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Pure Appl. Chem., 2009, Vol. 81, No. 6, pp. 1085-1091

Published online 2009-05-05

Structure-based synthesis: From natural products to drug prototypes

Stephen Hanessian

Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-ville, Montréal, QC, H3C 3J7, Canada

Abstract: X-ray crystallographic data available from complexes of natural and synthetic molecules with the enzyme thrombin has led to the design and synthesis of truncated and hydrid molecules exhibiting excellent inhibition in vitro. The design element has also been extended to the synthesis and in vitro inhibition of a series of achiral molecules deploying aromatic and heterocyclic core motifs with appropriately functionalized appendages that provide excellent binding interactions at the S1, S2, and S3 sites of thrombin. Excellent selectivity for thrombin over trypsin has also been observed. Thus, studies in total synthesis of highly active natural aeruginosins have inspired further work toward truncated and hybrid analogs with excellent inhibitory activities. Structure-based organic synthesis has guided our research from natural products toward unnatural drug-like prototypes.