lode, H. N.; Reisfeld, R. A.; Handgretinger, R.; Nicolaou, K. C.; Gaedicke, G.; Wrasidlo, W. Targeted Therapy with a Novel Enediyene Antibiotic Calicheamicin θ1I Effectively Suppresses Growth and Dissemination of Liver Metastases in a Syngeneic Model of Murine Neuroblastoma. Cancer Res. 1998, 58, 2925−2928. (14) Davies, J.; Wang, H.; Taylor, T.; Warabi, K.; Huang, X.-H.; Andersen, R. J. Uncialamycin, a New Enediyne Antibiotic. Org. Lett. 2005, 7, 5233−5236. (15) Nicolaou, K. C.; Zhang, H.; Chen, J. S.; Crawford, J. J.; Pasunoori, L. Total Synthesis and Stereochemistry of Uncialamycin. Angew. Chem., Int. Ed. 2007, 46, 4704−4707. (16) Nicolaou, K. C.; Chen, J. S.; Zhang, H.; Montero, A. Asymmetric Synthesis and Biological Properties of Uncialamycin and 26-epiUncialamycin. Angew. Chem., Int. Ed. 2008, 47, 185−189. (17) Nicolaou, K. C.; Wang, Y.; Lu, M.; Mandal, D.; Pattanayak, M. R.; Yu, R.; Shah, A. A.; Chen, J. S.; Zhang, H.; Crawford, J. J.; Pasunoori, L.; Poudel, Y. B.; Chowdari, N. S.; Pan, C.; Nazeer, A.; Gangwar, S.; Vite, G.; Pitsinos, E. N. Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations. J. Am. Chem. Soc. 2016, 138, 8235−8246. (18) Nicolaou, K. C.; Lu, M.; Chen, P.; Shah, A. A. Practical Synthesis of p- and o-Amino- and Methoxyphenolic Anthraquinones. Angew. Chem., Int. Ed. 2015, 54, 12687−12691. (19) (a) Khalil, M. W.; Sasse, F.; Lünsdorf, H.; Elnakady, Y. A.; Reichenbach, H. Mechanism of Action of Tubulysin, an Antimitotic Peptide from Myxobacteria. ChemBioChem 2006, 7, 678−683. (b) Kubicek, K.; Grimm, S. K.; Orts, J.; Sasse, F.; Carlomagno, T. The Tubulin-Bound Structure of the Antimitotic Drug Tubulysin. Angew. Chem., Int. Ed. 2010, 49, 4809−4812. (c) Steinmetz, H.; Glaser, N.; Herdtweck, E.; Sasse, F.; Reichenbach, H.; Höfle, G. Isolation, Crystal and Solution Structure Determination, and Biosynthesis of TubulysinsPowerful Inhibitors of Tubulin Polymerization from Myxobacteria. Angew. Chem., Int. Ed. 2004, 43, 4888−4892. (20) (a) Nicolaou, K. C.; Yin, J.; Mandal, D.; Erande, R. D.; Klahn, P.; Jin, M.; Aujay, M.; Sandoval, J.; Gavrilyuk, J.; Vourloumis, D. Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins. J. Am. Chem. Soc. 2016, 138, 1698−1708. (b) Nicolaou, K. C.; Erande, R. D.; Yin, J.; Vourloumis, D.; Aujay, M.; Sandoval, J.; Munneke, S.; Gavrilyuk, J. Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with

Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody−Drug Conjugates. J. Am. Chem. Soc. 2018, 140, 3690− 3711. (c) Dömling, A.; Beck, B.; Eichelberger, U.; Sakamuri, S.; Menon, S.; Chen, Q.-Z.; Lu, Y.; Wessjohann, L. A. Total Synthesis of Tubulysin U and V. Angew. Chem., Int. Ed. 2006, 45, 7235−7239. (d) Sani, M.; Fossati, G.; Huguenot, F.; Zanda, M. Total Synthesis of Tubulysins U and V. Angew. Chem., Int. Ed. 2007, 46, 3526−3529. (e) Balasubramanian, R.; Raghavan, B.; Begaye, A.; Sackett, D. L.; Fecik, R. A. Total Synthesis and Biological Evaluation of Tubulysin U, Tubulysin V, and Their Analogues. J. Med. Chem. 2009, 52, 238−240. (f) Shibue, T.; Hirai, T.; Okamoto, I.; Morita, N.; Masu, H.; Azumaya, I.; Tamura, O. Total Syntheses of Tubulysins. Chem. - Eur. J. 2010, 16, 11678−11688. (g) Shankar, S. P.; Jagodzinska, M.; Malpezzi, L.; Lazzari, P.; Manca, I.; Greig, I. R.; Sani, M.; Zanda, M. Synthesis and Structure−Activity Relationship Studies of Novel Tubulysin U Analogues − Effect on Cytotoxicity of Structural Variations in the Tubuvaline Fragment. Org. Biomol. Chem. 2013, 11, 2273−2287. (h) Wang, R.; Tian, P.; Lin, G. Stereoselective Total Synthesis of Tubulysin V. Chin. J. Chem. 2013, 31, 40−48. (i) Tao, W.; Zhou, W.; Zhou, Z.; Si, C.-M.; Sun, X.; Wei, B.-G. An Enantioselective Total Synthesis of Tubulysin V. Tetrahedron 2016, 72, 5928−5933. (21) (a) Shankar, P. S.; Bigotti, S.; Lazzari, P.; Manca, I.; Spiga, M.; Sani, M.; Zanda, M. Synthesis and Cytotoxicity Evaluation of Diastereoisomers and N-terminal Analogues of Tubulysin-U. Tetrahedron Lett. 2013, 54, 6137−6141. (b) Yang, X. D.; Dong, C. M.; Chen, J.; Ding, Y. H.; Liu, Q.; Ma, X. Y.; Zhang, Q.; Chen, Y. Total Synthesis of Tubulysin U and Its C-4 Epimer. Chem. - Asian J. 2013, 8, 1213−1222. (22) Chai, Y.; Ullrich, A.; Kazmaier, U.; Müller, R. Bioactive PreTubulysins and Use Thereof. PCT Int. Appl. WO2010034724A1, 2010. (23) (a) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chemistry of Acyl Radicals. Chem. Rev. 1999, 99, 1991−2070. (b) Yeung, C. S.; Dong, V. M. Catalytic Dehydrogenative Cross-Coupling: Forming Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds. Chem. Rev. 2011, 111, 1215−1292. (c) Matcha, K.; Antonchick, A. P. Metal-Free Cross-Dehydrogenative Coupling of Heterocycles with Aldehydes. Angew. Chem., Int. Ed. 2013, 52, 2082−2086. (d) Khemnar, A. B.; Bhanage, B. M. Direct C-2 Acylation of Thiazoles with Aldehydes via Metal- and Solvent-Free C−H Activation in the Presence of tertButyl Hydroperoxide. Synlett 2014, 25, 110−114. (24) (a) Š venda, J.; Hill, N.; Myers, A. G. A Multiply Convergent Platform for the Synthesis of Trioxacarcins. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 6709−6714. (b) Magauer, T.; Smaltz, D. J.; Myers, A. G. Component-Based Syntheses of Trioxacarcin A, DC-45-A1 and Structural Analogues. Nat. Chem. 2013, 5, 886−893. (25) (a) Nicolaou, K. C.; Cai, Q.; Qin, B.; Petersen, M. T.; Mikkelsen, R. J. T.; Heretsch, P. Total Synthesis of Trioxacarcin DC-45-A2. Angew. Chem., Int. Ed. 2015, 54, 3074−3078. (b) Nicolaou, K. C.; Cai, Q.; Sun, H.; Qin, B.; Zhu, S. Total Synthesis of Trioxacarcins DC-45-A1, A, D, C, and C7″-epi-C and Full Structural Assignment of Trioxacarcin C. J. Am. Chem. Soc. 2016, 138, 3118−3124. (c) Nicolaou, K. C.; Chen, P.; Zhu, S.; Cai, Q.; Erande, R. D.; Li, R.; Sun, H.; Pulukuri, K. K.; Rigol, S.; Aujay, M.; Sandoval, J.; Gavrilyuk, J. Streamlined Total Synthesis of Trioxacarcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxacarcin Analogues. J. Am. Chem. Soc. 2017, 139, 15467−15478. (26) Höfle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. Epothilone, deren Herstellungsverfahren sowie diese Verbindungen enthaltende Mittel. Ger. Offen. DE4138042, 1993. (27) (a) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.; Yang, Z. Total Synthesis of Epothilone A: The Macrolactonization Approach. Angew. Chem., Int. Ed. Engl. 1997, 36, 525−527. (b) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. Total Synthesis of Epothilone A: The Olefin Metathesis Approach. Angew. Chem., Int. Ed. Engl. 1997, 36, 166−168. (c) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Synthesis of Epothilones A and B in Solid and Solution Phase. Nature 1997, 387, 268−272. (d) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.; L


