Synthesis and Biological Evaluation of Phorboxazole Congeners Leading to the Discovery and Preparative-Scale Synthesis of (+)-Chlorophorboxazole A Possessing Picomolar Human Solid Tumor Cell Growth Inhibitory Activity

Highly convergent syntheses of eight phorboxazole congeners and their evaluation against a diverse panel of human solid tumor cancer cell lines have been achieved. Specifically, the C(45-46) alkyne, alkene, and alkane phorboxazole A analogues [(+)-4-(+)-6] were constructed and found to display single digit nanomolar cell growth inhibitory activities in a series of human cancer cell lines. The structurally simplified C(11-15)-acetal congener (+)-20Z also proved potent albeit reduced (cf. 34.6 nM) when evaluated against the same cell line panel. Importantly, (+)-C(46)-chlorophorboxazole A (3) displayed picomolar (pM) inhibitory activity in several cell lines.