Linear (−)‐Zampanolide: Flexibility in Conformation–Activity Relationships

We developed a linear variant of the potent cytotoxic (−)-zampanolide that retains nanomolar activity towards cancer cell lines. 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. High-field 2D-NMR, computational modeling, and antiproliferative assays were utilized to develop the conformation-activity relationship profile for this class of marine polyketide. This successful design strategy now provides three new sites for further analogue development; N-acyl hemiaminal side chain, C19 acyl group, and C9 ketone.

Abstract

Through 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.

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