Article

Accounts of Chemical Research Danishefsky, S. J. Total Syntheses of Epothilones A and B. J. Am. Chem. Soc. 1997, 119, 10073−10092. (e) Su, D.-S.; Meng, D.; Bertinato, P.; Balog, A.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Total Synthesis of (−)-Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure− Activity Relationships of the Epothilones. Angew. Chem., Int. Ed. Engl. 1997, 36, 757−759. (f) May, S. A.; Grieco, P. A. Total Synthesis of (−)-Epothilone B. Chem. Commun. 1998, 1597−1598. (g) Mulzer, J.; Mantoulidis, A.; Ö hler, E. Easy Access to the Epothilone Family − Synthesis of Epothilone B. Tetrahedron Lett. 1998, 39, 8633−8636. (h) Schinzer, D.; Bauer, A.; Schieber, J. Syntheses of (−)-Epothilone B. Chem. - Eur. J. 1999, 5, 2492−2500. (i) Valluri, M.; Hindupur, R. M.; Bijoy, P.; Labadie, G.; Jung, J.-C.; Avery, M. A. Total Synthesis of Epothilone B. Org. Lett. 2001, 3, 3607−3609. (j) White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. Total Synthesis of Epothilone B, Epothilone D, and cis- and trans-9,10-Dehydroepothilone D. J. Am. Chem. Soc. 2001, 123, 5407−5413. (k) Jung, J.-C.; Kache, R.; Vines, K. K.; Zheng, Y.-S.; Bijoy, P.; Valluri, M.; Avery, M. A. Total Syntheses of Epothilones B and D. J. Org. Chem. 2004, 69, 9269−9284. (l) Keck, G. E.; Giles, R. L.; Cee, V. J.; Wager, C. A.; Yu, T.; Kraft, M. B. Total Synthesis of Epothilones B and D: Stannane Equivalents for β-Keto Ester Dianions. J. Org. Chem. 2008, 73, 9675−9691. (m) Wang, J.; Sun, B.-F.; Cui, K.; Lin, G.-Q. An Efficient Total Synthesis of (−)-Epothilone B. Org. Lett. 2012, 14, 6354−6357. (28) (a) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Chemical Biology of Epothilones. Angew. Chem., Int. Ed. 1998, 37, 2014−2045. (b) Mulzer, J. H. The Epothilones: An Outstanding Family of Anti-Tumor Agents. From Soil to the Clinic; Springer: Vienna, 2009. (29) Jat, J. L.; Paudyal, M. P.; Gao, H.; Xu, Q.-L.; Yousufuddin, M.; Devarajan, D.; Ess, D. H.; Kürti, L.; Falck, J. R. Direct Stereospecific Synthesis of Unprotected N-H and N-Me Aziridines from Olefins. Science 2014, 343, 61−65. (30) Nicolaou, K. C.; Rhoades, D.; Wang, Y.; Bai, R.; Hamel, E.; Aujay, M.; Sandoval, J.; Gavrilyuk, J. 12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents. J. Am. Chem. Soc. 2017, 139, 7318−7334. (31) Liu, X.; Biswas, S.; Berg, M. G.; Antapli, C. M.; Xie, F.; Wang, Q.; Tang, M.-C.; Tang, G.-L.; Zhang, L.; Dreyfuss, G.; Cheng, Y.-Q. Genomics-Guided Discovery of Thailanstatins A, B, and C as PremRNA Splicing Inhibitors and Antiproliferative Agents from Burkholderia thailandensis MSMB43. J. Nat. Prod. 2013, 76, 685−693. (32) (a) Nicolaou, K. C.; Rhoades, D.; Lamani, M.; Pattanayak, M. R.; Kumar, S. M. Total Synthesis of Thailanstatin A. J. Am. Chem. Soc. 2016, 138, 7532−7535. (b) Nicolaou, K. C.; Rhoades, D.; Kumar, S. M. Total Syntheses of Thailanstatins A−C, Spliceostatin D, and Analogues Thereof. Stereodivergent Synthesis of Tetrasubstituted Dihydro- and Tetrahydropyrans and Design, Synthesis, Biological Evaluation, and Discovery of Potent Antitumor Agents. J. Am. Chem. Soc. 2018, 140, 8303−8320. (c) Ghosh, A. K.; Veitschegger, A. M.; Nie, S.; Relitti, N.; MacRae, A. J.; Jurica, M. S. Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition. J. Org. Chem. 2018, 83, 5187−5198. (33) Jansen, R.; Irschik, H.; Reichenbach, H.; Wray, V.; Höfle, G. Antibiotics from Gliding Bacteria, LIX. Disorazoles, Highly Cytotoxic Metabolites from the Sorangicin-Producing Bacterium Sorangium Cellulosum Strain So ce12. Liebigs Ann. Chem. 1994, 1994, 759−773. (34) (a) Irschik, H.; Jansen, R.; Gerth, K.; Höfle, G.; Reichenbach, H. Disorazol A, an Efficient Inhibitor of Eukaryotic Organisms Isolated from Myxobacteria. J. Antibiot. 1995, 48, 31−35. (b) Elnakady, Y. A.; Sasse, F.; Lünsdorf, H.; Reichenbach, H. Disorazol A1 a Highly Effective Antimitotic Agent Acting on Tubulin Polymerization and Inducing Apoptosis in Mammalian Cells. Biochem. Pharmacol. 2004, 67, 927− 935. (35) Nicolaou, K. C.; Bellavance, G.; Buchman, M.; Pulukuri, K. K. Total Syntheses of Disorazoles A1 and B1 and Full Structural Elucidation of Disorazole B1. J. Am. Chem. Soc. 2017, 139, 15636− 15639.

