COVER STORY MULTIPLYING POWER Synthetic organic chemistry yields compounds nature did not bother to make. core of penicillin, for example, because of intellectual property issues," Hardy says. Many ofthe company's scaffolds come from plants native to southern India. A good example of a scaffold, Hardy says, is galanthamine, a natural product isolated from various plants, including daffodil bulbs, and now used to treat Alzheimer's disease. The group of Harvard University chemistry professor Matthew D. Shair prepared a 2,527-member library directed at discovering new compounds with biological activities different from that of galanthamine. One member, the new compound named secramine, inhibits protein trafficking by the Golgi apparatus \J.Am. Chem. Soc, 123,6740 (2001)}. "We wouldn't necessarily make all the compounds" prepared by the Harvard group, Hardy says. Instead, at Aurigene, crystal structures of targets help direct what molecules will be made, he explains. "Combinatorial chemistry has great utility, but we need to seed it with information from natural products and refine it through rational design." Libraries developed with guidance from natural products make a lot of sense, because they match the elements of conservatism and diversity simultaneously expressed by biological targets, says Herbert Waldmann, a professor of chemical bioloA. MAUREEN ROUHI, C&EN WASHINGTON gy at Max Planck Institute of Molecular Physiology, Dortmund, and the UniversiANY PROGRAMS IN PLACE IN against vancomycin-resistant bacteria have ty of Dortmund, in Germany The same industry and academia make emerged from combinatorial libraries of can be said for privileged structures, which compounds based on natural vancomycin dimers [Curr. Opinion Drug are structural motifs that bind strongly to products or designed to be Discov. Dev., 5,304 (2002)}. various proteins. like natural products. They Scaffolds from natural produtilize three ways to go beyond natural K. C Nicolaou, a chemistry ucts already known to have bioproducts: building around natural product professor at Scripps Research Inlogical activity are a good place scaffolds with combinatorial chemistry stitute and at the University of to start, says Larry Hardy, directechniques, assembling natural-productCalifornia, San Diego, is a leadtor of biology at Aurigene Dislike compounds through diversity-orienting advocate of developing licovery Technologies, a Bostoned synthetic routes, and creating new natbraries based on privileged strucbased drug discovery company. ural product derivatives based on paths tures derived from natural A scaffold that's amenable to made accessible by target-oriented synproducts. "Scaffolds of natural convergent total synthesis, is itthesis. All can advance drug discovery origin, which presumably have self small, has multiple diversity undergone evolutionary selecpoints (points around which the Combinatorial libraries based on natuNATURAL tion over time, might confer fastructure can be varied) that are ral product scaffolds —core structures PRODUCTS vorable bioactivities and biodistant from each other, and has around which analogs and derivatives are availabilities to library members," he and good physical properties is an ideal candiproduced—are not new For example, comcoworkers wrote in the first reports of their date for a combinatorial library, he says. binatorial chemistry around scaffolds of efforts in this direction \Jf.Am. Chem. Soc, tubulin inhibitors is paving the way for new 122,9939,9954, and 9968 (2000)]. anticancer drugs. Libraries of paclitaxel ANOTHER THING to keep in mind is analogs have yielded four second-generaNicolaou's team prepared a 10,000whether the scaffold is already highly reption drug candidates in clinical trials. Those member combinatorial library based on resented in proprietary molecules. Although of curacin A have brought out viable can- Aurigene uses scaffolds in the public do2,2-dimethylbenzopyran, a motif found didates for drug development. And in the in more than 4,000 compounds, includmain, it is interested only in libraries that are anti-infectives area, compounds active ing natural products, that exhibit a wide patentable. "We wouldn't build around the
MOVING BEYOND NATURAL PRODUCTS
Organic synthetic chemistry amplifies the potential of natural products as drug leads
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aminations. We apply those observations range of biological activities. "Nature ob to diversity-oriented synthesis, which is to the compounds we want to synthesize." viously loves this skeleton for some rea combinatorial chemistry to produce diverse Diversity-oriented synthesis is not son," Nicolaou tells C&EN. Subsets of skeletons and stereochemistries with high about, but does not ex the libraries were distributed to various appending potential, clude, use of natural groups for biological investigations. The rather than appendage product scaffolds, Wipf harvest has been rich. variations on a single adds. " Y)u want to gen skeleton (C&EN, March T h e library has provided leads for, erate structures that are 3, page 51). among others, agents against methicillinquite different. If you resistant Staphylococcus aureus and inhibitors Part of the inspira simply play with a scaf of NADH:ubiquinone oxidoreductase, an tion for diversity-ori fold, you'll probably still enzyme involved in oxidative phosphory ented synthesis is natu be limiting yourself to lation. Most recently, in collaboration with ral products, says Peter less diversity than you Ronald M. Evans andJoseph P. Noel at the Wipf, a chemistry pro can access otherwise." Salk Institute for Biological Studies, Lajolfessor at the University Wipf says the Schrei la, Calif., and others, the Nicolaou team of Pittsburgh whose re ber group's 2 million-compound effort optimized a lead from the library to a po search includes diversity-oriented synthe bridges simple, appendage-modifying com tent ligand of the farnesoid X receptor sis. "Natural products are diverse because binatorial chemistry and diversity-orient (FXR), a key receptor in bile acid and cho of the presence of many rings—fused and ed synthesis. "They used known reactions lesterol metabolism [Org. Biomol. Chem., 1, bridged—with functionalizations at dif and readily available compounds," he ex 908 (2003)]. The developed compound, ferent positions, usually oxygenations and plains. "But the reactions dramati called fexaramine, has now made cally changed the structures of start possible the structure elucidation ADVANTAGED ing materials. In particular, a lot of of FXR[M?Z Cell, 11,1079 (2003)]. C o m b i n a t o r i a