natural product scaffolds as leads to drugs...natural product scaffolds as leads to drugs |...

1415ISSN 1756-8919Future Med. Chem. (2009) 1(8), 1415–142710.4155/FMC.09.113 © 2009 Future Science Ltd

Mini-Review

The number of natural product scaffolds (i.e., the base structure from the natural prod-uct that is utilized or modified by direct substi-tution and/or by use of isosteric modifications) that have led to, or are being investigated as, ‘leads to drugs’ in a large number of pharmaco-logic areas are manifold. The ‘base molecules’ have nominally been isolated from all domains of life [1]. In a number of recent cases, however, the actual producer of the compounds may well not be the organism from which they were iso-lated and identified. In this mini-review, we will simply note whether such a possibility exists and provide recent references to articles in the cur-rent literature, since the emphasis is upon the structure and not the source.

Generally, this article is divided by pharma-cological area, rather than by source, as, in this manner, we can demonstrate how a particular aspect of the structure was further developed. To ensure the brevity of this discussion, we will use suitable references to demonstrate a point rather than an exhaustive discussion of the structures/modifications themselves.

First, we will start by introducing the concept of ‘privileged structures and base scaffolds’, as an appreciation of such concepts will help to understand the point(s) that we are making with respect to the ‘value of natural product struc-tures’ (Appendix 1).

Use of privileged structures with multiple activitiesAll secondary metabolites, irrespective of nomi-nal or actual source, are ‘privileged structures’, a term first defined by Evans et al. when discuss-ing the biological activities of synthetic benzo-diazepines as cholecystokinin antagonists [2]. A seven-membered di-aza ring was reported before the turn of the 20th Century as a potential

dyestuff under the name ‘benzheptodiazine’ (or 4,5-benzo-[hept-1,2,6-oxdiazine] in the German literature). Sternbach remembered this work from his earlier years as a synthetic chemist in Poland before the Second World War and, although he subsequently corrected the structure to a quin-azoline 3-oxide (not a seven-membered ring sys-tem), the previous structure formed the basis for his work leading to Librium® and Valium® [3–5], building upon the simple syntheses of the ben-zodiazepines from O-phenylene diamine and benzaldehyde reported in 1934 [6]. Subsequently, close to 40 years after the first correct report of this structural class, natural product-derived molecules containing this structural feature, the tomaymycins, were identified in 1971 [7].

Since Evans’ introduction of the concept, major synthetic chemistry groups have shown the potential of such natural product-derived scaffolds and we will mention just two exam-ples: Nicolaou starting with plant-derived skel-etons, the benzofurans; and Waldmann with the marine-derived metabolite dysidiolide. Both these groups demonstrated how these relatively simple molecules, by clever use of focused com-binatorial libraries coupled to novel biochemi-cal screens and modification of the bioactive principle(s), led to structures with biological activities that would never have been dreamed of as being possible from prior knowledge of the base compound’s scaffold. Fuller details, including a discussion of Waldmann’s Biology Oriented Synthesis (BIOS) system, are given in the recent review by Cragg et al. [8].

In addition, extension of the concept into a related ‘dimension’, for instance, that of the role of the biosynthetic mechanisms involved in production of the secondary metabolites, has been discussed in detail by Quinn’s group in Australia, using the ‘protein-fold topology’

Natural product scaffolds as leads to drugs

Numerous ‘scaffolds’ that have been identified in natural product structures have led to very significant numbers of approved drugs and drug candidates for a multiplicity of diseases over the years. In this mini-review, we discuss the base scaffolds (chemical skeletons) that we feel have produced very significant numbers of agents as drugs or drug leads and, in a number of cases, compounds that can be used as chemical synthons or that present activities in biological areas that were not obvious from their earlier history.

David J Newman† & Gordon M Cragg†Author for correspondenceNatural Products Branch, Developmental Therapeutics Program, NCI-Frederick, Frederick, MD 21702, USATel.: +1 301 846 5387Fax: +1 301 846 6178E-mail: [email protected]

pRivileged stRuctuRe

Structure with intrinsic biological activity

For reprint orders, please contact [email protected]

Mini-Review | Newman & Cragg

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(PFT) method as the basis for assessment. In addition to the discussion of BIOS referred to previously, a further description of the comple-mentarity of these concepts was given recently by Newman, which should be consulted for the similarities and differences between these two concepts [9].

In the subsequent discussion, we will identify the base scaffold(s) involved and then briefly dis-cuss how they were/are used from a historical and current perspective. This mini-review can be thought of more as ‘a meta ana lysis’ designed to demonstrate the potential of the molecules rather than a discussion of primary literature.

Over the last decade in particular, the advent of rapid DNA- and RNA-sequence determi-nations and the greater understanding of the control of gene expression, coupled to the rec-ognition of what have become to be known as ‘cryptic clusters’ (gene clusters that may well be coding for novel secondary metabolites but whose expression systems have not yet been identified) as recently reviewed by Scherlach and Hertweck [10], and the explosion of knowledge about the intricacies of a major biosynthetic pro-cess (the polyketide synthases [PKS]), also very recently reviewed by Hertweck [11], mean that not only chemical manipulation of a scaffold, but the utilization of biosynthetic processes in such modifications, will become regular pro-cesses for deriving novel structures based upon privileged scaffolds.

