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Perspective

Natural Products in Medicine: the Transformational Outcome of Synthetic Chemistry Janek Szychowski, Jean-Francois Truchon, and Youssef L Bennani J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm500941m • Publication Date (Web): 21 Aug 2014 Downloaded from http://pubs.acs.org on August 25, 2014

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Journal of Medicinal Chemistry

Natural Products in Medicine: the Transformational Outcome of Synthetic Chemistry Janek Szychowski, Jean-François Truchon, and Youssef L. Bennani* Vertex Pharmaceuticals (Canada), Inc. 275 Armand-Frappier, Laval, Québec H7V 4A7, Canada Abstract

This perspective article brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chemical transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and β-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Molecular modelling or x-ray structures of NP/protein complexes supporting the observed boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chemistry, structure determination, as well as in the understanding of factors controlling pharmacokinetics, can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will re-ignite medicinal chemists’s interest in NPs and their derivatives.

ACS Paragon Plus Environment

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Introduction Pharmaceutical research and development (R&D) is undergoing dramatic changes caused by market and healthcare management pressures. Over the past 25-30 years, we have seen numerous shifts in drug discovery approaches, ranging from reliance on in vivo disease pharmacology to single-target based reductionist approaches.

More recently, with the

sequencing of the human genome, the expectation of massive numbers of valuable targets triggered investments in a) combinatorial-chemistry, b) structure-based drug design and c) rapid biochemical methods including protein crystallography, binding methods such as surface plasmon resonance and isothermal calorimetry, coupled with advances in mathematical models to accurately decipher target-engagement subtleties. In response to this, the medicinal chemistry community "perfected" the area of combinatorial chemistry, which in of itself, was not the answer to all problems. It is noteworthy that this expectation of target-abundance appears to be thinning out for pharmaceutical research, as more companies are relying on cell-based phenotypic assays, using either disease-based cellular models or stem-cell derived systems. These dramatic shifts, as well as the need to emerge to the market with differentiated products, have both been rewarding and unsettling to the pharmaceutical research community.

In a similar fashion, this perspective brings back to the forefront the topic of natural products (NPs), and how "going back to the future" might just be an answer to some of the needs. Over the past 20 years, pharmaceutical research has mostly turned its back on NPs-based drugs.1 Several companies have closed their NP-departments and sold off or shelved their NP repositories. The primary reasons for such drastic measures could be a) a historical inability to reproduce readouts, once the NP is purified from mixture(s), b) difficulties in producing and


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scaling-up NPs in quantities sufficient for development or commercialization from natural sources (plants, sea or microbial origins), or c) difficulty in synthesis and synthetic transformations, to name but a few.2 In the meantime, the field of synthetic chemistry has made tremendous progress, by not only developing novel, selective and high yielding methods to make accessible many transformations that had traditionally been difficult, but also by giving chemists the confidence to tackle almost any synthetic target, if it offers both a valuable biological rationale and a challenge.

The restricted region of chemical space explored by products from combinatorial synthesis, compared to NPs and their derivatives, may explain why Nature has been a productive source of lead compounds for drug development.3,4 Despite the prevalence of combinatorially-derived compound-libraries in the pharmaceutical industry, half of all new chemical entities introduced as drugs (540 out of 1073) were either NPs, modified NPs or synthetic compounds with a NP pharmacophore, over a 30 year period from January 1981 to December 2010.4 When compared to compounds prepared by combinatorial approaches, NPs tend to a) have more stereogenic centers, b) have a larger fraction of sp3 carbons, c) be less hydrophobic d) have more oxygen atoms, e) fewer nitrogens, sulfurs and halogens, f) fewer rotatable bonds, g) more fused, bridge and spiro rings, and h) have more solvated hydrogen bond donors and acceptors.3 Some of these parameters, such as a), b), and c) are linked to cleaner off-target profiles or decreased promiscuity,5,6 perhaps leading to less toxic molecular profiles acknowledging that toxicity remains as one of the leading attrition cause in clinical development.7,8 In the late 90s, it was recognized that the poor bioavailability of leads coming from high throughput screening (HTS) campaigns and from molecules optimized on potency was an issue responsible for the late lead


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optimization attrition rate. Simple rules, such as the Lipinski rule of five9, based on calculated properties helped to rationalize and improve the profile of molecules added to sample repositories. For not yet understood reasons NPs tend not to comply with those rules and often display good oral bioavailability.10

The following article highlights, in a non-exhaustive fashion, several examples of approved drugs that required simple, but transformative modifications, providing a solution to an existing issue (pharmacokinetics, stability, potency or selectivity). The aim of this paper is to stimulate scientists to rediscover the value of NP chemistry to drug discovery, as there might be some valuable medicines we now can access more easily. The sections are divided into chemical classes such as macrolides, β-lactams, opioids, and taxanes.


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Macrolides: everolimus and temsirolimus Scheme 1. Synthesis of everolimus and temsirolimus from rapamycin. OH O

OH O O HO H

O

O

O O

a for everolimus b for temsirolimus

O O

RO

O

OH

H

O

1, sirolimus (rapamycin)

a

H

O O O O

N

O

N

O

O

O

OH

H

O

2, everolimus, R = CH2CH2OH 3, temsirolimus, R = C(O)C(CH2OH)2CH3

Reagents and conditions: (a) (1) TBSOCH2CH2OTf, 2,6-lutidine; (2) HCl in MeOH; (b) (1)

TMSCl, imidazole; (2) 0.5N H2SO4; (3) 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid, DIPEA, 2,4,6-Trichlorobenzoyl chloride, DMAP; (4) 2N H2SO4.

