Underexplored Opportunities for Natural Products in Drug Discovery

Perspective pubs.acs.org/jmc

Underexplored Opportunities for Natural Products in Drug Discovery Miniperspective Bart L. DeCorte* Janssen Pharmaceutical Companies of Johnson & Johnson, 1400 McKean Road, Spring House, Pennsylvania 19477, United States

ABSTRACT: The importance of natural products in the treatment of human disease is well documented. While natural products continue to have a profound impact on human health, chemists have succeeded in generating semisynthetic analogues that sometimes overshadow the original natural product in terms of clinical significance. Synthetic efforts based on natural products have primarily focused on improving their drug-like features while targeting utility in the same biological space. A less documented phenomenon is that natural products can serve as powerful starting materials to generate drug substances with novel therapeutic utility that is unrelated to the biological space of the natural product starting material. In this Perspective, examples of natural product derived marketed drugs with therapeutic utility in clinical space that is different from the biological profile of the starting material are presented, demonstrating that this is not merely a theoretical concept but both a clinical reality and an underexplored opportunity. used for the treatment of a number of cancers.15−17 In the cardiovascular space, the fungal metabolite lovastatin was found to inhibit cholesterol biosynthesis and became commercialized as Mevacor.18,19 Natural products from marine sources are also having an increasing impact on the treatment of human disease, particularly as anticancer agents.20 Ecteinascidin 743 (ET 743), marketed as Yondelis, is used clinically for the treatment of liposarcoma or leiomyosarcoma (Figure 2).21 1.2. Improving the Drug-Likeness of Natural Products. Not surprisingly, chemists in both industrial and academic settings have attempted to improve the drug-likeness of natural products with clinical potential. Those activities were motivated by the assumption that natural products from botanical and microbial origins were never produced with the goal of treating human disease but rather to provide those organisms with a survival advantage in the ecosystems they inhabit. Additionally, synthetic modifications of those natural product substances provide the opportunity to generate novel composition of matter and associated intellectual property, and in the antimicrobial space, semisynthetic modifications led to compounds with increased potency and broader antimicrobial activity. As a result, a number of clinically important natural product analogues have reached the marketplace, in some cases

1. INTRODUCTION 1.1. The Use of Natural Products “As Is”. The impact of natural products on the treatment of a broad range of diseases has been documented extensively.1−7 Plant derived natural products in particular have been used for centuries to treat a wide variety of ailments.8−11 Until relatively recently, those natural products were used in crude form as extracts and oils. Scientific progress in the last century has allowed for the isolation, structural elucidation, and formulation of key active ingredients from those plants, and a number of natural products are now available in pure form as drug substances. Prominent examples of such substances include morphine, quinine, reserpine, cocaine, and ephedrine (Figure 1). While these advances have transformed the treatment of disease in “developed” countries, a majority of the world population does not have access to those medicines and still relies on the traditional medicines in impure form.8 The arsenal of natural product drug substances derived from plants has been expanded upon significantly with the addition of secondary metabolites of microbial origin (Figure 2).9−11 The landmark discovery of penicillin G was soon followed by the discovery of the tetracyclines and other classes of antibiotic microbial natural products.12−14 The discovery of these antibacterial agents is considered one of the most transformational breakthroughs in the history of medicine. Natural products of microbial origin have been and continue to be used in oncology; mitomycin C and daunorubicin are clinically © 2016 American Chemical Society

Received: March 30, 2016 Published: June 22, 2016 9295

DOI: 10.1021/acs.jmedchem.6b00473 J. Med. Chem. 2016, 59, 9295−9304

Journal of Medicinal Chemistry

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Figure 1. Plant derived natural products, their trade name, source, and clinical utility.