Anti-infectives�� Antibacterials: b-lactams

One may argue, and we will, that the most important natural product structure as a lead to a complete drug class, when expressed as ‘numbers of lives saved’, is the relatively simple b-lactam, exemplified by penicillin G (1), and its many variations. Some of these later molecules are based on the natural product, including the penicillins and cephalosporins, as exemplified by cephalosporin C (2) [12], and the monobactams, such as nocardicin (3) [13]. Others are modifica-tions based upon a single- or fused-ring struc-ture containing the b-lactam, such as the pen-ems based on thienamycin (4), totally synthetic variations on cephems, such as moxalactam where oxygen was substituted for the sulfur (5), or even variations outside of the anti-infective arena, such as ezetimibe (6) [14], or synthons with the Holton semisynthesis of taxanes [15]. Even now, effectively 80 years since Fleming’s origi-nal report, there are still b-lactams in advanced

clinical trials as anti-infective agents, with examples from the cephalosporin class being ceftaroline in Phase III, FR-264205 in Phase I and the very interesting combination of a vanco-mycin and a cephalosporin known as TD-1792 in Phase II.

�� Antibacterials: tetracyclinesA second major structural class that, as with the b-lactam, is still very much alive and well, is the third of the three major early antibiotic classes, the tetracycline base structure. Work by a signifi-cant number of investigators identified the mini-mum pharmacophore as 6-deoxy-6-demethyltet-racycline (7) and chemists were able to derive the optimal stereochemical and substitution patterns for antibacterial activity [16].

Prior to this identification, and obviously essential chemical, biochemical and microbiolog-ical precursors to that suggestion, was the launch, in 1948, of the natural 7-chloro- and 5-hydroxy-derivatives as Aureomycin® (8) and Terramycin® (9), respectively, with the base molecule, but not the minimum pharmacophore, being launched in 1953 as Achromycin®. Together with the relatively simple dimethylamino derivative, Minocin® (10) (launched in 1972), these four compounds are considered to be members of the first- (1948–1963) and second- (1965–1972) generation tetracyclines.

This basic four-ring structure and its bio-logical responses in bacteria led to the use of classical approaches and later, molecular genet-ics approaches to identify the multiple tetracy-cline efflux pumps and the protective ribosomal mechanisms. The import of these discoveries cannot be overemphasized as they led to the recognition of drug efflux systems in eukaryotic cells and discoveries of prime import in chemo-therapy in later years. A thorough discussion of these factors is given in the 2001 review by Chopra and Roberts [16], and suggestive evi-dence of the monophyletic origin of these genes, plus the potential for cross-contamination from animal sources, was presented in 2002 by Aminov et al. [17].

Following on the major resistance problems with the first- and second-generation tetra-cyclines, a series of synthetic and semisynthetic modifications of the base pharmacophore were made, with special emphasis on position 9 of the molecule. Previous attempts to modify at this position with 9-nitro, 9-amino or 9-hydroxy derivatives led to molecules with poor anti-bacterial activities. However, scientists at the

b-lActAMs

The ‘class name’ for penicillins and cephalosporins

cRyptic clusteRs

Putatively biosynthetic gene clusters not expressed under regular conditions

Anti-infectives

Agents against microbial, viral and parasitic diseases

Natural product scaffolds as leads to drugs | Mini-Review

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then Lederle Laboratories (currently Wyeth, but due to combine with Pfizer in late 2009) reported that 9-acylamido derivatives of mino-cycline had activities comparable to the first- and second-generation molecules, but did not have activity against resistant organisms [18].

Continuing work at Lederle/Wyeth led to the report in 1999 on the synthesis of a gly-cyl derivative of a modified doxycycline mol-ecule (GAR-936; tigecycline) (11), which was approved in 2005 by the US FDA with broad-spectrum activity against Gram-positive and Gram-negative bacteria and methicillin-resistant Staphylococcus aureus (MRSA). Thus, by utili-zation of what are effectively relatively simple chemical modifications to an old molecule, chemists generated a new lease of life for these elderly base structures, providing a new drug series with activity against clinically important infections [19,20].

Another aspect of this base scaffold was that it was not until this century that the total syn-thesis of a nonracemic tetracycline molecule was reported by Tatsuta’s group in Japan, starting from d-glucosamine [21,22]. This was followed in 2005 by a short report from the Myers group at Harvard, starting with benzoic acid [23]. Their methodology was very recently expanded to give a generalized synthetic method that also gives novel pentacyclic molecules not previously reported [24]. Examples are 12–14 and include the tigcycline homologue (15), all of which dem-onstrate activities in vitro and in vivo against normal and resistant microbes; more details are available in Sun et al. [24].

�� Antibacterials: erythromycin/macrolidesFollowing the pattern of novel modifications of old scaffolds that bind to ribosomes, thus inhibit-ing protein synthesis [25], there have been three molecules since 2000 formally based upon the erythromycin chemotype (16) that have entered clinical trials, namely cethromycin (ABT-773; Phase III), [26] EDP-420 (EP-013420, S-013420; Phase II) and the product of glyco-optimization, CEM-101 (Phase I). A very interesting modifica-tion of the base erythromycin structure, the ‘bicy-clolide’ EDP-420 (17), which is a bridged bicyclic derivative [27,28], is currently in Phase II trials for treatment of community-acquired pneumonia by both Enanta and Shionogi. Interestingly, this molecule is also quite active in a murine model of Mycobacterium avium, a common infection in immunosuppressed patients [29], which may well expand its usage in future trials.

In order to further modify the base structure, Lewis et al. have recently reported the use of novel peptidic catalysts in order to acylate the unreac-tive secondary hydroxyl group in the 11-position in the macrolide ring of erythromycin, rather than having to proceed via the two sugar-linked primary hydroxyl groups (2´ and 4´) in the hex-ose substituents [30]. The earlier methods that produced the fully acylated derivatives involved difficult ester hydrolyses in order to obtain the desired products, both 11-acylated derivatives and 4 -́phosphorylated compounds, that mim-icked the putative method(s) of resistance by bac-teria. Although the synthetic compounds were roughly 16-fold less active than erythromycin A against the organisms tested, the potential of this type of catalytic access to unreactive sites was adequately demonstrated. Even today, 60 years after the original reports by Duggar [31], this old class of antibiotics is generating significant inter-est both chemically and biologically. Thus, the new knowledge from genetic analyses of erythro-mycin biosynthesis in bacteria, coupled with the combination of new chemical synthetic meth-ods (vide infra) and advances in the biosynthetic processes, as recently reported by Pickens and Tang [32], bode well for the future of this com-pound class, with the potential to significantly increase the number of ‘un-natural natural prod-ucts’ for further evaluation by utilizing unnatural starting substrates in initial bio synthetic processes coupled with later (bio)chemical modification of the expressed compounds.

�� Antivirals: modified nucleosidesIt can be argued quite successfully that the derivation of the nucleoside-based antiviral agents can be traced back to the early 1950s, when Bergmann et al. reported on two arabi-nose compounds that they had isolated from marine sponges, spongouridine and spongothy-midine [33–35]. Thus, for the first time, naturally occurring biologically active nucleosides were found containing sugars other than ribose or deoxyribose (an expansion of the privileged nucleoside structure). These two compounds can be thought of as the prototypes of all of the modified nucleoside analogues made by chemists that have crossed the antiviral and anti-tumor stages since then.

Following these discoveries, chemists began to substitute acyclic entities and cyclic sugars with unusual substituents for ribose/deoxyribose. Vast numbers of derivatives were tested exten-sively as antiviral and anti-tumor agents over

O

CO2-

SCoA

OH

CO2-

SCoA

OH

CO2-

NADPH NADPH

H+ H+OH



the next 30 years or more. Suckling, in a 1991 review, showed how such structures evolved in the (then) Wellcome laboratories, leading to the very well-known antiviral agents, acyclovir and its later prodrug derivatives, as well as AZT and, incidentally, to Nobel prizes for Hitchens and Elion [36].

In an interesting temporal reversal (remi-niscent of the benzodiazepine synthesis story and tomaymycin discovery, as discussed earlier) arabinosyl-adenine (Ara-A; 18) was synthesized in 1960 as a potential anti-tumor agent [37], but was later found by fermentation of S. antibi-oticus NRRL3238 and isolated, together with spongouridine [38], from the Mediterranean gorgonian Eunicella cavolini in 1984.

Although very significant numbers of antivi-ral vaccines have either been approved or are in clinical trials for a variety of viral diseases, small molecules based upon ‘modified nucleosides’ are still being approved by either the FDA or the EMEA. Since 2000, seven such agents have been approved for antiviral treatments covering anti-HIV, hepatitis B and cytomegalovirus (CMV). In 2001, brivudine was approved as an antiherpes drug and is currently in Phase II trials for pan-creatic cancer in conjunction with gemcitabine. That same year, the synthetic guanine derivative valganciclovir hydrochloride was launched by Roche for the oral treatment of CMV retinitis in patients with AIDS; it was later approved in 2003 for the treatment of CMV retinitis and CMV infection in transplant patients.

It was also 2001 that saw tenofovir disoproxil fumarate, a prodrug of tenofovir approved for treatment of HIV, subsequently being prereg-istered in the USA for treatment of hepatitis B. Adefovir dipivoxil, an acyclic AMP analogue, was launched in 2002 as an antihepatitis B agent, although it was originally tested as an anti-HIV agent and, the following year, emtricitabine was launched as an anti-HIV agent and is now in Phase III trials as an antihepatitis B agent. In the last 2 years, telbivudine was launched by Idenix

and Novartis in 2006 as an antihepatitis B drug functioning as a DNA polymerase inhibitor and, in 2007, Eisai launched clevudine in Korea as a treatment for hepatitis B.

Thus, even half a century after Bergmann’s discovery of bioactive arabinose nucleosides, small molecules synthesized as a result of his discoveries are still in clinical use and in clini-cal trials for treatment of viral diseases and also for chemotherapeutic treatments in various tumor types.

AnticholesterolemicsIn eukaryotes (both fungi and higher organ-isms), the rate-limiting step in the biosynthesis of cholesterol is the reduction of hydroxymethyl-glutaryl coenzyme A (HMG-CoA) to produce mevalonic acid (figuRe 1). This step was recog-nized by Endo in the 1970s as a potential site for inhibition of cholesterol biosynthesis [39]. After screening over 6000 microbial fermentation broths, Endo reported the inhibitory activity of a fungal metabolite, compactin (mevastatin; 19) in 1975 [40], followed by two other reports in 1976 [41,42]. Mevastatin (as compactin) was reported very shortly thereafter by Brown et al. from Beecham in the UK as an antifungal agent. It was shown to be a competitive inhibitor of the HMG-CoA reductase enzyme with K

i val-

ues in the nanomolar range, but was not further developed due to apparent toxicity [43]. Later work showed that the material seen in sections of mouse and rat livers, the proximate reason for the ‘apparent toxicity findings’, were deposits of cholesterol produced due to the strong induc-tion of HMG-CoA reductase in rodents [39,44]. Comparison of the structure of compactin with figuRe 1 indicates that the lactone ring on the top side is probably the ‘active pharmacophore’ in this compound, as it will form the ring-opened structure in vivo.