Rapamycin produced by Streptomyces hygroscopicus was isolated from a soil sample found on Easter Island.11 The macrolide was originally discovered as an antifungal agent, but discarded due to its toxic in vivo profile. Twenty years later, the discovery and elucidation of its potent immunosuppressive and antiproliferative properties changed the course of its development.12 Rapamycin exerts its biological effect by binding to the peptidyl-prolyl cis-trans isomerase FKBP12, and the resultant complex inhibits the kinase activity of the mammalian target of rapamycin (mTOR). The latter plays a role in cell growth and proliferation via the regulation of protein synthesis.12,13,14,15 The suboptimal physicochemical properties of rapamycin limited its clinical use and prompted the search for analogues, hence numerous rapalogues (rapamycin analogues) were prepared. Everolimus is a rapalogue with improved hydrophilicity and


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pharmacokinetics over the parent compound.16 Selective O-Alkylation of rapamycin (1) with 2((tert-butyldimethylsilyl)oxy)ethyl trifluoromethanesulfonate followed by O-silyl deprotection yielded 40-O-(2-hydroxyethyl)-rapamycin named everolimus (2) (Scheme 1).17 It is orally administered, once daily, and used as an immunosuppressant to prevent organ transplant rejection and for the treatment of some cancers.14,18 A similar derivatization of rapamycin with 2, 2-dihydroxymethylpropanoic acid yielded temsirolimus (3) (Scheme 1).14,19,20 It is an intravenous drug approved for the treatment of renal cell carcinoma.21 The rapalogues literature is vast; everolimus and temsirolimus demonstrate rational and simple modifications of the natural product rapamycin that yielded a successful drug. It is interesting to notice that the coordinates from the X-ray crystal structure point to only three substitution anchors compatible with the biologically active complex formed with rapamycin as shown in Figure 1. These orient the substituents into the solvent-exposed area, which should not affect the compound affinity, allowing the independent modulation of the physical properties of the drug through synthesis.

mTOR

R1

rapamycin

FRB


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Figure 1. The X-ray structure of rapamycin (cyan) complexing FKBP12 (blue ribbon) and the FKBP12-rapamycin binding (FRB) domain of mTOR (white solid surface). The substituents leading to everolimus (R1= CH2CH2OH) and temsirolimus (R2= P(O)Me2) are pointed towards the solvent exposed areas by branching off from the identified hydroxyl group. This maintains the binding affinity while the physicochemical properties of the macrolides can be modulated.

Cyclic nonribosomal peptides: alisporivir Scheme 2. Synthesis of alisporivir from cyclosporine A

O O HO

O O 4

N

3 N

HN

N O

NH N

O

H N

O

O a, b

O N

O

O HN

NH

N O

NH

O O

N

N H

O

AcO

N

O

N

N

O

O

H N

O N

N H

O

4, cyclosporin A

c, d, e

O O

N N

O

5

OH

O O NH O

O

N

N

H N

O

N

N

N

HN

NH

f, g

N O

O

O O

N H 6

a

O N

O

O

O

HN

NBoc

HO

O

AcO

N

N N

O

O

N

H N O

O

O N H

N

N

O

N

O

O 7, alisporivir

Reagents and conditions: (a) Ac2O, DMAP; (b) (1) Me3OBF4; (2) NaOMe; (3) H2SO4; (c) (1)

PhNCS, DMAP; (2) CF3CO2H; (d) Boc-D-MeAla-EtVal-OH, TFFH, DIEA; (e) NaBH4; (f) (1) MsOH; (2) NaOMe; (3) NaOH; (g) PyAOP, 2,4,6-collidine.


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Cyclosporin A was isolated in 1969 from the fungus Tolypocladium inflatum found in a soil sample from Norway.22,23 It is a potent immunosuppressive agent, used to prevent organ transplantation rejection, and to treat many autoimmune disorders. Years after intensive clinical use as an immunosuppressive, its potential as a hepatitis C treatment was observed, when chimpanzees chronically infected with HCV were treated with cyclosporin A.24 However it was already acknowledged that its immunosuppressive properties would be undesirable to treat a chronic viral infection. Hence the development of alisporivir, which blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the host cyclophilin A.22,23 By modifying cyclosporine A at residues 3 and 4 (see Scheme 2), located at the cyclophilin- and calcineurinbinding domains respectively, it was possible to drastically decrease its immunosuppressant activity with a beneficial effect on its antiviral potency.25,26,27 The semi-synthesis of alisporivir was initiated with the O-acetylation of the non-canonical alkenyl amino acid (Scheme 2). Opening of cyclosporine A (4) between NMeLeu at position 4 and sarcosine at position 3 to yield compound 5 enabled the replacement of NMeLeu residue by NEtVal-BocNMeAla. Reduction of the sarcosine methyl ester to the primary alcohol with NaBH4 yielded compound 6 and allowed the amide to ester exchange upon treatment with MsOH with concomitant NBoc deprotection. The resulting ester was saponified, resulting in the removal of the sarcosine residue. A final amide coupling between the two ends of the linear peptide afforded alisporivir (7).28 The clinical development of alisporivir was put on hold in 2012 but phase II trials resumed.

The cyclophilin, calcineurin and cyclosporine complex X-ray crystal structure (PDB access code 1M63)29, depicted in Figure 2, suggests that the two residue modifications are at the interface of the calcineurin and cyclophilin binding sites. The mechanism by which the complex


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affinity to calcineurin is dialed out is not clear. The methyl to ethyl modification causes a clash of the ethyl with the cyclophilin backbone and might trigger either an alisporivir or cyclophilin conformational change, either of which might be responsible for the reduced affinity toward calcineurin. From X-ray coordinates analysis, one can identify other substitution sites to achieve the same effect. With macrocycles however, the impact of a substituent on conformation is often key yet difficult to assess, although recent advances in molecular modeling tools make this possible.30–32

Trp352

cyclophilin

Phe356

cyclosporin

Figure 2. Cyclophilin (grey surface), cyclosporine (cyan), calcineurin A (orange), calcineurin B (blue). Showing the cyclosporine modifications which led to alisporivir (modifications in purple) (PDB access code 1M63).

Taxanes: docetaxel Scheme 3. Synthesis of docetaxel from 10-deacetylbaccatin III and structure of paclitaxel.


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a

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Reagents and conditions: (a) TrocCl, pyridine; (b) cinnamoyl chloride, AgCN; (c) (1)

mCPBA; (2) NaN3; (3) Zn dust in AcOH; (d) Boc2O, pyridine.

Paclitaxel (11) was discovered when several thousand plant extracts were screened for anticancer activity.33 It was isolated as the active component from the bark of the scarce yew Taxus brevifolia in exceptionally poor yields.34 As paclitaxel clinical studies required larger amounts of the natural product, it was recognized that supply of paclitaxel would have detrimental environmental implications. The search for more readily available analogues led to the discovery of docetaxel prepared from 10-deacetylbaccatin III, which can be obtained in a renewable fashion from leaves of the more abundant yew Taxus baccata.35,36 Also, as compared to paclitaxel, docetaxel has a better water solubility (0.1 mg/ml compare to 0.7 µg/ml). The first preparation of docetaxel involved a selective protection of the two most reactive hydroxyls of 10-deacetylbaccatin III (8) as trichloroethylcarbamates, followed by cinnamoylation of the least reactive allylic alcohol to yield compound 9 (Scheme 3).37 Epoxidation of the cinnamoyl unsaturation and opening with sodium azide, afforded two separable diastereomeric azido alcohols. Treatment with zinc dust in acetic acid resulted in a concomitant reduction of the azido group and removal of the trichloroethylcarbonates protecting groups. The amine was then treated with Boc2O to yield docetaxel (10).38 Docetaxel promotes and stabilizes microtubule assembly, leading to a decrease in free tubulin needed for microtubule formation and thereby inhibiting cell proliferation, by inducing a


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sustained mitotic block at the metaphase/anaphase boundary.39,33 Docetaxel is approved to be used alone or in combination with other drugs for the treatment of a variety of cancers including breast, gastric, prostate, non-small cell lung cancer, and squamous cell carcinoma of the head and neck.40,33

Polyketide macrolactone: ixabepilone Scheme 4. Synthesis of ixabepilone from epothilone B

a

Reagents and conditions: (a) Pd(PPh3)4, NaN3, 20 min, then PMe3, 1-2 h; (b) EDCl, HOBt, 4-

12 h.

The rise of paclitaxel-resistant tumors in patients triggered the search for new microtubule stabilizing agents for cancer therapy. Antifungal and cytotoxic activity of epothilones A and B were discovered in a screening campaign from extracts of the myxobacterium Sorangium cellulosum.41,42 Like the taxanes, they promote tumor cell death by stabilizing microtubules and inducing apoptosis.41 Epothilone B showed good antineoplastic activity against multiple tumor


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cell lines in vitro. However, reduced in vivo efficacy was observed due to its poor metabolic stability and pharmacokinetic properties.43,44,45 Since esterase-mediated lactone hydrolysis of epothilone B was a major obstacle for clinical utility, the lactone was replaced by a lactam. This one-atom modification provided a better metabolic stability profile to ixabepilone, which is less susceptible to esterase-mediated hydrolysis. Moreover, this one atom change enhanced water solubility, allowing for an improved formulation containing a smaller amount of the undesirable solubilizing agent cremophor.43,44,45 As shown in Figure 3, a crystal structure of epothilone A bound to tubulin46 suggests that the amide nitrogen of ixabepilone can stabilize the bioactive conformer through an intramolecular H-bond (proton added for clarity). This explains why this transformation does not negatively impact the affinity of ixabepilone toward tubulin. Epothilones have been the subject of ample synthetic efforts and ixabepilone is a noteworthy one-atom modification that yielded a successful drug. Opening of the allylic lactone of epothilone B (12) with Pd(Ph3)4 formed the π-allylpalladium complex (13) which was trapped by the azide anion to yield the allylic azide that was reduced with PMe3 to yield the amine 14 (Scheme 4). Lactam formation yielded ixabepilone (15) from epothilone B in a single reaction vessel, without isolation of intermediates.47 Furthermore, this remarkable process, including purification, could be accomplished in one day to afford ixabepilone in 20% overall yield. Ixabepilone is used for the treatment of various chemotherapy resistant cancers.48


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Figure 3. Epothilone A bound to α,β tubulin (PDB access code 1TVK) with the lactone modified to a lactam, which reflects the suggested ixabepilone binding mode. The amide nitrogen could form an intramolecular H-bond with the epoxide oxygen. This single atom modification is therefore compatible with the binding mode of the macrocycles and does not affect the proteinligand interactions while increasing the overall polarity of the drug by a drop in calculated logP of 0.6 units. Proton added for clarity.


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β-lactams: ceftriaxone Scheme 5. Synthesis of ceftriaxone from cephalosporin C. OH

O O O H2N

O

N N H

H

OH

N

S

N

H2N

OH

N H2N a

H

S S

N

H

N

OH

N

O

18 b

S

17

Cl

O

O

H N O

O

HS

O

N

16, Cephalosporin C

O

N

O

O

a

HO O

OH

O

O

N S

Cl N O

20

O

H2N

OH

N

N

OH

N

O

O N

O

N S

c 19

N

N H O

H

S S

21, ceftriaxone

Reagents and conditions: (a) enzymatic hydrolysis; (b) (1) BF3,18; (2) NaOH; (c) (1) NaOH,

