The bengamides are marine natural products, isolated from Jaspidae sponges, which display a wide range of biological activities. Their antitumor properties in particular have prompted intense research efforts, including the development of LAF389 by Novartis as a clinical candidate. The study of LAF389 was halted, however, by poor pharmacokinetic properties and unclear side effects during the phase I clinical trial.In an effort to improve the pharmacokinetic and antitumor properties of bengamide-related compounds, we have designed a novel series of analogues in which the caprolactam ring is replaced with a linear alkyl chain. Among these caprolactam ring-opened analogues, several show potent antitumor activity against MDA-MB-435 human breast cancer cells (IC50= 4-20 nM) and good water solubility. These analogues are synthetically more accessible than the parent natural products and provide possibilities for further SAR studies to afford novel candidates for development.

Design, synthesis, and biological evaluation of ring-opened bengamide analogs as anticancer agents

247th National Meeting (2014)

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