COVER STORY COMBI CATALYSTS In a combinatorial study to optimize a homogeneous catalysis reaction, researchers plotted results from screening various conditions for a palladium-catalyzed Heck reaction. Horizontal axes show different solvents and bases used in the reaction, vertical displacement of spheres represents percent conversion of substrate to product, and sphere size indicates level of undesired palladium black formation indicative of catalyst deactivation. DMA = dimethylacetamide, DMSO = dimethyl sulfoxide, TEA = triethylamine.
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CHEMISTRY Progress reported in key areas such as natural-product-like libraries, dynamic combichem, catalyst optimization, and multicomponent reactions
STU BORMAN, C&EN WASHINGTON
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OMBINATORIAL C H E M I S T R Y — T H E SYNTHESIS OF
chemical compounds as ensembles (libraries) and the screening of those libraries for compounds with desirable properties—continues to evolve as a potentially speedy route to new drugs, catalysts, and other useful compounds and materials. % t the field is facing increasing criticism for not having delivered results fast enough to justify the huge investments made in it by industry academia, and government. HTTP://WWW.CEN-ONLINE.ORG
At a number of conferences held this year, researchers debated that issue and discussed advances in several areas, including natural-product-like libraries, dynamic combinatorial chemistry combinatorial optimization of catalysts, and multicomponent reactions. 'The subtleties of nature do not allowus to easily design compounds with perfect properties," says Morten Meldal, leader of the Center for Solid Phase Organic Combinatorial Chemistry at Carlsberg Laboratory in Copenhagen. He chaired Eurocombi 2—the 2nd European SympoC&EN
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COVER STORY sium on Combinatorial Sciences in Biolo gy Chemistry, Catalysts & Materials—held this summer in Copenhagen. The field "is still in its infancy, together with genomics and proteomics," Meldal tells C&EN. It has already had a dramatic influence on the chemical discovery process, "but it still has a long way to go before its full potential can be realized." "Combinatorial chemistry is useful in drug discovery, it can be an intellectually stimulating activity, and it does create val ue to society," said Anthony W Czarnik, editor of theJournal'oj'Combinatorial'Chem istry, at an American Chemical Society Prospectives conference on combinator ial chemistry last month in Leesburg, Va. "I don't think there's anyone today who would stand up and put their name and reputation behind the statement that com binatorial chemistry is useless." By applying the tools of combinatorial synthesis to make and screen large num bers of molecules, "we're coming up with new leads that could not have been found before simply by screening natural prod ucts," Czarnik continued. He cochaired the Prospectives conference with associate professor of chemistry Michael G. Organ, who is director of the Combinatorial Chemistry Facility at York University, Toronto, and reader A. Ganesan of the Combinatorial Centre of Excellence at the University of Southampton, England.
Hapalosin
Hapalosin analogs
DIVERSITY In hapalosin analogs synthesized by Maier and coworkers (bottom), a variety of amino acid side chains are incorporated at R\ and aldol condensation is used to add a range of functional groups at R 2 andR 3 .
