Affiliation:
1. Department of Chemistry and Biochemistry and the Warren Center for Drug Discovery University of Notre Dame Notre Dame IN 46556–5670 USA
2. Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD 20892 USA
3. Center for Cancer Research National Cancer Institute Bethesda MD 20892 USA
Abstract
AbstractThrough an understanding of the conformational preferences of the polyketide natural product (−)‐zampanolide, and the structural motifs that control these preferences, we developed a linear zampanolide analogue that exhibits potent cytotoxicity against cancer cell lines. This discovery provides a set of three structural handles for further structure‐activity relationship (SAR) studies of this potent microtubule‐stabilizing agent. Moreover, it provides additional evidence of the complex relationship between ligand preorganization, conformational flexibility, and biological potency. In contrast to medicinal chemistry dogma, these results demonstrate that increased overall conformational flexibility is not necessarily detrimental to protein binding affinity and biological activity.
Funder
National Institutes of Health
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology