5 - Purity and Quantity Determination of Parallel Synthesis Compound Libraries

Abstract

Combinatorial chemistry covers a large variety of synthetic approaches designed to form diverse libraries of compounds with the promise that some molecules will successfully target diseases and lead to new medicines. Split-and-pool and parallel synthesis are two such synthesis techniques. Split-and-pool approaches aim to maximize molecular diversity within a single reaction vessel. Parallel synthesis strategies attempt to create a single product per well. It is the most labor intensive of the combinatorial processes with respect to compound preparation and analysis, but there is a significant advantage since it can be used to produce compounds that can be screened for initial hits and used directly in late-stage studies. Regardless of the production method, ultimately, compounds must be positively identified and they must be of a high quality with sufficient purity and quantity to identify hits against disease targets, but to support late-stage drug discovery studies including toxicology and pharmacokinetics. ArQule, Inc. was one of the first companies to develop and successfully implement automated high throughput parallel synthesis of several hundred thousand single compounds per year in a spatially addressable format. The characterization of compounds produced in such an automated high throughput process, places significant demands on laboratory workflow; chromatographic methodology; instrument capacity; and data capture, processing and storage. To address the requirements of characterization in an efficient and cost-effective manner, a defined analytical strategy must be developed and employed. The need for more efficient and effective compound synthesis to support drug discovery has thus fueled the development of high throughput parallel synthesis to expand the efficiency of traditional medicinal chemistry.