"Has combinatorial chemistry delivered on providing compounds with important properties?" asked University of Califor nia, Berkeley chemistry professor Jonathan A. Ellman at the same meeting. "I would argue that it has delivered in providing use ful and important compounds. The con cept of making compounds in parallel and testing them in parallel to more rapidly ob tain new properties—it's very clear that this has played an important role and will continue to play an important role in avast range of disciplines." Synthesizing or purchasing libraries of purified, discrete compounds has become the norm at many drug companies, Ellman said. "There are certainly applications where mixtures can be useful, but it's clear that discretes are primarily what are pro duced and that purification and character ization are highly valued." FOR THE MOST PART, libraries are being made either by parallel synthesis or by mix ture synthesis with "directed sorting," an ap proach used to keep track ofindividual com pounds. SpHt-and-mix synthesis, a technique for synthesizing compounds in large num bers and with great diversity, "has dropped to a more minor contributor, relative to these other strategies," Ellman notes. Meldal agrees that an initial emphasis on creating mixtures ofvery large numbers of compounds "has largely given way in in dustry to a more measured approach based on arrays of fewer, well-characterized com pounds." And he notes a particularly strong move toward the synthesis of complex nat ural-product-like compounds—molecules that bear a close structural resemblance to approved natural-product-based drugs. Jeremy Κ. Μ. Sanders, head of the de partment of chemistry at Cambridge Uni versity, says that Very large libraries ofa mil lion compounds or more are going out of fashion, but smaller, more focused libraries are still much in evidence. The main divi dend ofcombichem in pharma is that it pro vided the stimulus for robot-controlled and immobilization strategies that allow highthroughput and multiple parallel ap proaches to drug discovery Combinatorial approaches are also now being adopted for solid-state and materials applications and in the search for new catalysts." Professor of medicinal chemistry Rob M.J. Liskamp of Utrecht University, in the Netherlands, adds that "combinatorial
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"The field does not have to demonstrate its value any more, and expectations for it are now at a realistic level." 46
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COVER STORY to discovery" highlighted in the N I H road map announced last month (http://nihroad map.nih.gov). As part ofthis program, N I H will assemble a huge combinatorial library as a source of new drug candidates. According to N I H , "National centers will initially establish a collection of 500,000 chemically diverse small mole cules of both known and unknown activi ties. Over time, this collection will be ex panded and modified to provide a working set ofcompounds that will target larger do mains of'biological space,' the total set of biomolecular surface domains that are ca pable ofinteracting with a small molecule." The library will "offer public-sector bio medical researchers access to small organ ic molecules [that] can be used as chemi cal probes to study cellular pathways in
complex compounds that are highly like ly to exhibit interesting and useful types of biological activity At the ACS Prospectives conference, researcher Michael A. Foley of Infinity Pharmaceuticals, Cambridge, Mass., point ed to a number of problems with earlier combinatorial libraries. They were often based on a single skeleton, the individual library members were structurally similar, only a limited number of skeletons were accessible, and compounds tended to be predominantly achiral or racemic. Such compounds couldn't reach many biologi cal target types, he said. Foley and colleagues use diversity-ori ented synthesis to design complex libraries that will potentially prove to have fewer drawbacks. They use biologically relevant building blocks and branching net Free-energy landscape^ works of reactions to produce li Building blocks braries of natural-product-like compounds that have properties consistent with those ofdrug leads. Infinity is currently screening such libraries for compounds with anti bacterial, antifungal, and anticancer High-affinity activity • Library of receptor A potential step toward natu interconverting receptors identified ral-product-like libraries of un precedented diversity was made last week, when Schreiber and /V-Methylisoquinolinium coworkers reported a strategy for Dynamic combinatorial guest library of interconverting making small-molecule libraries macrocyclic disulfides with all possible combinations of a set of both core skeletal struc tures and peripheral groups [Sci Dithiol building Receptor with micromolar blocks ence, 302, 613 (2003)]. In most li affinity amplified brary syntheses, diverse peripheral groups are attached to a single PROOF OF PRINCIPLE In dynamic combinatorial chemistry (top), receptorcore. The new approach achieves guest interactions in an equilibrium system are used to amplify the best binding core and peripheral diversity si components (receptor molecules in lowest-energy potential well at right). A recent multaneously by using special core example is an experimental study (bottom) by Otto's group in which addition of a structures ("latent intermediates") guest to a dynamic library of macrocyclic disulfide receptors resulted in that react with peripheral groups amplification of a receptor with high affinity for that guest. ("skeletal information elements") to generate diverse skeletons. greater depth." The initiative will