Compactin was first tested in humans in 1978 and demonstrated a 30% drop in cholesterol levels in a hypercholesterolemic patient [39]. Subsequently, Endo reported the isolation of the 7-methyl derivative as monacolin K (mevinolin, now known as lovastatin; 20) from Monascus ruber [45,46] and, concomitantly, workers at Merck in the USA discovered the same material from Aspergillus terreus, using an isolated HMG-CoA reductase assay (effectively the reaction in figuRe 1), in contrast to Endo’s sterol produc-tion assay. Lovastatin (Mevacor®) subsequently became the first commercialized HMG-CoA reductase inhibitor in 1987 [47].

Figure 1. HMG-CoA reductase mechanism.



Further work by Merck and Sankyo led to the entry of two slightly modified versions in 1988 and 1989, respectively. In simvastatin (21), the 2-methylbutanoate side chain of lovastatin was converted to 2,2-dimethyl butanoate. Sankyo biotransformed mevastatin, producing the lac-tone ring-opened 7-hydroxy derivative pravasta-tin (22), subsequently licensed to Bristol-Myers Squibb. In both cases, the same ‘partial privi-leged structure’ or what can be considered the ‘warhead’, was, in these human-approved drug entities, either the lactone or its ring-opened hydroxy acid moiety.

Following the success of these agents, pharma-ceutical companies used the information from mevastatin and lovastatin, that is the ‘warhead structure’, in the syntheses of both the original compounds, as well as potential new drugs. If one searches for the earlier examples, then the first reports, aside from the patent literature, are from the Merck group that identified mevino-lin, demonstrating that simpler molecules where either the lactone or ring-opened ‘warhead’ is coupled to simple dichlorobenzene or fluorinated phenyl derivatives can produce compounds with activities comparable to, or better than, compactin [48–50].

These reports were followed up by sci-entists at the then Parke-Davis division of Warner-Lambert, well before the takeover by Pfizer, demonstrating that the same ‘natural product warhead’ as in mevinolin, coupled to either f luorophenyl-substituted pyrroles [51] or 1,3,5-trisubstituted triazoles [52], were also active entities, basically comparable to compac-tin, although reference to the patent literature shows that a Sandoz scientist had filed a US pat-ent in 1985 (issued in 1986) [101] covering the pyrazole nucleus. Contemporaneously, Rosen and Heathcock published an excellent review covering the synthesis of mevinic acids that also showed some of the early ‘synthetic derivatives of mevinolin’ [53]. From an historical viewpoint, the 2002 review by Roth [54] makes very inter-esting reading on the internal debate at Parke-Davis/Warner-Lambert over the development of atorvastatin (23) prior to their purchase by Pfizer.

Thus, one can argue quite successfully that all subsequent agents containing the lactonized or ring-opened ‘warhead, linked to different substituents designed to give improved phar-macokinetics/dynamics (or to avoid IP issues)’ that went into clinical trials and subsequent use as anticholesterolemics, are definitively derived from the natural products described previously.

These ‘natural product-inspired synthetic agents’ thus include the best-selling drug of all time, atorvastatin (Lipitor®; 23), whose sales in 2005, 2006, 2007 and 2008 were US$12.2, 12.9, 12.7 and 13.4 billion worldwide, respec-tively, and three further agents, similar in con-cept to atorvastin, in clinical use today, which have the lactonized or ring-opened form of the ‘warhead from nature’ coupled to different lipophilic entities.

Currently, there are two compounds con-taining the natural product warhead currently in Phase I clinical trials: BMS-644950 (24) from Bristol-Myers Squibb, which has a lower reported myotoxicity than other current com-pounds [55]; and RBx-10558 (25) from Ranbaxy, both of which contain the ring-opened version of the warhead.

Anti-tumor agents Although one can write books on natural prod-uct scaffolds as leads to anti-tumor agents, we have elected to discuss only two basic scaffolds: epothilone and rapamycin. These demonstrate very nicely how relatively simple (epothilone) and more complex (rapamycin) macrolidic struc-tures have led to agents in clinical use and in clinical trials as chemotherapeutic agents, even though, with rapamycin, the base structure was initially approved for an entirely different pharmacological area.

�� Rapamycins The base scaffold, rapamycin (26), was origi-nally reported in 1975 as a potential antifungal agent produced by fermentation of a Streptomyces hygroscopicus bacterium collected from Easter Island [56,57]. The compound was not successful as such, but its potential as a possible (includ-ing oral) anti-tumor agent was reported by the Ayerst Canada group in 1984 using syngeneic murine tumors [58].

The anti-tumor activity was not developed at that time, but the rapamycin base scaffold has since spawned a plethora of molecules with a variety of different pharmacological activities, including cancer. Initially, modifications were at one site, the carbon atom at position 43, and led to five clinical drugs, with the rapamycin base molecule being approved as sirolimus (26) in 1999, initially as an immunosuppressive agent, and is now in Phase I/II trials against various cancers. Similarly, everolimus (27) was launched in 2004 as an immunosuppressive agent, and it is also in Phase II/III trials against various cancers

AnticholesteRoleMics

Agents that reduce the synthesis of cholesterol in mammals



in the EU, Japan and the USA, with approval as a renal cancer agent under the name Afinitor® being given by the FDA in March 2009. The third variation, temsirolimus (28), was approved as a treatment for renal carcinoma in the USA in 2007 and is in Phase I/II trials against various carcinomas in the USA, mainly under the aus-pices of the National Cancer Institute. A fourth, zotarolimus (29), was launched in the USA in 2005 as part of method of delivery via a drug-eluting stent for the treatment of restenosis. A fifth, biolimus A9 (30), is the active principle of the Nobori™ stent, and was launched in 2008.

