s e ie η c e / t e c h η ο I o g y
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and decorated it with amino acid side chains. In the late 1980s, the groups of me dicinal chemist Gary L. Olson, then at Hoffmann-La Roche, Nutley, N.J., and chemistry professor Ralph F. Hirschmann of the University of Pennsylvania indepen dently explored the concept. Olson em ployed a cyclohexane scaffold, whereas Hirschmann, working in collaboration with K. C. Nicolaou, then a chemistry pro fessor at Penn, used β-D-glucose. After 1989, when Nicolaou moved to Scripps Research Institute in La Jolla, Calif., Penn Stu Borman in which they're needed—problems re- chemistry professor Amos B. Smith III ex C&EN Washington lated in part to their amide backbone tended the collaboration with Hirsch mann to studies on diverse monosaccha structures. arbohydrates play a vital role in moA strategy to design peptidomimetics ride scaffolds. "Hirschmann's putting substituents on lecular recognition, cell signaling, by totally discarding their problematical biomolecular transport, the immune amide backbones and replacing them with the oxygens of carbohydrate scaffolds is system, and, in fact, in virtually every es- novel structures—while still retaining the one of the best ideas in carbohydrate sential biological process. So it's ironic that amino acid side chains required for recep- chemistry in recent times," says chemistry when it comes to combinatorial chemis- tor binding—was first proposed in 1980 professor Daniel E. Kahne of Princeton try—the synthesis of collections of varied by Patrick S. Farmer of the College of Phar- University, who specializes in research on molecules and the subsequent identifica- macy at Dalhousie University in Halifax, bioactive oligosaccharides and glycoconjution of those with useful properties—sug- Nova Scotia. He suggested cyclohexane as gates. "It's really clever. Hirschmann and ar-based molecules are about the last thing the scaffold but was unsuccessful at dem- coworkers said sugars ought to be able to present side chains as well as peptides, researchers think about. onstrating the concept experimentally. This is largely because sugar-based In 1986, Patrice C. Bélanger and and they showed that it worked. It was compounds are darned ornery from a Claude Dufresne of the medicinal chem- just fantastic—really creative." Later on, Hirschmann, Nicolaou, and synthetic standpoint. Nevertheless, sev- istry department at Merck Frosst Canada, eral research groups are beginning to de- Pointe-Claire/Dorval, Quebec, first suc- Smith at Penn; biologists Catherine D. velop increasingly useful strategies for cessfully employed this strategy. Bé- Strader and Margaret A. Cascieri at Merck producing combinatorial libraries (collec- langer and Dufresne replaced the pep- Research Laboratories (Rahway, N.J.); biol tions of diverse compounds) based on tide backbone by a nonpeptide frame- ogy professor Wylie W. Vale at Salk Insti these difficult and contrary molecules. work—a bicyclo[2.2.2]octane scaffold— tute (La Jolla, Calif.); biochemist Laurie T. Maechler at MDS Panlabs An example of this trend is ——••— (Bothell, Wash.); and cowork an idea of using molecular ^—— ers showed that derivatized "scaffolds" for the display of Subtle structural changes affect monosaccharides were sur organic functional groups. The receptor binding prisingly good at binding a va idea, conceived in the early riety of biological targets [/. 1980s and reintroduced later Am. Chem. Soc, 114, 9217 in that decade, now is being (1992)]. translated into a novel combiThe researchers synthe natorial strategy for carbohysized a series of glucose-based drate-based drug discovery. peptidomimetics that they be The concept of varying molieved would bind to recep lecular structure and properOCHo tors for the peptide hormone ties systematically by decoratsomatostatin, and some of ing molecular scaffolds with a the compounds did so. But variety of functional groups two of the peptidomimetics stems from research efforts in 0(CH 2 ) 5 NH 2 '-0(CH 2 ) 5 NH 2 RO' also bound to other targets, in the 1970s and '80s to design R =benzyl cluding the receptor for sub peptidomimetics, compounds Source: Hirschmann and coworkers [J. Med. Chem., 41,1382 (1998)] stance P, a peptide involved in that mimic structural features Sugar-based peptidomimetic at lower right binds somatopain transmission—an unex of peptides but often have statin receptors by a different binding mode than related pected and surprising finding better potential as drugs. Peppeptidomimetics (such as the other three shown). Moreover, because somatostatin doesn't tides themselves aren't always acetylating the primary amino group of the compound at upbind the substance Ρ receptor the best drug candidates. They per left greatly enhances its affinity at the substance Ρ recep and substance Ρ doesn't bind tend to get broken down by tor but eliminates binding at somatostatin receptors--showsomatostatin receptors. In ad proteases in the gut and ing that the bioacthdty of these peptidomimetics is sensitive dition, these two peptidomi bloodstream and frequently to relatively minor structural modifications. metics bound to the β2-adrenhave trouble entering the cells
COMBINATORIAL CARBOHYDRATES
Prospects are looking sweet for use of sugar-based combinatorial libraries to find novel bioactive substances
C
JULY 20, 1998 C&EN 49
science/technology