20; (2) H2SO4. Ceftriaxone is a widely used third generation cephalosporin antibiotic with broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria.49,50,51,52 Much like other β-lactam antibiotics, it binds to the penicillin-binding proteins (PBPs) and inhibits the transpeptidation step in peptidoglycan synthesis, which is required for bacterial cell wall biosynthesis.53,54 Ceftriaxone bears methoxyiminoaminothiazolyl and triazinylthiol moieties that contribute to its better resistance profile to β-lactamases and to its longer half-life, allowing once daily dosing.50,55 Cephalosporin C (16) isolated from Cephalosporium acremonium can be enzymatically hydrolyzed to 7-aminocephalosporanic acid (17).56,57,58 Treatment of the latter with boron trifluoride and the triazinylthiol 18 yielded compound 19 that was N-acylated with acyl chloride 20 to afford ceftriaxone (21) upon N-deprotection of the aminothioazole (Scheme 5).59,60 The modifications around cephalosporin’s core allowed the modulation of the physical


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properties, potency and ADME profile.61 The X-ray crystal structure of the PBP complexed to ceftriaxone62 shows how the triazinylthiol moiety can form two H-bonds with Gln411 (c.f. Figure 4). The amino thiazole moiety lies flat over a hydrophobic region of PBP. This extra polarity and the tridimensional shape may be responsible for the superior resistance profile of ceftriaxone.

Asn283

R1

R2 Gln411

Figure 4. Ceftriaxone bound to PBP (PDB access code 3UPP). The R1 and R2 substitutions optimized from cephalosporin are in close contact with the active site residues but fill solvent accessible areas, which allow a wide variety of chemical modifications consistent with the productive binding mode of this class of antibiotics. The R1 substituent was modeled in due to poor observable density. To be noted: the ceftriaxone R1 tautomer, most adapted to form Hbonds with PBP, is shown here. The protons were added for clarity. Opioids: naloxone, oxycodone and buprenorphine Scheme 6. Synthesis of multiple opioids from morphine.


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HO

HO N

H O

O

O

O

N OH

25, oxymorphone

e, f

N OH

O 24, oxycodone O

O

HO

a

H

O 23, codeine

HO 22, morphine

d

H

b, c

O

H

H

O N

H a

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NH

H

g

O

OAc

H O

N OH

HO

AcO 26

27, naloxone

Reagents and conditions: (a) Me3N+PhCl-, MeOH, KOH; (b) K2Cr2O7, AcOH; (c) H2, Pd; (d)

HBr; (e) Ac2O; (f) (1) BrCN; (2) HCl; (g) NaHCO3, allyl bromide. Scheme 7. Synthesis of buprenorphine from thebaine.

a

Reagents and conditions: (a) Methyl vinyl ketone; (b) H2, Pd/C; (c) tert-BuMgCl; (d) (1)

BrCN; (2) KOH; (e) (1) cyclopropylcarbonyl chloride, Et3N; (2) LiAlH4; (f) KOH.


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The opioid alkaloids are amongst the oldest drugs known to humanity. The active ingredient in opium was isolated in 1806 and named morphine after the God of dreams Morpheus.63 Its poor oral bioavailability, potential for addiction, tolerance, and respiratory depression triggered one of the first medicinal chemistry endeavors.64 Several semi-synthetic opioids were prepared without information on their biological targets that were later found to be various subtypes of G proteincoupled receptors.64 Oxycodone, an agonist of the µ-receptor such as morphine, is one of the successful semi-synthetic opioids being used in clinical practice since 1917.65 The active metabolite oxymorphone, which is formed from oxycodone in the liver, has a more potent analgesic effect than morphine itself. Today oxycodone is used as controlled-release or immediate-release tablets for pain management.65 Phenolic O-methylation of morphine (22) afforded codeine (23) which was oxidized and hydrogenated to yield oxycodone (24) (Scheme 6).66 Buprenorphine was discovered after several decades of research to identify opioids with adequate analgesic properties with potential for lower addiction and respiratory depression.67,68 Its µ-agonistic and κ-antagonistic receptor-binding profiles combined with its lipophilicity are thought to play a central role on its valuable pharmacology.69 Buprenorphine is prepared from thebaine (28), another natural opioid. Cycloaddition of methyl vinyl ketone with the alkaloid followed by hydrogentation of the resulting adduct yielded compound 29. Grignard addition on the methyl ketone afforded compound 30, which was N-demethylated with cyanogen bromide to yield compound 31 (Scheme 7). N-acylation with cyclopropanecarbonyl chloride followed by amide reduction with lithium aluminum hydride yielded compound 32 and phenolic Odemethylation afforded buprenorphine (33).70,71 Buprenorphine can be combined with the opioid antagonist naloxone to deter the abuse of tablets by intravenous injection.72 Naloxone is a


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competitive antagonist of most opioid receptors which is used to counter the effects of opioid overdose.73 Phenolic O-demethylation of oxycodone (24) yielded oxymorphone (compound 25), which was O-acetylated and N-demethylated to yield compound 26 (Scheme 7). The latter was deacetylated and N-allylated to afford naloxone (27).74 Recently, the µ-opioid receptor was co-crystallized with an irreversible morphinan antagonist,75 which paves the way for structural rationalization of activity and selectivity for future drug development.76

Steroids: finasteride and dutasteride Scheme 8. Synthesis of finasteride and dutasteride from progesterone.

a

Reagents and conditions: (a) KMnO4, NaIO4; (b) NH3; (c) H2, Pt, AcOH; (d) DCC, HOBT,

H2NCMe3; (e) (C6H5SeO)2O.