In all of these examples, the binding areas on the east and west ‘sides’ of the base rapamycin scaffold for the mammalian target of rapamycin (mTOR; a specific serine/threonine kinase) and the FK506-binding protein (FKBP12), respec-tively, were not altered, since modifications in these areas are thought to negate the basic bio-logical activity of this molecule [59,60], so all of the different activities reported are due to very subtle interactions of the substitutions at C43 with the protein complex(es) to which they bind.

The reason(s) for these manifold different activities from the subtle modifications made are not known at the present time, but many groups are investigating these with the aims of improving their properties, particularly in the anti-tumor role [61]. One possibility is that, because mTOR exists in two functionally dis-tinct complexes, mTORC1 and mTORC2, which are inhibited by very different levels of rapamycin, the interactions may well be quite different depending upon the relative levels of mTORC1, mTORC2 and rapamycin (or deriva-tives) [62]. Investigations into the ternary complex of FKBP–rapamycin–mTOR are also ongoing, with methods based upon ‘proximity biotinyl-ation’ analyses, which have the potential to be able to use a variety of other ligands as part of the process, not just the normal ternary complex [63].

Currently, deforolimus (A23573; 31) is in Phase III clinical trials for cancer, and two prodrugs of rapamycin, Abraxis’ ABI-009 (a nanoparticle encapsulated formulation of rapa-mycin) and Isotechnika’s TAFA-93 (structure not yet published), are in Phase I cancer trials.

There is one rapamycin derivative, ILS-920 (32), where the triene portion of the molecule has a modification deliberately designed to disrupt mTOR binding, and appears to have a differ-ent target, as it is a nonimmunosuppressive neurotrophic rapamycin analogue. As such, it has demonstrated a greater than 200-fold

higher binding affinity for the previously iden-tified FK506-binding protein, FKBP52 over FKBP12, promoted neuronal survival and out-growth in vitro, and bound to the b1-subunit of l-type calcium channels (CACNB1) [64]. It entered Phase 0 clinical trials, and is now sched-uled for a Phase I trial under the trial number NCT00827190 but, at the time of writing, no patients appear to have been recruited; two recent reviews update the story of the compound from a chemical and biological perspective [65,66].

What is of further potential interest is that inhibition of FKBP 52 is also reported to affect tubulin interactions in cells [67], so there is a pos-sibility that this agent may also have anti-tumor activity in due course, although no reports of such activity have yet been published.

Thus, from this one base molecule, the origi-nal and four with slight structural modifications have been approved as drugs. In addition, there are other modifications, as mentioned earlier, in cancer trials, as well as a compound dem-onstrating that modifications in the macrolide ring’s triene moiety produce an entirely different activity in neurology. In addition, from the pat-ent literature, other variations are in preclinical studies in a variety of pharmacologic areas.

�� EpothilonesFollowing the identification of the myxobacte-rial products epothilones A and B (33 & 34) by Reichenbach and Hoefle in the middle to late 1980s [68], and their subsequent identification as tubulin stabilizers (similar mechanistically to Taxol) by Bollag et al. in 1995 [69], came an avalanche of chemical, biochemical and even genomic modifications in order to further explore the utility of the base skeleton. Although not formally related to the taxane skeleton when drawn in 2D, the 3D structures do have poten-tial common pharmacophores [70,71]; although the structural reasons for epothilone activity in taxane-resistant cell lines has not yet been explained at the molecular level. This culmi-nated in the approval in October 2007 by the FDA of the semisynthetic epothilone 16-aza-epothilone B, known generically as ixabepi-lone (35), where the macrolide ring oxygen has been exchanged for an imine, for the treatment of breast cancer.

Currently, there are five other compounds based upon the epothilone scaffold in active development as anticancer agents listed in the Prous Integrity database. The natural product epothilone B (patupilone; 34) is in Phase III



clinical trials in conjunction with Novartis and the original discoverers. A totally synthetic deriv-ative, although very close to the base scaffold, sagopilone (ZK-EPO; 36), is in Phase II trials under Bayer-Schering [72]. Much fuller details of this and the opportunities for synthesis of other agents are given in three recent reviews [73–75] and one book chapter [76], which should be consulted for further details.

There are two agents derived from work origi-nating in Danishefsky’s laboratory at Memorial Sloan-Kettering being developed by Kosan (now part of Bristol-Myers Squibb). The first is (E)-9,10-didehydroepothilone D or dehydelone (37), currently in Phase II clinical trials, where chemists at Kosan performed modifications of the structure while retaining the activity [77]. The second is isoxazolefludelone (38) [78], cur-rently in preclinical evaluation [79]. A recent discussion of the chemistry leading to the com-pound and other derivatives produced en route was reported by the same group in late 2008 [80].

Finally, there has been a very interesting folate receptor-targeted molecule synthesized as a result of collaboration between Endocyte and Bristol-Myers Squibb (BMS-753493), where folic acid has been linked to an aza-modified epothilone [81]. The compound is now in Phase I/II trials under the name epofolate (39) against folate receptor-positive tumors.

Now that the genetic sequence of the original producing myxobacterium has been published, we can expect further reports in the near future, not just of combinatorial biosyntheses giving rise to modifications of the base skeleton, but also of the isolation of a number of different secondary metabolites from the same microbe [82–84].