Figure 2. Marketed microbial and marine derived natural products, their source, and clinical utility.

the desire to improve their drug-likeness and that the clinical utility of the resulting novel chemical entities resides in the same biological space as the original natural product. Both penicillin G and amoxicillin are antibacterial agents, and lovastatin and its semisynthetic analogues are cholesterol lowering agents.

overshadowing the utility of the original natural product (Figure 3). Amoxicillin, prepared semisynthetically from penicillin G, continues to be used as first-line therapy for the treatment of bacterial infections.22 The marketing of lovastatin was soon followed by the introduction of simvastatin (Zocor), a closely related analogue produced via biosynthetic modification by the addition of a different precursor to the fermentation.23 It is noteworthy that the difference between lovastatin and simvastatin is a single methyl group, arguably the most lucrative methyl group in pharmaceutical history. Similarly, commercialization of the tubulin inhibitor paclitaxel (Taxol) was soon followed by docetaxel (Taxotere), prepared semisynthetically from 10-deacetylbaccatin III.24 It is important to emphasize that in all the examples cited above, synthetic modification of natural products was driven by

2. NATURE’S WAY OF GENERATING BIOACTIVE SUBSTANCES The chemical diversity of secondary metabolites produced in nature is astonishing, particularly given the very limited number of building blocks plants and microorganisms have at their disposal. With the benefit of hundreds of millions of years of evolution, plants and microorganisms have succeeded in 9296



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Figure 3. Marketed semisynthetically produced drug substances, their source, and clinical utility.

Figure 4. Synthesis of strictosidine and conversion to clinically important indole and quinoline alkaloids.

assembling a remarkable array of architecturally and stereo-

The number of assembly tools organisms have at their disposal is limited. While many are catalyzed by enzymes, the chemical principles and mechanisms are rather straightforward and not unlike what synthetic chemists can employ in the laboratory: alkylations, C−C bond forming reactions, rearrangements, Schiff base formation, Mannich reactions, transaminations, decarboxylations, oxidative couplings, and oxida-

chemically complex molecules that presumably provide them with a competitive advantage in the ecosystems they inhabit. In addition, the biosynthesis of those molecules is intimately regulated by environmental factors, including the presence of stress and the need for reproduction.25 9297



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Figure 5. Conversion of morphine, thebaine, and oripavine to apomorphine.

Figure 6. Thebaine-derived marketed drug substances.

inspiration for topotecan (Hycamptin) and irinotecan (Camptosar; CPT-11; 7-ethyl-10-hydroxycamptothecin), two closely related analogues with improved solubility and side effect profiles.36 In the context of this Perspective, it is important to emphasize that the biological and clinical utility of these compounds was by no means predicted by the biological activity of strictosidine, the biosynthetic precursor. In fact, to the best of my knowledge, no particular biological or clinical utility has been associated with strictosidine. The question then becomes: is this an isolated phenomenon or an observation that is worth exploring synthetically? Indeed, as described in the examples that follow, there are a number of clinically important medicines that are produced semisynthetically from natural product building blocks that lack biological activity or that possess biological activity unrelated to the effectiveness of the semisynthetic product.

tions and reductions account for the vast majority of chemical transformations observed in cells.25 In the biosynthesis of secondary metabolites, the initial biochemical transformations are often identical in a broad array of plants, and the chemical diversity of the final products is the result of divergent biosynthetic pathways in the later stages of the biosynthesis. As an example, while approximately 2000 monoterpenoid indole alkaloids of remarkable chemical diversity have been reported, strictosidine serves as the common chemical intermediate in their synthesis across a number of plant genera such as Cinchona, Camptotheca, Catharanthus, Rauwolfia, Vinca, etc.26,27 The strictosidine building block is obtained via the strictosidine synthase catalyzed condensation of tryptamine with secologanin. Depending on the plant species and the ecosystem in which the plant resides, strictosidine is the synthetic building block for a number of important drug substances, including quinine, quinidine, vinblastine, vincristine, camptothecin, ajmalicine, reserpine, and camptothecin (Figure 4).28−35 With the exception of camptothecin, all of these alkaloids became marketed drugs with broad clinical utility ranging from the treatment of infections and cancer to sedatives and medicines for cardiovascular disease. Camptothecin itself became the