As part of investigations into birth defects, it was discovered that 24 cases of male pseudohermaphrodites from 13 families were localized in a village in the Dominican Republic.77


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These males were found to have a genetic mutation causing deficiencies of the 5α-reductase enzyme and androgen hormone dihydrotestosterone.78 Male pseudohermaphrodites having this mutation were born with external genitalia ambiguity and were initially raised as girls, but then had a marked virilization at puberty including the development of external male genitalia. Interestingly, it was observed that prostate growth and incidence of male pattern baldness do not occur in these individuals.77,78 These observations led to the creation of a drug targeting the 5αreductase enzyme, to treat older men suffering from benign prostatic hyperplasia. Finasteride was synthesized from progesterone, a natural progestogen found in mammals but also in some plants.79,80 The methyl ketone and the cyclic enone of progesterone (34) were oxidized to the corresponding bis-acid 35 (Scheme 8). Treatment with ammonia followed by a reductive condition afforded the lactam 36. After tert-butyl amide formation, treatment with benzeneselenic anhydride introduced the A-ring unsaturation in finasteride (37).81,82 It is approved for the treatment of benign prostatic hyperplasia and male pattern baldness. While finasteride displays a much shorter half-life of 6-8 hours and inhibits only one isoform of the 5αreductase, dutasteride (38) (T1/2 = 5 weeks) inhibits two of the three isoforms and is only approved for treatment of benign prostatic hyperplasia.83,84

Lipopeptides: caspofungin Scheme 9. Synthesis of caspofungin from pneumocandin B0.


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a

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Reagents and conditions: (a) PhB(OH)2, PhSH, TfOH; (b) PhB(OH)2, BSTFA, BH3; (c)

H2NCH2CH2NH2.

The pneumocandins belong to the echinocandins, a family of N-fatty acylated macrocyclic hexapeptides. Following the isolation of multiple echinocandins since 1974, the isolation of pneumocandin B0 from Glarea lozoyensis, previously identified as Zalerion arboricola, was reported in 1992.85,86 The anti-fungal properties of echinocandins arise from the inhibition of the β-(1,3)-D-glucan synthase involved in the biosynthesis of β-(1,3)-D-glucan, an essential cell wall component of many fungi.87,88,89 Fermentation development for the production of pneumocandin B0 was crucial for the supply of the natural product in sufficient quantity and purity.90 The original fermentation produced a mixture pneumocandins (A0, B0 and C0) in few mg per liter, with A0 as the dominant product. Pneumocandin A0 and C0 were almost absent in the optimized fermentation that yielded pneumocandin B0 in the range of a gram per liter. Addition of cationic chains to pneumocandin B0 was found to be beneficial91 and opened the way to the discovery of caspofungin which was prepared in three steps from pneumocandin B0.92 Conversion of the cyclic boronate generated in situ from pneumocandin B0 (39) allowed the clean transformation to its phenylthioaminal derivative 40 (Scheme 9). A chemoselective borane reduction of the sole primary amide and substitution of the phenylthioaminal by ethylenediamine yielded caspofungin


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(41) in 45% overall yield. This pneumocandin derivative was selected for clinical development mainly because of its potent and broad spectrum antifungal activities but also due to its superior stability, water solubility and pharmacokinetic profile compared to the parent compound.90 caspofungin is now used as an anti-fungal for a variety of infections.89

Aminoglycosides: amikacin

Figure 4. Structure of ribostamycin and butirosin. Scheme 10. Synthesis of amikacin from kanamycin A. O OH H2N HO

H2N

H2N NH2 O

O O OH

HO

O HO

44, kanamycin A

a

NH2 a, b, c

OH OH

O CbzHN

O O

OH

45

NH

H2N

OH OH O

HO

O

N

HO

NH2 O O

OH

O

HO

NH2 OH OH

46, amikacin

Reagents and conditions: (a) CbzOSu; (b) 45; (c) H2, Pd/C.

Aminoglycoside antibiotics interfere with the vital process of protein biosynthesis by binding to the A-site of the prokaryotic ribosome. X-ray structures of the 30S subunit of the ribosome


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with and without aminoglycosides bound to the A-site shed some light on how these antibiotics increase the error rate during protein translation.93,94 Two similar aminoglycoside antibiotics, ribostamycin (42) and butirosin (43) were isolated in 1969 from Bacillus circulans and Streptomyces ribosidificus, respectively (Figure 4).95,96 The comparison between the two revealed that the (2S)-4-amino-2-hydroxybutanoyl group at the N1 position enhanced the antibiotic properties. Such observations stimulated the N1-acylation of kanamycin A, which was isolated from Streptomyces kanamyceticus.97 The resulting semi-synthetic amikacin was obtained in three steps as an improved antimicrobial agent.98 Protection of the primary amine in kanamycin A (44) upon treatment with benzyloxycarbonyl N-hydroxysuccinimide (45) enabled the selective acylation of N1, which yielded amikacin (46) after hydrogenolysis of the protecting groups (Scheme 10). Structural biology efforts suggest that the N1 position is compatible with the binding to the bacterial ribosome as shown in Figure 5. Similarly, arbekacin was prepared from kanamycin B which was also isolated from Streptomyces kanamyceticus.97,99 The 3'4'dideoxygenation of kanamycin B (47) towards arbekacin (48) is another example of successful natural product modification inspired from nature.100 Indeed, the 3'4'-dideoxygenated motif was originally found in the gentamicins such as gentamicin C1a (49) isolated from Micromonospora purpurea (Figure 6).101 These antibiotics have been widely used to treat bacterial infections over the last decades, but the emergence of resistant bacterial strains expressing various aminoglycoside deactivating enzymes is becoming a major limitation for the use of these powerful antibiotics.102 The differences in some of the aminoglycosides’ resistance profile are clarified by recently available X-ray crystal structures. For example, the superior resistance profile of amikacin over kanamycin can be related to the extra three-dimensional constraints brought by the l-HABA group that


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affects the binding on known modifying enzymes.102,103 Examples are shown in Figure 7 where amikacin could not fit into the kanamycin binding pocket of APH(3'), a bacterial phosphotransferase, and ANT(4'), an adenylyltransferase.104,105 Although this rationale was not directly used in the development process of aminoglycosides, this shows how new advances in structural biology can better guide the sites of chemical optimization on antibiotics and defeat bacterial resistance.106

Solvent exposed

Figure 5. Kanamycin A crystal structure (cyan, PDB access code 2ESI) overlayed on amikacin (yellow, PDB access code 2G5Q). The binding modes of the antiobiotics are the same, except that the l-HABA side chain of amikacin forms an extra H-bond extend into an area that is largely solvent exposed. Protons were added for clarity.