also ty-oriented synthesis and is headed by Chemistry professor Martin E. Maier "speed the development of new drugs and chemistry and chemical biology professor and coworkers at the University of Tubin agents to definitively detect and treat com and Howard Hughes Medical Institute in gen, Germany have been using parallel syn mon and rare diseases by providing earlyvestigator Stuart L. Schreiber. NIGMS es thesis to create natural-product-like li stage compounds that encompass a broad timates that the CMLD awards will total braries of cyclic depsipeptide analogs. range of novel targets and activities." nearly $40 million over the five-year initial Depsipeptides are peptidelike compounds grant lifetimes of all four centers. with both ester and amide linkages instead NATURAL-PRODUCT-LIKE LIBRARIES. "Together with an array of recent ad ofjust amide bonds. Maier's group has syn vances in biomedicine, the broad avail Pharmaceutical companies have now been thesized libraries of hapalosins, depsipep ability of diverse chemical libraries could using combinatorial chemistry for drug tides with known activity in reversing mul help launch a new and exciting era of pre discovery for about a decade. Some of the tidrug antibiotic resistance. Some hapalosin clinical disease detection and personalized earlier libraries they synthesized have been analogs they made have turned out to be and targeted medicines," said N I H Di discredited for being poorly designed, un biologically active. The researchers are cur rector Elias A. Zerhouni in announcing the practically large, and structurally simplis rently developing methods to isomerize altwo new CMLDs. tic. That's why drug researchers are in dols and other small-molecule building creasingly embracing natural-product-like The topic of "molecular libraries and blocks, combine them, and then cyclize libraries—moderate-size collections of imaging" is also one of five "new pathways Earlier this month, the National Insti tute of General Medical Sciences (NIGMS), a unit of the National Institutes of Health, renewed an earlier vote of confidence in combinatorial technology by awarding a total of $5.6 million in first-year funding to two new Centers of Excellence in Chem ical Methodologies & Library Develop ment (CMLDs). The first two CMLDs—at Boston Uni versity and the University of Pittsburgh— were funded in September 2002 (C&EN, Nov 11,2002, page 43). Two more are now being set up: One, at the University of Kansas, Lawrence, focuses on the design of molecular scaffolds (combinatorial core structures) and is led by medicinal chem istry professorJeffrey Aube. The other, at Harvard University, specializes in diversi-
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COVER STORY them to form depsipeptides—a method that mimics the way terpenes are synthe sized biologically. Cyclic depsipeptides have also been syn thesized by other groups, including those of chemistry professors Richard B. Silverman of Northwestern Univer sity, Dale L. Boger of Scripps Research Insti tute, and Takashi Takahashi of Tokyo Institute of Technology Last year, Boger and coworkers synthesized a library of cyclic depsipeptides and developed a "chemical mutagenesis" approach to defining their structure-function properties. And fol lowing up on their total syntheses of the natural depsipeptide sansalvamide A and the natural cyclic peptide scytalidamide A, Silverman and coworkers recently made a library of sansalvamide A analogs and found two of them to be more potent than the natural product. Chemistry professor Sidney M. Hecht and coworkers at the University of Virginia,
Charlottesville, have been synthesizing bleomycins and bleomycin analogs, both as mechanistic probes and potentially bioactive agents. Bleomycins are glycopeptide antitumor antibiotics that are believed to act by a se quence-selective nucle ic acid cleavage mecha nism and are used to treat squamous cell carcinomas, malignant lymphomas, and other cancers. Hecht's group recently synthesized, purified, and character ized a library of 10 8 deglycobleomycin analogs \J.Am. Chem. Soc, 125,8218 (2003)]. The study was the first in which analogs of bleomycin or deglycobleomycin were found to have greater DNA cleavage ac tivity than the parent bleomycins from which they were derived. Liskamp and coworkers are designing tripodal (triple-binding) agents "to obtain molecular constructs with levels of affini ty and selectivity similar to those of anti bodies," Liskamp explains. The antigen-
"The subtleties of nature do not allow us to easily design compounds with perfect properties."
binding site of an antibody is composed of six hypervariable loops, or complemen tarity-determining regions (CDRs). "We use relatively small synthesized molecules as scaffolds that each present three differ ent peptide chains, or loops," he says. "Two such sets of loops, if covalently combined, would lead to a molecular construct con taining six loops, like an antibody's CDRs. The idea is to have six different ligands in teracting with different sites on the same antigenic protein." Last year, Liskamp and coworkers took a key step toward this goal by decorating a triazacyclophane scaffold with three dif ferent peptides \J. Comb. Chem., 4, 275 (2002)]. More recently, they showed that cyclotriveratrylene can be used as a scaffold for the solid-phase synthesis of a library of tripodal "receptors" with peptidic arms \J. Comb. Chem., published online Aug. 26, http://dx.doi.org/10.1021/cc034003u]. DYNAMIC C0MBICHEM. Dynamic com binatorial chemistry (DCC) is a relatively new way of synthesizing and identifying small molecules that bind with high affin ity to macromolecular receptors—or con-
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