3. NATURAL PRODUCTS AS ENTRY POINT INTO NOVEL BIOLOGICAL SPACE 3.1. Morphinanes. 3.1.1. Morphine and Apomorphine. The chemical structure of morphine was first reported in the 9298



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1920s by Gulland and Robinson, but synthetic modifications of morphine predate that report by more than 50 years.37−39 In fact, in 1869, Matthiesen and Wright reported that morphine (called morphia at the time) underwent a skeletal rearrangement upon treatment with concentrated hydrochloric acid to yield apomorphine.40 More recently, thebaine and oripavine were shown to undergo a similar rearrangement upon exposure to methanesulfonic acid (Figure 5).41 Not surprisingly, the architectural transformation of the morphine skeleton into apomorphine results in a loss of binding affinity for the μ opioid receptor. What was not predicted, however, is that apomorphine possesses significant dopamine receptor agonist activity. In fact, apomorphine is marketed as Apokyn for the symptomatic treatment of Parkinson’s disease and erectile dysfunction.42 Both therapeutic utilities are attributed to the dopaminergic activity of apomorphine. This may well be the only example in which a drug substance (morphine) marketed for a particular indication (pain) has been converted in a single step into a different marketed drug (apomorphine) with a different therapeutic indication (Parkinson’s disease/erectile disfunction). 3.1.2. Thebaine and Morphinane Drugs. The opium poppy has been used for thousands of years as an analgesic, narcotic, and cough suppressant. While the poppy contains many alkaloids, most of the alkaloid content consists of morphine, codeine, thebaine, papaverine, noscapine, and narceine.43,44 The biological activity of thebaine is limited, and its primary value is as a building block for the semisynthesis of a variety of morphinanes. In fact, the discovery of the top1 poppy mutant which accumulates thebaine rather than morphine and codeine has transformed thebaine from an unwanted opium byproduct to a valuable synthetic building block for the preparation of a range of marketed drugs.45 While the majority of the thebainederived clinical agents are μ opioid agonists used for the treatment of pain, synthetic modifications of thebaine have also led to mixed μ/δ/κ opioid agonists and antagonists useful in the treatment of addiction, constipation, and emesis (Figure 6). In that sense, thebaine is a beautiful example of a natural product with unimpressive intrinsic biological activity that can be converted to therapeutic agents that are useful in multiple disease areas. The therapeutic space in which the thebainederived substances are active is not necessarily predictable based on the biological activity of thebaine itself. 3.2. Safracin B and Ecteinascidin 743. Ecteinascidin 743 is the first marine anticancer agent to receive regulatory approval for the treatment of cancer.46 As the result of a broad survey of pharmacological activity of marine species conducted by the U.S. National Cancer Institute, an extract from the mangrove tunicate Ecteinascidia turbinata containing ecteinascidin 743 was first identified in 1969 to have anticancer activity. Identification and structural elucidation of ecteinascidin 743 was delayed until the early 1990s, in large part because of the lack of adequate supply.47 In 1996, E. J. Corey and co-workers reported the first total synthesis of ecteinascidin 743, followed by two additional total syntheses by Fukayama (2002) and Zhu (2006).48−50 Today, clinical supplies of ecteinascidin 743 are produced semisynthetically from readily available safracin B, itself obtained by fermentation from the bacterium Pseudomonas fluorescens (Figure 7).46 Safracin B was first known to possess antibiotic properties, and shortly thereafter, its antiproliferative activity was reported.51 The synthetic transformation of safracin B to ecteinascidin 743, initially pursued to address a clinical supply

Figure 7. Semisynthesis of ecteinascidin 743 from safracin B.

challenge, serves as an example in which the chemical transformation of a natural product starting material with known antibiotic and antiproliferative activity yields a derivative with clinically useful anticancer activity. 3.3. Fructose and Topiramate. The discovery of topiramate (Topamax) was the result of both serendipity and an open-mindedness to evaluate novel chemical entities in pharmacological models different from the disease area that was targeted during the initial drug discovery effort.52 Topiramate was first prepared from D-fructose as part of an antidiabetic drug discovery program targeting the enzyme fructose-1,6bisphosphatase (Figure 8). Fortuitously, the molecule was