Future perspectiveAlthough this is a mini-review, it can be seen from the examples given that structures whose nominal ages range from their teens/early twenties to old age are still teaching medici-nal chemists how to produce molecules that have pharmacological activities in areas from anti-infectives to cancer and, in particular, in previously unknown pharmacological areas, as demontrated by the rapamycin analogues.

What is of prime import, and it has been alluded to repeatedly in the article, is the inter-face between standard natural product chemis-try using bioactivity-driven isolation techniques in most cases, and the current rapidly evolving empirical knowledge related to biosynthetic gene clusters identified from the producing organism.

At present, the flood of information on identified gene clusters, predominately in the protein kinase substrate (PKS) or the nonribosomal protein syn-thase (NRPS) systems, and their role(s) in the production of specific molecules that are clearly PKS or NRPS sourced is relatively well under-stood, but the understanding of the production of mixed agents in the biosynthetic context is not at the same level.

What is of immense potential is the bio-chemical and genomic dissection of the loading domains in either system (or mixed ones), as the potential to use unnatural start-ing materials in a well-defined biosynthetic scheme opens up significant possibilities from a structure–activity perspective.

What is also of significant import is the ability to probe metagenomes (e.g., soils, marine muds, seas and marine invertebrates), looking for novel gene clusters without the necessity for isolation of the producers. Examples of this are the reports from Schimer et al. on the novel PKS genes asso-ciated with the sponge from which the tubulin-interactive agent (and clinical cancer candidate) discodermolide was isolated, showing the pres-ence of previously unrecognized PKS clusters [85]; the recent review by Uria and Piel on investiga-tions of the chemistry of noncultured symbiotic marine bacteria [86] and the very recent example of the novel PKS-based molecule, erdacin (40), isolated from a soil metagenomic digest, whose structure has not been previously reported from any culture-dependent natural product study [87].

When one couples these reports with the recog-nition of the vast number of symbiotic microbes now implicated in the production of secondary metabolites from other organisms [88], and the continuing publication of complete microbial genomes, then the potential for unknown privi-leged structures with as yet unknown biological properties as leads to active agents in multiple pharmacological areas is incalculable.

Financial & competing interests disclosureThe views expressed in this article are those of the authors and do not necessarily ref lect the views of the US Government. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock own-ership or options, expert t estimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.



Executive summary

Anti-infectives

�� Structures that are 60–80 years of age are still being utilized as the basis for current approved and clinical candidates in antibacterial and antiviral areas.

�� These include b-lactam, tetracycline and macrolide base scaffolds as antibacterials and modified nucleosides (both base and sugar moieties).

Anticholesterolemics

�� Rigorous evidence is given from the primary and review literature demonstrating that all agents other than the fibrates and bile acid derivatives are based upon the original natural product warhead.

Anti-tumor agents

�� The rapamycin scaffold is used as a demonstration of the subtleties involved in modifying such agents. A modification at one peripheral site has given rise to novel agents with differential activities.

�� Similar effects on modification of the base epothilone scaffold are also discussed.

Future perspective

�� The dramatic potential for the modification of scaffolds from the interplay of genomic information on biosynthesis and synthetic modifications is elaborated on.

�� Examples are given on the equally dramatic potential of ‘metagenomic’ studies on the biosynthetic clusters isolable from as yet uncultivated microbial sources, without the necessity to culture.

BibliographyPapers of special note have been highlighted as:� of interest�� of considerable interest

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27 Wang G, Niu D, Qiu YL et al. Synthesis of novel 6,11-O-bridged bicyclic ketolides via a palladium-catalyzed bis-allylation. Org. Lett. 6, 4455–4458 (2004).

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�� Examples of how one can use modern genomic techniques to alter basic molecules.

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�� Opened up the modification of nucleoside sugars as a route to new agents.

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35 Bergmann W, Burke DC. Contributions to the study of marine products. XL. The nucleosides of sponges. IV. Spongosine. J. Org. Chem. 21, 226–228 (1956).

36 Suckling CJ. Chemical approaches to the discovery of new drugs. Sci. Prog. 75, 323–359 (1991).

37 Lee WW, Benitez A, Goodman L, Baker BR. Potential anticancer agents. XL. Synthesis of the earlier-anomer of 9-(d-arabinofuranosyl)adenine. J. Am. Chem. Soc. 82, 2648–2649 (1960).

38 Cimino G, de Rosa S, de Stefano S. Antiviral agents from a gorgonian, Eunicella cavolini. Experientia 40, 339–340 (1984).

39 Endo A. A gift from nature: the birth of the statins. Nat. Med. 14, 1050–1052 (2008).

�� The history of the statins from the discoverer of the first natural product agent.

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41 Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 72, 323–326 (1976).

42 Endo A, Kuroda M, Tsujita Y. ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum. J. Antibiot. 29, 1346–1348 (1976).

43 Brown AG, Smale TC, King TJ, Hasenkamp R, Thompson RH. Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum. J. Chem. Soc. Perkin Trans. 1, 1165–1170 (1976).

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47 Vagelos RP. Are prescription drug prices too high? Science 252, 1080–1084 (1991).

48 Stokker GE, Hoffman WF, Alberts AA et al. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 1. Structural modification of 5-substituted 3,5-dihydroxypentanoic acids and their lactone derivatives. J. Med. Chem. 28, 347–358 (1985).