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Figure 6. Structure of kanamycin B and arbekacin.

a

b

Figure 7. Kanamycin A bound to kanamycin nucleotidyltransferase (PDB access code 1KNY) (a) kanamycin bound to APH(3') (PDB access code 1L8T) (b) The addition of l-HABA on the circled nitrogen of kanamycin A, a substrate of these enzymes, cannot fit in these enzymes’ binding pocket which may explain the better selectivity profile of amikacin.

Sesquiterpene lactone: artemisinin Scheme 11. Synthesis of artemether from artemisinin.


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a

Reagents and conditions: (a) NaBH4; (b) Amberlyst-15, MeOH.

The discovery of artemisinin’s antimalarial property occurred during a Chinese nationwide program, established in 1967, to search for new antimalarial drugs.107,108,109 Extracts from Artemisia annua (qinghao from chinese) inhibited malaria parasite growth and artemisinin was found to be the active ingredient. Extracts from A. annua had been known to treat hemorrhoids and fever for roughly two millennia.107 The peroxide motif of the sesquiterpene lactone is required for its antimalarial activity, although there is no consensus regarding the mechanism by which artemisinin affects the malaria parasites.110,111 The reduction of artemisinin (50) with NaBH4 in MeOH followed by the addition of a sulfonic acid-based resin afforded artemether (51) which possesses superior solubility and potency profiles than the parent compound (Scheme 11).112 The improved solubility of artemether, allowing intravenous and intramuscular injection, is important because oral administration for patients with severe malaria is often impossible.107

Glucocorticoid: prednisolone Scheme 12. Synthesis of prednisolone from hydrocortisone.


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a

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Reagents and conditions: (a) Corynebacterium simplex ATCC 5946.

It was shown in the early 1950s that systemic administration of cortisone was effective to treat various dermatoses, whereas hydrocortisone was also effective topically.113,114 Because topical administration was more desirable, it was deemed necessary to devise an effective synthesis of hydrocortisone, an important human glucocorticoid.115 During the synthesis of hydrocortisone, the required hydrolysis of the 11β-acetate was problematic, hence a microbial mediated hydrolysis

was

attempted.116

Treatment

of

hydrocortisone

11,21-di-O-acetate

with

Corinebacteria simplex yielded prednisolone diacetate via a dehydrogenation instead of the expected deacetylation.117,118 The same dehydrogenation approach was used successfully to transform hydrocortisone (52) to prednisolone (53) (Scheme 12), which had been previously isolated from the suprarenal cortex.119,120,121 Prednisolone was found to have enhanced glucocorticoid activity (three to five times that of cortisone), while reduced mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions.122,123 Glucocorticoids are believed to mediate their effects by binding to the cytosolic glucocorticoid receptor, which is activated upon ligand binding. The activated complex can upregulate the expression of anti-inflammatory proteins by transactivation, and repress the expression of pro-inflammatory proteins by transrepression.124,125


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Glucocorticoid: mifepristone Scheme 13. Synthesis of mifepristone from estradiol. OH H H

11

a,b

H

H

H

HO

H

N

HO h, i

HO 11

j, k

H

O

58

17

H

H

O

H

56

55

H

57

H

H O

O

O

H

c, d

O

54, estradiol

e, f, g

O

OH

H O 59, mifepristone

a

Reagents and conditions: (a) Me2SO4, NaOH; (b) Na, NH3, THF, tBuOH; (c) (CO2H)2; (d)

CrO3; (e) Aspergillus ochraceus NRRL-405; (f) POCl3, pyridine; (g) HCl, MeOH; (h) (CH2OH)2, PTSA; (i) MeCCMgCl; (j) H2O2; (k) (1) pMe2NPhMgBr; (2) HCl.

The steroid hormone progesterone was found to play an important role in the establishment and maintenance of pregnancy in 1930.126 Discovery of the uterine progesterone receptor, followed by development of screening methods through competitive binding with radiolabeled progesterone, enabled the identification of high affinity compounds.127,128 These developments, combined with novel access to 11β-substituted steroids, allowed the preparation and identification of compounds with antagonist activities.129,130 A progesterone receptor antagonist having a 11β-p-dimethylaminophenyl substituent and lacking the C19 methyl group found in several natural glucocorticoids was named mifepristone.131 The 17α-propynyl group found in mifepristone was known to improve selectivity of other steroid hormones and may explain the low affinity of mifepristone for the mineralocorticoid receptor despite high affinities for both the


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progesterone and glucocorticoid receptors.132 Mifepristone can be prepared from estradiol in several steps including chemical and biochemical transformations. The phenol of estradiol (54) was methylated and the resulting ether was treated under Birch reduction conditions to yield compound 55. Treatment with a mild acid afforded the desired keto alcohol that was oxidized to the diketone 56 (Scheme 13).133,134 Enzymatic oxidation of C11, followed by dehydration yielded the conjugated dienone 57.135 Protection of the enone carbonyl under acidic conditions resulted in concomitant double bond migration.136 Grignard addition at the C17 carbonyl afforded the 17α-propynyl diastereoisomer 58. Epoxidation of the tetrasubstituted alkene followed by epoxide opening with 4-dimethylaminophenylmagnesium bromide yielded mifepristone (59) after treatment with HCl.137 Mifepristone is mainly used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive.138 Once again, the information obtained from structural biology rationalizes how the two key substitutions make mifepristone more selective. From Figure 8, the progesterone (pink, PDB access code 1A28)139 binding site shows an unoccupied pocket that is further opened by the movement of the flexible Met909 side chain when mifepristone binds to the progesterone140. The propynyl can fit in a pocket created by a conformational change of the Phe794 side chain. This explains why mifepristone, despite its large substituents, still fits in the PR binding site. To the contrary, the mineralocorticoid receptor does not offer space to the mifepristone propynyl as shown by the crystal structure of progesterone bound to the mineralocorticoid receptor141 in Figure 8 when compared to the progesterone receptor-mifepristone complex140. Indeed, the Met845 side chain does not have the possibility to move downward due to the presence of Ser843 (not shown). Furthermore, the Leu960 side chain is not as flexible as the corresponding Met909 and the pocket cannot easily


