Optimization of experimental antimitotic agents: classical and combinatorial methods.

Compounds that affect the progress of the cell cycle have served as useful tools for elucidating biological function and as leads for pharmacological agents. Historically, natural products derived from terrestrial and aquatic organisms have been the richest source of lead compounds and novel pharmacophores. Discovery and development of lead compounds from natural products has traditionally involved isolation of a natural product with the biochemical activity of interest, elucidation of its structure, development of chemical or biosynthetic methods for producing the compound and related compounds in larger quantities, and eventually examination of structure-activity relationships and pharmacological properties. Combinatorial chemistry has emerged as a powerful tool for the assembly of large collections of synthetic molecules; as such, it has been adopted in grand style by the pharmaceutical industry. Combinatorial chemistry can be applied in two modes: a diversity-generating mode, where known or novel scaffolds are elaborated into libraries and screened for new activities; or a focused mode, where attention is centered on a particular site in an effort to enhance a particular property (activity, selectivity, solubility, stability, bioavailability). In either mode, identification and development of compounds of interest is dependent on iterative rounds of compound optimization based on efficient and reliable biochemical, cellular, and phenotypic assays.