Figure 8. Semisynthesis of topiramate from D-fructose.

profiled in an electroshock seizure test in mice, a screening assay for potential antiepileptic agents. Follow-up studies with topiramate demonstrated anticonvulsant activity worthy of further clinical evaluation.53 The topiramate story is fascinating in that no antiepileptic activity is associated with fructose. And while the sulfamate functionality is key to topiramate’s anticonvulsant activity and the sugar framework can be replaced by a variety of appendages, topiramate did find its origins in the chemical transformation of a carbohydrate molecule that did not at any time suggest antiepileptic potential.54,55 3.4. Shikimic Acid and Oseltamivir. Oseltamivir, marketed as Tamiflu, is the ethyl ester prodrug of the potent influenza neuraminidase inhibitor oseltamivir carboxylate (GS4071) and is indicated for the treatment and prevention of infections due to influenza A and B viruses.56 While a number of elegant total syntheses of oseltamivir have been reported,57−59 shikimic acid has been the primary source for its semisynthetic commercial production (Figure 9).60−63 In fact, commercial shortages of oseltamivir have been attributed to the lack of availability of shikimic acid. Shikimic acid is a central intermediate in the shikimate pathway and provides microorganisms and plants a route to a number of aromatic compounds, particularly aromatic amino acids. The Japanese star anise, Illicium anisatum, is an important source of large scale quantities of shikimic acid for the production of 9299



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Figure 9. Semisynthesis of oseltamivir from (−)-quinic and shikimic acid.

As illustrated in Figure 11, steroidal clinical agents find therapeutic use in disease areas far beyond the intrinsic biological activity of the steroidal saponin and phytosterol precursors. Moreover, the therapeutic value of those compounds is not necessarily predicted based on the biological activity of the natural product starting materials.

oseltamivir. More recently, production in genetically engineered bacteria has also been reported.64 Quinic acid, derived from the bark of the cinchona tree, serves as a potential alternative starting material for the production of oseltamivir.60,65 No antiviral activity has been associated with shikimic acid. In fact, shikimic acid has been classified as a group 3 carcinogen by the International Agency for Research on Cancer (IARC).66 Quinic acid has been reported to possess some antihepatitis B virus activity, but its clinical utility as an antiviral agent has not been demonstrated.67 3.5. Saponins, Phytosterols, and Steroidal Drugs. More than 100 drugs approved by regulatory agencies possess a steroidal skeleton as their core.68 Many of those compounds are prepared semisynthetically from steroidal saponins and phytosterols. Diosgenin, obtained from Mexican yams (Dioscorea spp.), became a key starting material for a large number of steroidal drugs ever since researchers at Syntex in the 1940s reported the use of Marker’s diosgenin degradation for the industrial production of progesterone, cortisone, and the birth control pill.69−71 Diosgenin itself has been reported to possess antitumor activtity,72−74 and while the powdered Dioscorea root or extract is marketed for the treatment of menopause symptoms, the clinical utility of semisynthetic steroids derived from diosgenin has expanded far beyond hormone replacement therapy. In fact, most corticosteroids or soft corticosteroids, anabolic steroids, sex hormones, and oral contraceptives are synthesized from 16-dehydropregnenolone acetate (16-DPA), which itself is obtained from diosgenin.75 Besides diosgenin, hecogenin, stigmasterol, and sitosterol are also used for the production of steroidal drugs (Figure 10).