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accommodate the dimethylated aniline moiety from mifepristone. These small differences are sufficient to explain the improved selectivity profile of mifepristone. b)

a)

Figure 8. (a) Progesterone (pink, PDB access code 1A28)139 binding site shows an unoccupied pocket that is further open by the movement of the flexible Met909 side chain when mifepristone binds to the progesterone receptor (or PR) (cyan, PDB access code 2W8Y)140. The propynyl can fit in a pocket created by a conformational change of the Phe794 side chain. This explains why mifepristone, in spite of its large substituents, still fits in the PR binding site. To the contrary, the mineralocorticoid receptor (MR) (b) does not have room for the mifepristone propynyl as shown by the crystal structure of progesterone bound to the MR (pink, PDB access code 2AA5)141 when compared to the PR:mifepristone crystal structure (cyan PDB access code 2W8Y140).

Statin: orlistat and simvastatin Scheme 14. Synthesis of orlistat from lipstatin.


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a

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Reagents and conditions: (a) H2, Pd/C.

Lipstatin was isolated from Streptomyces toxytricini following a screen of microbial broths from soil organisms completed to identify inhibitors of pancreatic lipase, a key enzyme for dietary triglyceride absorption.142,143,144 Hydrogenation of lipstatin (60) yielded orlistat (61) (Scheme 14) that is more stable upon long term storage.145 It irreversibly binds to a serine of the pancreatic lipase and is approved to treat obesity.146,147

Scheme 15. Synthesis of simvastatin from lovastatin.

a

Reagents and conditions: (a) LiOH; (b) TBDMSCl, imidazole; (c) 2,2-dimethylbutanoyl

chloride, 4-DMAP, pyridine; (d) TBAF


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In the early 1970s, thousands of microbial strains were tested for their ability to produce compounds that would interfere with lipid synthesis because it was hoped that certain bacteria would produce such compounds as a weapon to fight other microbes that required sterols or other isoprenoids for growth.148 Following the observation that the antibiotic citrinin, isolated from the fungus Pythium ultimum, was able to inhibit cholesterol synthesis,149 the continuous search for such natural products from micro-organisms led to isolation of mevastatin (62) from Penicillium citrinum and lovastatin (63) from Aspergillus terreus.150,151,152 These statins act by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase (hHMG-CoA), an important enzyme involved in the rate-limiting step in cholesterol biosynthesis.153,154 Mevastatin, lovastatin and simvastatin are reversible prodrugs less active as lactones, but potent inhibitors of the hHMG-CoA in their open acid form. Studies performed in rats and dogs showed a selective concentration of the acid in the liver – the major organ involved in the homeostasis of cholesterol.155 The synthesis of side chain ester derivatives of lovastatin led to the identification of the more potent gem-dimethyl moiety found in simvastatin.152,156 Hydrolysis of lovastatin lactone produced the much more potent mevinolinic acid and triggered efforts to understand the structure activity relationship of lovastatin.152 Lovastatin (63) (S)-2-methylbutanoate side chain was saponified with LiOH and the δ-valerolactone hydroxyl was protected as a silyl ether (compound 64) (Scheme 15). Acylation of the remaining hydroxyl and silyl ether deprotection yielded simvastatin (65) that is more potent than the parent lovastatin.156 Simvastatin is approved for use to control elevated cholesterol, or hypercholesterolemia.157 Examination of the X-ray crystallographically determined binding mode of simvastatin (c.f. Figure 9), the rigidity of the core and its three-dimensional substitution pattern nicely fills the binding pocket. The H-bond


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complementarity between the dihydroxy pentanoic acid that sits in the pocket of the natural substrate mevalonic acid, and catalytic polar side chain is remarkable. The gem-dimethyl moiety of simvastatin better fills a hydrophobic pocket, which explains its greater potency versus lovastatin. The lead optimization of these first natural product-based drugs preceded the publication of the corresponding crystal structures. More recently, 25 years after the discovery of the first statins, more potent hHMG-CoA reductase inhibitors with better hepatoselectivity were designed from structural and thermodynamic data. These newer inhibitors should be less prone to statin-induced myalgia.158 A close examination of the crystal structures show that the statin core could be further substituted to reach out an additional pocket as shown in Figure 9.


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a)

b)

Figure 9. (a) Simvastatin (cyan) bound to hHMG-CoA receptor (pink) in its open active form from a crystallographic X-ray structure (PDB access code 1HW9).153 The dihydroxy pentanoic acid motif is a key pharmacophore and forms hydrogen bonds with seven different polar side chains of the receptor. The potency enhancing gem dimethyl of simvastatin (over lovastatin) better fills the hydrophobic pocket. (b) The X-ray crystal structure of simvastatin (cyan and solid molecular surface) is superimposed to a newer imidazole core based inhibitor158 (pink and mesh molecular surface, PDB access code 3CCW) to highlight the shape-conserved active site and the difference in the connectivity from the core. The pink molecule adds an amide H-bond to the protein and a benzyl group responsible for additional hydrophobic interactions with the protein.


