August 19, 2000
Diversity-oriented synthesis (often referred to as combinatorial chemical synthesis) is a process by which multiple compounds are generated simultaneously in a predictable fashion by using techniques that involve parallel chemical transformations. A chemical library may be small (e.g., dozens of compounds) and focus on a narrow range of structural variants, or it may be large (e.g., thousands of compounds) and encompass a wide variety of structures. When subjected to high-throughput biological screens, chemical diversity libraries provide unprecedented opportunities for the rapid identification of small molecules with potent physiological effects.
National Institute of General Medical Sciences staff convened this meeting to discuss the needs and opportunities in diversity-oriented synthesis and library development. The discussion was organized into three major topics:
There was broad agreement on the lasting value of diversity-oriented synthesis and that the challenges are substantially different from those of target-oriented, single molecule synthesis. Three general areas of need were identified--development of enabling methodologies, generation of diversity libraries, and screening of libraries (including sample preparation)--each with its own challenges and opportunities. At this early stage in the development of diversity-oriented synthesis, the tools for building chemical diversity libraries (see below) are limited in both number and sophistication, which in turn constrains the structural complexity, diversity, and quality of libraries. The limited range of chemistry that can now be employed reliably is especially problematic as it applies to the generation of focused libraries used to follow up initial "hits." Furthermore, because this is such a new area, the principles that should guide development of methods for diversity-oriented synthesis as well as the strategies for library design have not been completely established. Even the phrase "diversity-oriented synthesis," which most of the participants preferred to "combinatorial chemistry," needs to be defined carefully within an initiative. Training in this new area has not yet been incorporated into many academic curricula.
Some of the specific research topics that warrant immediate investigation include the following: new synthetic methods (especially catalytic methods) and adaptation of existing methods, imaginative synthetic strategies that lead to increased diversity within libraries, novel molecular diversity (e.g., the development of new "scaffolds" that can be elaborated into diverse families of chemical structures), solid phase chemistry, methods for chemical analysis of library components, separation and purification methods, encoding strategies, sample handling technologies, and novel resins and linkers. Clearly, the best way to make rapid progress on these topics is through interactive efforts of chemists from a wide range of specialties.
There also was strong agreement that the development of methodologies for diversity-oriented synthesis is a legitimate undertaking for academic (and not just industrial) chemists. Industrial chemists are under pressure to produce libraries that can be screened to identify commercial drug candidates and often do not have the time or latitude to pursue broad, fundamental studies of methodology or strategy. Moreover, much of the methodological research conducted in industry is proprietary and therefore unavailable to the academic community. The participants were unconcerned that academic chemists might "rediscover" methods already known to industrial chemists, since "rediscovery" and publication in scholarly journals would allow the entire scientific community to adopt these methods. Even so, it was deemed important that researchers be afforded the flexibility to protect intellectual property.
There was agreement that in order to have a significant impact, chemical methods development must not be conducted "in isolation." All too often, new methods that work reliably and efficiently on trivial substrates are ineffective on substrates of even moderate complexity. Similarly, while new methods may work well under more standard reaction conditions, it is essential that they be validated (at a minimum, by appropriate chemical analysis) in the context of generating actual libraries. At times, biological screening will be required for process validation, particularly when strategies for library design or methods for sample preparation are being tested.
Several participants spoke to biologists' unmet need for access to chemical libraries and indicated that as synthetic organic chemists, they are approached frequently by biologists with requests to collaborate. However, collaborations frequently fail to materialize because the projects are not chemically challenging. Many chemists are reluctant to conduct large-scale and/or repetitive generation of libraries where there does not appear to be significant potential for fundamental discoveries in chemistry.
A substantial limitation to progress in diversity-oriented synthesis is the difficulty in obtaining expensive, specialized equipment, such as automated synthesizers, sampling apparatus, plate and chip readers, robotics, and liquid chromatograph-mass spectrometers. Technical support personnel for operating and maintaining this equipment are also needed.
There was significant agreement on the value of collaborative approaches for this area of research and the need for infrastructure to support teams of investigators. It was also felt that because this area still is in its infancy in academia, and because it is now beginning to be embraced by academic chemists, the timing is right for an initiative to have a major impact. Several participants commented on the desirability of changing the "culture of chemistry," which traditionally has discouraged collaborative research. A center grant type of mechanism would provide a strong stimulus for changing this pattern.
There was strong agreement that a center-type mechanism would effectively address the needs in this area. However, there was a range of opinion on how best to structure the initiative. Some participants proposed that current needs could be met by infrastructure support only. A majority felt that exploring the fundamental chemistry and validating new methods for library construction were valuable per se and thought that biological collaborations should not be required, at least initially. However, some discussants were more excited by the prospect of collaborations with biologists (for validating chemical methodology through library screening) than with other chemists (for the development of enabling methodologies). Moreover, it was urged that biologists not be excluded, although their participation should not be required. Most discussants argued strongly for flexibility in structuring an initiative.
There was general agreement that the unique challenges and opportunities presented by diversity-oriented synthesis would justify the establishment of training courses. Such courses could be administered and taught through groups of collaborators.
The discussants felt that an initiative would be received quite enthusiastically by the chemistry community, including synthetic organic chemists. There was strong agreement that an initiative would stimulate the development of technologies that would have a major impact on projects that involve the generation and screening of chemical diversity libraries.
Camille Dreyfus Professor of Chemistry
Massachusetts Institute of Technology
Distinguished Service Professor of Chemistry and Bayer Professor
University of Pittsburgh
Professor of Chemistry
University of California, Berkeley
Kenan Professor of Chemistry
University of North Carolina, Chapel Hill
Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry
Director, Global Chemical Process Research & Development
Eli Lilly and Company
Darlene Shiley Professor of Chemistry, L.S. Skaggs Professor of Chemical Biology, and Chairman of the Department of Chemistry
Scripps Research Institute
Assistant Professor of Chemistry
Director, Division of Pharmacology, Physiology, and Biological Chemistry
Warner Lambert/Parke Davis Professor of Chemistry
University of Michigan
Program Director, Pharmacology, Physiology, and Biological Chemistry
Philip W. West Professor of Chemistry
Louisiana State University
*Member of the National Advisory General Medical Sciences Council