Smith: diverse monosaccharide scaffolds
Hirschmann: sugars are privileged platforms
ergic receptor, whose endogenous ligand (the catecholamine adrenaline) is not even a peptide. Based on these findings, Hirschmann, Smith, and coworkers speculated that so matostatin and substance Ρ receptors had some heretofore unrecognized features in common. They later demonstrated this ex perimentally by readily converting a cyclic hexapeptide that acts as a highly potent and selective somatostatin receptor ligand
Sofia: pharmacophore mapping libraries
into a similarly potent and selective sub stance Ρ receptor ligand \J. Med. Chem., 39, 2441 (1996)]. Since then, they have also shown that subtle changes in a sugar scaffold—such as going from D-glucose to L-glucose or L-mannose—can lead to a sub stantial change in the biological profile of a sugar-based peptidomimetic. "This work represented the first clue that sugars represent 'privileged plat forms'—meaning that they can display
affinity to diverse receptors," says Hirschmann. "That is, there is some thing about the sugar scaffold that allows carbohydrate peptidomimetics to interact with all kinds of differ ent proteins." And it turns out that when you build combinatorial libraries to screen for biologically active "leads" (drug candidates), that's exactly what you want. Earlier this year Hirschmann, Smith, senior research fellow Susan P. Rohrer of Merck Research Labo ratories, and coworkers demonstrat ed the use of carbohydrate scaf folds to develop a potent receptor ligand for human somatostatin re ceptor subtype 4 and showed that selec tivity for specific receptors can be ob tained by modifying the substituents around a sugar ring [/. Med. Chem., 41, 1382 (1998)]. One of the most noteworthy results of this research was the discovery that one particular sugar-based peptidomimetic bound somatostatin receptors through a different mode than other sugar-based peptidomimetics. This was unexpected
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[email protected] because compounds of the same structur Edmonton, and chemistry professor Chi- an effort to identify novel ligands of carbo hydrate-binding proteins. al class most frequently bind a target in the Huey Wong of Scripps. "Oligosaccharides that bind proteins Around 1995, Kahne and coworkers same way. "But in fact you can't assume that this is the case, and that's the point of constructed the first solid-phase carbohy normally bind very weakly," says Hinds this whole business," says Hirschmann. He drate library, using oligosaccharide solid- gaul, "so we don't try to mimic oligosac notes that the alternate binding mode phe phase synthesis chemistry developed earli charides. We decided to just admit that nomenon had been previously demon er by his group, and Hindsgaul and sugars don't have the right stuff for tight strated for protease inhibitors by the coworkers developed a "random glycosyl- binding and to add some nonsugar groups, groups of professor of chemistry and phar ation" strategy for making oligosaccharide which is why we call the compounds car macy Daniel H. Rich of the University of libraries in solution. More recently, Hinds- bohybrids." Hindsgaul and coworkers Ulf Wisconsin, Madison, and chemistry profes gaul's group has been busy synthesizing J. Nilsson and Eric J-L. Fournier recently sor Dagmar Ringe of Brandeis University, " carbohybrids "—carbohydrates derivat- identified a carbohybrid that inhibits the ized with organic functional groups—in enzyme β-galactosidase with the highest Waltham, Mass. Researchers at Intercardia Research Laboratories (formerly Transcell Tech nologies), Cranbury, N.J., have been im plementing and expanding on the con B A S F I N T E R M E D I A T E S cepts devised by Hirschmann and co workers. Whereas Hirschmann's group showed how a sugar with added amino acid side chains can potentially bind re NEOL® neopentylglycol offers ceptors that the sugar wouldn't normal unique properties for coatings. ly recognize, Intercardia scientists are us ing solid-support chemistry to actually make large combinatorial libraries of such compounds. The Intercardia researchers produce an enormous amount of molecular diversity by functionalizing sugar-based ring sys tems with different kinds of protecting groups. "We were looking for a strategy that would allow us to use carbohydrates for generating libraries that could be screened against a wide variety of biomolecular targets, not just those targets that naturally recognize sugars, and we felt that this primary screening library would need NEOL offers rapid esterification to exhibit small-molecule druglike charac > / and high chemical and thermal teristics," says Michael J. Sofia, Intercarstability for your: Mike Travers dia's vice president of research and direc (800)526-1072 Gel Coat Resins tor of chemistry. Sofia and coworkers re Ext: 4773 • NEOL improves hydrolytic and cently generated such a library based on Fax: (973) 426-4752 chemical stability. monosaccharide scaffolds that have three Canada: (416) 674-2888 • Increases corrosion resistance. sites where chemical diversity could be in Fax: (416)674-2839 • Produces high-quality resins with high troduced rapidly \J. Org. Cbem., 63, 2802 molecular weight. (1998)]. "We call these libraries universal phar Powder Coating Resins macophore mapping libraries," says Sofia, • NEOL-based powder coating resins exhibit "because