49 Hoffman WF, Alberts AA, Cragoe Jr EJ et al. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 2. Structural modification of 7-(substituted aryl)-3,5-dihydroxy-6-heptenoic acids and their lactone derivatives. J. Med. Chem. 29, 159–169 (1986).

�� Earliest published report of a non-natural anticholesterolemic based on the natural product ‘warhead’.

50 Stokker GE, Alberts AA, Anderson PS et al. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 3. 7-(3,5-disubstituted [1,1́ -biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactone derivatives. J. Med. Chem. 29, 170–181 (1986).

51 Roth BD, Ortwine DF, Hoefle ML et al. Inhibitors of cholesterol biosynthesis. 1. trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a novel series of HMG-CoA reductase inhibitors. 1. Effects of structural modifications at the 2- and 5-positions of the pyrrole nucleus. J. Med. Chem. 33, 21–31 (1990).

52 Sliskovic DR, Roth BD, Wilson MW, Hoefle ML, Newton RS. Inhibitors of cholesterol biosynthesis. 2. 1,3,5-trisubstituted [2-(tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. J. Med. Chem. 33, 31–38 (1990).

53 Rosen T, Heathcock CH. The synthesis of mevinic acids. Tetrahedron 42, 4909–4951 (1986).

54 Roth BD. The discovery and development of atorvastatin, a potent hypolipidemic agent. Prog. Med. Chem. 40, 1–22 (2002).

�� The story of atorvastatin by its original developer at Warner Lambert/Parke-Davis.

55 Ahmad S, Madsen CS, Stein PD et al. (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1h-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950): a rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-a reductase inhibitor with reduced myotoxicity potential. J. Med. Chem. 51, 2722–2733 (2008).

56 Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J. Antibiot. 28, 727–732 (1975).

57 Baker H, Sidorowicz A, Sehgal SN, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation. J. Antibiot. 31, 539–545 (1978).

58 Eng CP, Sehgal SN, Vezina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J. Antibiot. 37, 1231–1237 (1984).

59 Koehn FE. Therapeutic potential of natural product signal transduction agents. Curr. Opin. Biotech. 17, 631–637 (2006).

60 Tsang CK, Qi H, Liu LF, Zheng XFS. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov. Today 12, 112–124 (2007).

61 Teachey DT, Grupp SA, Brown VI. Mammalian target of rapamycin inhibitors and their potential role in leukaemia and other haematological malignancies. Brit. J. Haematol. 145, 569–580 (2009).



62 Foster DA, Toschi A. Targeting mTor with rapamycin: one dose does not fit all. Cell Cycle 8, 1026–1029 (2009).

63 Fernandez-Suarez M, Chen TS, Ting AY. Protein–proten interaction detection in vitro and in cells by proximity biotinylation. J. Am. Chem. Soc. 130, 9251–9253 (2008).

64 Ruan B, Pong K, Jow F et al. Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proc. Natl Acad. Sci. USA 105, 33–38 (2008).

�� First report of a neuroprotective agent based on the rapamycin scaffold.

65 Abou-Gharbia M. Discovery of innovative small molecule therapeutics. J. Med. Chem. 52, 2–9 (2009).

66 Graziani EI. Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs. Nat. Prod. Rep. 26, 602–609 (2009).

67 Chambraud B, Belabes H, Fontaine-Lenoir V, Fellous A, Baulieu EE. The immunophilin FKBP52 specifically binds to tubulin and prevents microtubule formation. Faseb J. 21, 2787–2797 (2007).

68 Hoefle G, Reichenbach H. Epothilone, a myxobacterial metabolite with promising antitumor activity. In: Anticancer Agents from Natural Products. Cragg GM, Kingston DGI, Newman DJ (Eds). Taylor and Francis, Oxford, UK 413–450 (2005).

69 Bollag DM, McQueney PA, Zhu J et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 55, 2325–2333 (1995).

�� First report of tubulin-stabilizing activity by epothilones.

70 Giannakakou R, Gussio R, Nogales E et al. A common pharmacophore for epothilones and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc. Natl Acad. Sci. USA 97, 2904–2909 (2000).

71 He LF, Jagtap PJ, Kingston DGI, Shen HJ, Orr GA, Horwitz SB. A common pharmacophore or taxol and the epothilones

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72 Klar U, Buchmann B, Schwede W, Skuballa W, Hoffmann J, Lichtner RB. Total synthesis and antitumor activity of ZK-EPO: the first fully synthetic epothilone in clinical development. Angew. Chem. Int. Ed. 45, 7942–7948 (2006).

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74 Altmann KH, Pfeiffer B, Arseniyadis S, Pratt BA, Nicolaou KC. The chemistry and biology of epothilones-the wheel keeps turning. ChemMedChem 2, 396–423 (2007).

75 Feyen F, Cachoux F, Gertsch J, Wartmann M, Altmann K-H. Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization. Acc. Chem. Res. 41, 21–31 (2008).

76 Altmann KH, Memmert K. Epothilones as lead structures for new anticancer drugs – pharmacology, fermentation, and structure – activity relationships. Prog. Drug Res. 66, 275–334 (2006).

77 Hearn BR, Zhang D, Li Y, Myles DC. C-15 thiazol-4-yl analogues of (E)-9,10-didehydroepothilone D: synthesis and cytotoxicity. Org. Lett. 8, 3057–3059 (2006).

78 Cho YS, Wu KD, Moore MAS, Chou TC, Danishefsky SJ. Second-generation epothilones: discovery of fludelone and its extraordinary antitumor properties. Drugs Fut. 30, 737–745 (2005).