l c h e m i s t r y based on a privileged rings were introduced. The next "The three-dimensional struc structure... step now is to increase the number ture of FXR was unknown until we of reactions that can make such found a lead from the benzopyran dramatic changes." library," Nicolaou says. "Now we Methodologies are being worked have a crystal structure of the lig out by many groups, including those and binding in the pocket of the re of Schreiber, Shair, and Wipf. With ceptor, which could be the begin 2,2-Dimethyl-2H-benzopyran diverse skeletons, far fewer than 2 ning of a drug discovery program." ... f u r n i s h e s potent inhibitors of d i s e a s e - r e l a t e d million compounds might suffice. Meanwhile, there is a school of proteins... Does diversity-oriented synthe thought that believes the universe sis matter for drug discovery? Some of natural products does not have people think so. For example, at enough members to probe all bio VivoQuest, an early-stage pharma logical processes and/or treat human ceutical company based in Valley diseases. Therefore, what is required Cottage, Ν. Υ, creating combinato is a collection of small molecules that rial libraries through diversity-ori have the complexity of, but are not (CH3)2N^^^ " ^ " ^ ^C0CH3 ented synthesis is a major focus, says necessarily based on, natural prod Fexaramine, inhibitor of farnesoid X receptor Anthony Sandrasagra, director of ucts and that will populate regions biology The firm's chemistry direc of chemical space broadly tor, Zhen Yang, trained with Nico OCHo laou and Schreiber and is steeped in FIVE YEARS AGO, Harvard Uni both total synthesis of natural prod versity chemistry professor Stuart ucts and combinatorial synthesis of OCHo L. Schreiber and coworkers under natural-product-like compounds. took a combinatorial chemistry ef OCHo fort toward preparing such a col Others believe that diversity-ori Inhibitor of NADH:ubiquinone oxidoreductase lection. They made 2 million ented synthesis will deliver tools to ... a n d a g e n t s a g a i n s t m e t h i c i l l i n - r e s i s t a n t compounds that can be used for probe basic biology but not neces bacteria chemical genetics—the use of small sarily drug leads. "When you follow molecules to interrogate biological nature's leads, you already have bio processes \J. Am. Chem. Soc, 120, logical activity somewhere there," 8565 (1998)]. Science named the feat Nicolaou says. "The chance of find one of the top 10 scientific achieve ing activity among compounds un ments of 1998. related to nature, I believe, is less." Waldmann concurs. "For basic Now, Schreiber says that the 2 biology, I fully subscribe to diversi million compounds are disappoint ty-oriented synthesis," he says. "No ing. W h e n mapped on chemical doubt, that is a valid and proven way space, the compounds form clumps, to find compounds for chemical ge because most of the structural di netics. It has the potential to dis versity is due to appendage modifi cover new opportunities not procation. The focus has since shifted
"Combinatorial chemistry has great utility, but we need to seed it with information from natural products/'
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COVER STORY vided by nature. But when it comes to drugs, compounds that are meaningful to nature, I believe, will have a higher success rate." Diversity-oriented synthesis makes a lot of sense for the highthroughput-screening paradigm of current drug discovery, says Samuel J. Danishefsky, a chemistry professor at Columbia University and director of the Laboratory for Bioorganic Chemistry at Sloan-Kettering Institute for Cancer Research, New York City "But I think the dividend in terms of drugs will take longer to be realized." Danishefsky is a prime proponent of yet another way to go beyond natural products for drug discovery. And that is by preparing hypothesis-driven natural product analogs through paths made accessible by the mastery of molecular architecture that total synthesis enables. Medicinal chemistry starting with a natural product can only go so far. Structural changes that can lead to better properties may not
NATURE LEADS A library based on a natural product...
CHoO
Galanthamine, an antidementia drug
... turns up a new compound with a different activity
OCHo
Secramine, a galanthamine-based molecule that blocks protein trafficking
be possible with the natural product as starting material. But they might be implemented if the compound is built from scratch. Structural modifications of epothilones implemented in this manner by the Nicolaou and Danishefsky groups in the late 1990s have led to designed epothilones that are in clinical trials for cancer chemotherapy A more recent example is the case of radicicol, a compound with novel antitumor properties in vitro that is not active in vivo. Danishefsky and coworkers guessed that converting the epoxide in radicicol to a cyclopropane ring would lead to a compound that's active in vivo. It would have been prohibitive to make that change starting with radicicol, he says. "The rest of the molecule would have crumbled under the force of the reactions you would have had to use. So we built in the cyclopropane from the beginning." Danishefsky's lab has developed two routes to cycloproparadicicol [Angew. Chem. Int. Ed., 42, 1280
National Chemistry Week 9>fc l·
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naflonal cneiïiistrv wa»> NCW products available at chemistry.org /store T-shirts • Goggles
Join volunteers across the country: - visit schools, museums, and libraries - present chemical demonstrations - conduct hands-on activities - host contests and games
Periodic Tables
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(2003); J. Am. Chem. Soc, 125, 9602 (2003)}. As predicted, the compound is active in vivo. Another recent example is the designed epothilone called 26trifluoromethyl-(E)-9,10-dehydrodesoxyepothilone B. On the surface, it is only slightly differ ent from the original natural prod uct epothilone B. It has a double bond where the original has an epoxide and a trifluoromethyl group where the original has a methyl group. The changes, the Danishefsky team thought, would yield an analog with much better pharmacokinetic properties and bioavailability The compound now has been prepared and tested against tu mors in mice. At a dose of 30 mg per kg, the compound obliter ates tumors with no relapse for more than two months [Angew. Chem. Int. Ed., 42,4761 (2003)}. Danishefsky says the structural changes, especially the intro duction of the trifluoromethyl
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