(36) Nicolaou, K. C.; Buchman, M.; Bellavance, G.; Krieger, J.; Subramanian, P.; Pulukuri, K. K. Syntheses of Cyclopropyl Analogues of Disorazoles A1 and B1 and Their Thiazole Counterparts. J. Org. Chem. 2018, 83, 12374−12389. (37) Oku, N.; Matsunaga, S.; Fusetani, N. Shishijimicins A−C, Novel Enediyne Antitumor Antibiotics from the Ascidian Didemnum proliferum. J. Am. Chem. Soc. 2003, 125, 2044−2045. (38) Nicolaou, K. C.; Lu, Z.; Li, R.; Woods, J. R.; Sohn, T.-i. Total Synthesis of Shishijimicin A. J. Am. Chem. Soc. 2015, 137, 8716−8719. (39) Nicolaou, K. C.; Li, R.; Lu, Z.; Pitsinos, E. N.; Alemany, L. B.; Aujay, M.; Lee, C.; Sandoval, J.; Gavrilyuk, J. Streamlined Total Synthesis of Shishijimicin A and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues thereof and Practical Syntheses of PhthNSSMe and Related Sulfenylating Reagents. J. Am. Chem. Soc. 2018, 140, 12120−12136. (40) McDonald, L. A.; Capson, T. L.; Krishnamurthy, G.; Ding, W.D.; Ellestad, G. A.; Bernan, V. S.; Maiese, W. M.; Lassota, P.; Kramer, R. A.; Ireland, C. M. Namenamicin, a New Enediyne Antitumor Antibiotic from the Marine Ascidian Polysyncraton lithostrotum. J. Am. Chem. Soc. 1996, 118, 10898−10899. (41) Nicolaou, K. C.; Li, R.; Lu, Z.; Pitsinos, E. N.; Alemany, L. B. Total Synthesis and Full Structural Assignment of Namenamicin. J. Am. Chem. Soc. 2018, 140, 8091−8095. (42) Wöhler, F. Ueber künstliche Bildung des Harnstoffs. Ann. Phys. 1828, 88, 253−256. (43) (a) Nicolaou, K. C. Catalyst: Synthetic Organic Chemistry as a Force for Good. Chem. 2016, 1, 331−334. (b) Nicolaou, K. C.; Rigol, S. The Evolution and Impact of Total Synthesis on Chemistry, Biology and Medicine. Isr. J. Chem. 2017, 57, 179−191. (c) Nicolaou, K. C. The Emergence and Evolution of Organic Synthesis and Why It Is Important to Sustain It as an Advancing Art and Science for Its Own Sake. Isr. J. Chem. 2018, 58, 104−113.

M


Total Synthesis in Search of Potent AntibodyâDrug Conjugate

Recommend Documents

Total Synthesis in Search of Potent AntibodyâDrug Conjugate