79 Chou TC, Zhang XG, Dong H et al. Iso-oxazole-fludelone (KOS-1803) as a potent and efficacious microtubule-stablization epothilone against xenograft tumors. Proc. Am. Assoc. Cancer Res. 1402 (2008).

80 Chou TC, Zhang X, Zhong Z et al. Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones. Proc. Natl Acad. Sci. USA 105, 13157–13162 (2008).

81 Leamon CP. Folate-targeted drug strategies for the treatment of cancer. Curr. Opin. Investig. Drugs 9, 1277–1286 (2008).

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83 Schneiker S, Perlova O, Kaiser O et al. Complete genome sequence of the myxobacterium Sorangium cellulosum. Nat. Biotech. 25, 1281–1289 (2007).

84 Wenzel SC, Müller R. Myxobacterial natural product assembly lines: fascinating examples of curious biochemistry. Nat. Prod. Rep. 24, 1211–1224 (2007).

�� Excellent discussion of the potential for genomic modification of mycobacterial secondary metabolites.

85 Schimer A, Gadkari R, Reeves CD, Ibrahim F, de Long EF, Hutchinson CR. Metagenomic analysis reveals diverse polyketide synthase gene clusters in microorganisms associated with the marine sponge Discodermia dissoluta. Appl. Environ. Microbiol. 71, 4840–4849 (2005).

86 Uria A, Piel J. Cultivation-independent approach to investigate the chemistry of marine symbiotic bacteria. Phytochem. Revs. 2009, 401–414 (2009).

87 King RW, Bauer, JD, Brady SF. An environmental DNA-derived type II polyketide biosynthetic pathway encodes the biosynthesis of the pentacyclic polyketide erdacin. Angew. Chem. Int. Ed. 48, 6257–6261 (2009).

88 Piel J. Metabolites from symbiotic bacteria. Nat. Prod. Rep. 26, 338–362 (2009).

�� Patent101 Wareing JR. Cholesterol biosynthesis

inhibiting pyrazole analogs of mevalonolactone and its derivatives: USP 4,613,610 (1986).

N

S

O

HN

O OH

O

1 Penicillin G

S

N O

OO OH

O

HHHN

O

O

HO

NH2

2 Cephalosporin C

N

OH

OOHH

HN

H

O

NOH

O

O

O

HO

NH2H

3 Nocardicin A

NS

NH2

O

HH

HOH

OOH

4 Thienamycin

HN

O

N

O

OO

O OH

O OH

S N

N

HO N

N

5 Moxalactam

NO

OHOH

F

F

6 Exetimibe

OH

N

OH O

OH

O

NH2

OOH

HH

7 6-Deoxy-6-demethytetracycline

OH

N

OH O

OH

O

NH2

OOH

HH

12

OH

N

OH O

OH

O

NH2

OOH

HH

N

13

OH

N

OH O

OH

O

NH2

O

N

OH

NH

OHN

HH

11 Tigecycline

9

OH

N

OH O

OH

O

NH2

OOH

HHHN

14

OH

N

OH O

OH

O

NH2

OOH

HH

HN

15

OH

N

OH O

OH

OH

O

NH2

OOH

HHCl

8 Aureomicin®

OH

N

OH O

OH

OH

O

NH2

OOH

HHOH

9 Terramycin®

OH

N

OH O

OH

O

NH2

O

N

OH

HH

10 Minocin®

Appendix 1



OHO

O

O

HO

OO

O

N

O

O

HO

OH

HO

16 Erythromycin

O

O O

O

N

N

HO

O

O

N

O

O

O

HO

NNN

17 EDP-420

NN

O

N

OH

N

NH2

HO

HO

18 Ara-A

O

O_+

HO O

H

19 Compactin (Mevastatin®); R = H20 Mevinolin (Lovastatin®); R = CH3

R

O

OO

HO

H

O

21 Simvastatin

O

HO

OOH

HO

O

O-

H

22 Pravastatin

N

HN

O

OH

F

HO

O

O-

23 Atorvastatin

NN

N

N N

N

F

OH

HO O-

O

Na+

24 BMS-644950

N

OH

HO

O

OH

O

HN

OH

F

25 RBx-10558

N

OO

O O

O

O

HOO

O OH

O

26 Rapamycin (Sirolimus®)

O

HO

FKBP12m TOR

O

OHO

R

27 Everolimus; R = macrolide ring

O

O

R

O

HO

HO

28 Temsrolimus; R = macrolide ring

O

R

N

NN

N

29 Zotarolimus; R = macrolide ring

O

OO

R

30 Biolimus A9; R = macrolide ring



O

OP

R

O

31 Deforolimus; R = Macrolide ring

N

OO

O O

O

O

HOO

O OH

O

32 ILS-920

O

HO

O N

OR1

R

O

NHO

S

OHO

33 Epothilone A; R = O, R1 = H34 Epothilone B ; R = O, R1 = CH3

351 6-Aza-epothiloneB; R = NH, R1 = CH3

N

S

O

OO

HO

OH

O

36 Sagopilone

N

O

S

O O

HO

OH

37 Dehydelone

N O

O

O

FFF

OHO

HO

38 Isoxazolefludelone

HN

O

O

OH

NH

O

HN NH2

NH

HN

O

O

OH

NH

O

S

O

O

NHO

S

OHO

N

OO

O

S

OH

NN

NHN

O

H2N

NH

NH

O

OH

O

O

39 Epofolate

O

HO

O

OHO

OHO OH

H

HO

40 Erdacin



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