4. BIOLOGICAL SCREENING STRATEGIES Until the 1980s, the biological activity of most marketed drugs, whether derived from nature or obtained through de novo synthesis, was identified through animal pharmacology.76,77 In the past 25 years, there has been a dramatic shift in the way small molecules are being profiled biologically, and most drug discovery programs in large pharmaceutical companies, biotech and academia alike are often referred to by the name of the macromolecular entity (receptor, enzyme, DNA, RNA) that is being targeted.78 This evolution has been made possible thanks to enormous scientific progress in genomics and proteomics and technological advances in high throughput screening. But even in the past 15 years, the contribution of phenotypic screening to the discovery of f irst-in-class small-molecule drugs continues to match or even exceed that of molecular targetbased approaches.79−83 While the pros and cons of the various screening strategies is not the focus of discussion in this Perspective, an open-minded and opportunistic approach to the biological profiling of natural product-derived novel chemical entities is critical to revealing their therapeutic potential. Uncovering the therapeutic potential of novel natural product derived chemical entities will require broad molecular target based and phenotypic screening strategies that cast a wide net and allow for the probing of multiple biologically relevant pathways in a target-agnostic fashion. High content phenotypic screens that translate preclinical read-outs more effectively into clinical effects in patients are uniquely placed to do that. 5. CONCLUSIONS AND OUTLOOK The synthetic modification of natural products dates back to the 19th century and was largely explored as a tool to unlock their structural and architectural identity. While these efforts occasionally led to high-profile structural misassignments, the structural elucidation of compounds like morphine, cocaine, quinine, and estradiol inspired numerous organic chemists to pursue totally synthetic strategies to access those molecules. In the process, synthetic tools were developed that form the basis of many chemical transformations used all over the world today.84 The remarkable clinical effect of some of these substances motivated chemists to synthesize structural analogues to improve their drug-like characteristics. As a result, novel semisynthetic drug substances were identified that obscured the original natural product both in terms of clinical utility and revenue generation.22−24

Figure 10. Important natural product building blocks for steroid synthesis and their respective plant sources. 9300



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Figure 11. Selected marketed drug substances derived from diosgenin, hecogenin, stigmasterol, and sitosterol.

Notes

The semisynthetic transformation of natural product building blocks complements total synthesis strategies such as diversityoriented synthesis and biologically oriented synthesis.85−101 In recent years, several research groups have expanded on this theme, demonstrating that diverse sets of complex natural product-based libraries can be accessed via the architectural remodeling of natural product cores.102 Hergenrother and coworkers have reported on the application of ring cleavage, expansion, fusion, and rearrangement reactions of gibberellic acid, andrenosterone, quinine, abietic acid, and pleuromutilin, a strategy they coined complexity-to-diversity (CtD).103−105 A similar strategy has been applied to lanosterol and bryonolic acid by Tochtrop and co-workers.106−108 It is encouraging to see that there is a renewed interest in using natural product building blocks to access novel drug-like chemical space. The examples described in this Perspective are testimony to the power of this strategy and advocate for an open-minded, opportunistic approach to the use of natural products in drug discovery. Creative chemistry performed on natural product building blocks, coupled with a pragmatic and target-agnostic biological profiling strategy, has the potential to lead to novel chemical entities with clinical utility that is different from and goes far beyond the biological activity of the natural product starting material.

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The author declares no competing financial interest. Biography Bart L. DeCorte completed his undergraduate education in Agricultural and Chemical Engineering at the University of Gent, Belgium. After performing graduate and postdoctoral work at the Université de Rennes, France, the University at Albany, State University of New York, NY, and Vanderbilt University in Nashville, TN, he joined Johnson & Johnson in 1993, where he is currently Associate Scientific Director. In the past three years, he served as the scientific founder and chemistry leader of a natural products based internal drug discovery venture. In the two decades prior to that, he worked for J&J on three continents in the areas of HIV, mycology, oncology, pain, inflammation, and metabolic disease. He is a coinventor of Intelence, J&J’s first FDA-approved NNRTI for the treatment of HIV.

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ACKNOWLEDGMENTS The author wishes to thank Drs. Chris Teleha and Ed Lawson for helpful discussions and editorial suggestions.

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Corresponding Author

*Phone: 215-514-9668 E-mail: [email protected]. 9301



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