an analysis showed that they can greater thermal and UV stability. access chemical diversity space that is not Alkyd Coating Resins only wide-ranging but also unique when • Provides improved stability to heat and compared to, let's say, a tripeptide system ultraviolet radiation. or a small-molecule database of [noncarBASF NEOL is produced at Freeport, Texas, bohydrate] druglike molecules." Intercarunder ISO 9002 certification. dia is using the libraries to identify antiCreative Chemistry for infective agents in an internal screening At BASF, we don't make your products. Creative Chemists. program and also intends to use them in We help make them better. collaborative screening efforts with other companies. Other groups working on carbohy NEOL is a registered trademark of BASF Corporation drate-based combinatorial strategies in clude those of Kahne, chemistry professor CIRCLE 2 ON READER SERVICE CARD Ole Hindsgaul at the University of Alberta,
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BASF
JULY 20, 1998 C&EN 51
science/technology
Carbohybrids target carbohydrate-binding proteins OFt^OR Ο
II
R0Ο II R = C(CH2)10CH3
OR
SCCH3
Wong, "and you can selectively deprotect any of these positions for the glycosylation reaction" used to couple carbohydrate units. Wong's group demonstrated the technique by using it to synthesize a 45member oligosaccharide library as individ ual molecular entities. The researchers are currently screening the library for com pounds that bind to lectins and antibodies. "The application of combinatorial and
education
carbohydrate chemistry to the develop ment of novel pharmaceuticals is still in the early stages," notes Hindsgaul. "The fact that several very different approaches are being used by the various groups in creases the chances that important new discoveries will be made. In the jargon of combinatorial chemistry, not only 'molec ular diversity' but also 'research diversity' is at play"^
lm&'M.~
Lehigh offers polymer education at a distance At the start of this year, six employees of materials scientists and engineers are en industrial firms far from Lehigh Universi gaged in some form of polymer science ty in Bethlehem, Pa., began studies for and engineering at any one time, only a master's degrees in polymer science and fraction of these people have had as much engineering from the university. These as one regular polymer course," says Leslie first distance-education M.S. students in H. Sperling, director of Lehigh's Engineer Lehigh's Center for Polymer Science & ing Polymers Laboratory. "While the situa Engineering have been attending classes tion is slowly improving, polymer educa Hindsgaul and coworkers modify televised to their workplaces. They will tion clearly still lags behind as an academ carbohydrates to generate carbohy even do research for their theses without ic subject. The objective of this distance brids, such as structure at bottom—a ever going to Bethlehem. monosaccharide attached to a small The six students took two organic ring derivatized with an three-credit courses: a chem amino acid. istry course called Organic Polymer Science and a chemi activity ever achieved for inhibitors of that cal engineering course called enzyme, work that will be reported in an Polymer Interfaces. The class upcoming issue of Bioorganic & Medici sessions were televised from nal Chemistry. the campus and the encrypt Wong and coworkers recently report ed signal decoded from Le ed use of a new protection and deprotec- high at each of the work sites. tion strategy for synthesizing carbohy Students had voice tele drate-based libraries \J. Am. Chem. Soc, phone and fax links to the Le 120, 7137 (1998)]. "We have four differ high classroom and could also ent protecting groups for a sugar," says communicate by computer with Lehigh's interactive com puter. Videotape backups Sperling lectures to Polymer Interfaces students in were available when students one of two distance learning classrooms at Lehigh. missed classes because they were traveling. In addition to participating education program is to make available to in live classes, students could interact with professionals around America a chance to each other and with students on campus by address this problem." logging on to chat rooms associated with Companies interested in distance edu each course. cation partnerships with Lehigh are ex The students will eventually amass 24 pected to designate support personnel, set credits in courses from the departments aside two classrooms, and acquire the of chemistry, chemical engineering, me needed television equipment, computers, chanical engineering, materials, or phys and phone and fax lines. Lehigh charges ics, plus six credits of research. Students no partnership fees. Persons interested in applying as stu will do research on nonproprietary top ics at their workplaces, codirected by dents or who have questions about involv their employers and Lehigh professors. ing their companies should contact Peg The full-time equivalent of four to six Kercsmar, manager of the Office of Dis months of work may be needed to com tance Education, Lehigh University, 36 Uni versity Dr., Bethlehem, Pa. 18015; phone: plete their theses. "While one-third to one-half of all de (610) 758-5794, e-mail:
[email protected]. Hindsgaul: synthesizing carbohybrids greed chemical engineers, chemists, and Stephen Stinson 52 JULY 20, 1998 C&EN