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Conclusion This perspective article highlights the extraordinary successes that targeted chemical modifications of NPs have had in drug discovery. Multiple scaffold classes of NPs (macrolides, opioids, steroids, and β-lactams) used to treat conditions such as cancers, infections, inflammation or used as immunosuppressant were examined. As expected from NP-derived drugs, the success stories discussed here showcase compounds with generally high sp3 carbon fraction, a high number of stereogenic centers and in cases such as artemether, amikacin, caspofungin, docetaxel, ceftriaxone and everolimus, a high density of hydrogen bond donors and acceptors, relative to purely synthetic drugs. Among the examined chemical classes, an improvement in biological target selectivity was essential for the successful development of the opioid buprenorphine, the steroids dutasteride, prednisolone and mifepristone, and the cyclic non-ribosomal peptide alisporivir. The remarkable rigidity and three-dimensional branching of some NPs are partly responsible for their specificity. Improvement in NPs physicochemical properties and pharmacokinetic profiles were also important features in other examples such as everolimus, ixabepilone, ceftriaxone, oxycodone, docetaxel, caspofungin, artemether, and orlistat. The success stories discussed here indicate that optimization of pharmacokinetics, stability, potency and/or selectivity of NPs by targeted chemical modifications enables the development of NP-based drugs.

This article also reports published structural biology data that allowed the rationalization of some key features for the development of NPs into drugs. In some cases where the parent NP had good affinity for its biological target but displayed other poor properties (ADME or solubility), the modifications resulted in either extending the ligand into a solvent exposed region of the


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bound complex or replacing a chemical group without disturbing the overall binding mode of the ligand. It appears that the development of most drugs discussed here did not rely on crystallographic data, mainly because the protein-ligand X-ray coordinates were not available at the time. However, new developments in this field are expanding the realm of possibilities. Advances in crystallization techniques, X-ray sources, and computational tools allow crystallography to have a timely impact in drug discovery projects.159,160 Nowadays, around 10,000 new crystal structures are deposited to the protein data bank (PDB) every year, indicating the growing interest in this field. The PDB has just reached a total of 100 K structures. Furthermore, the complexity of the new crystallized protein complexes is increasing.161 The progress in crystallography coupled to modern synthetic transformations and techniques suggest that the development of NP-based leads into drugs should now be easier.

The fields of medicinal and synthetic chemistry as well as chemical biology have also evolved considerably in the past decades to better position drug discovery teams to undertake NPs and their derivatives as leads. Significant advancements have been realized in the understanding of the factors controlling pharmacokinetics, metabolic stability and chemical physical properties. Nature has provided us with an impressive array of structurally diverse scaffolds. As chemists we have the opportunity to capitalize on this diversity by transforming molecules found in nature into viable drug candidates for the treatment of human diseases. We hope that the beneficial NP synthetic modifications outlined here will inspire medicinal chemists to revisit existing or pursue novel classes of NPs and their derivatives as valuable leads.

Corresponding Author


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*E-mail: [email protected]. Phone: 450-978-7873. Biographies

Janek Szychowski obtained is Ph.D. in 2008 from Université de Montréal working with Prof. Stephen Hanessian in the field of the medicinal chemistry of aminoglycoside antibiotics. He was a Postdoctoral Fellow at the California Institute of Technology in the group of Prof. David A. Tirrell working on a methodology that utilizes artificial amino acids for the selective isolation, identification and labeling of newly synthesized proteins in cells. He has been at Vertex Pharmaceuticals since 2012 as a research scientist working on projects related to inflammatory bowel diseases.

Jean-François Truchon is a senior scientist at Vertex Pharmaceuticals and adjunct professor in the chemistry department at Université de Montréal. He completed a Ph.D. in theoretical chemistry at Université de Montréal under the supervision of Benoît Roux (University of Chicago), Christopher Bayly (Merck Frosst Canada) and Radu Iftimie (Université de Montréal). He joined Merck Frosst as a molecular modeler in 2002 where he contributed to projects related to osteoporosis, pain, HIV and COPD. He moved to Chemical Computing Group in 2010 as a research scientist where he added the Solvent Analysis tool to the MOE platform. He joined Vertex in 2013 as a molecular modeler focusing on inflammatory bowel disease projects.

Youssef L. Bennani is currently Site-Head and Vice-President, R&D at Vertex Pharmaceuticals (Canada) Inc. He previously served as Vice-President of Drug Innovation (Integrated Discovery Chemistry and DMPK) at Vertex Pharmaceuticals in Cambridge, MA,


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USA. Over the years, he successfully led multiple research programs in neurology, metabolism, immunology, infection and oncology, delivering several new molecular entities, currently at various stages of pre-clinical, clinical development and market stages. His education consists of a Doctorate degree (PhD) in chemistry from Université de Montréal, under the direction of Dr. S. Hanessian, and post-doctoral studies at The Scripps Research Institute under Dr. K. B. Sharpless), in La Jolla; as well as an E-MBA from LFGSM, in Chicago, Illinois.

Acknowledgments We thank our colleagues Luc Farmer, Bingcan Liu, Georgia McGaughey, Oswy Pereira, Louis Plamondon, Carl Poisson, Yeeman Ramtohul, T. Jagadeeswar Reddy, Claudio Sturino, Frédéric Vallée, and Constantin Yannopoulos for their constructive comments on the manuscript. References

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(2)

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Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Small Molecules of Different Origins Have Distinct Distributions of Structural Complexity That Correlate with Protein-Binding Profiles. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 18787–18792.

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Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; Decrescenzo, G. A.; Devraj, R. V; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Greene, N.; Huang, E.; KriegerBurke, T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Physiochemical Drug Properties Associated with in Vivo Toxicological Outcomes. Bioorg. Med. Chem. Lett. 2008, 18, 4872–4875.

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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 Deliv. Rev. 1997, 23, 3–25.


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