Data from A Simplified Synthesis of Novel Dictyostatin Analogues with <i>In Vitro</i> Activity against Epothilone B–Resistant Cells and Antiangiogenic Activity in Zebrafish Embryos

Abstract

<div>Abstract<p>The natural product (−)-dictyostatin is a microtubule-stabilizing agent that potently inhibits the growth of human cancer cells, including paclitaxel-resistant clones. Extensive structure–activity relationship studies have revealed several regions of the molecule that can be altered without loss of activity. The most potent synthetic dictyostatin analogue described to date, 6-<i>epi</i>-dictyostatin, has superior <i>in vivo</i> antitumor activity against human breast cancer xenografts compared with paclitaxel. In spite of their encouraging activities in preclinical studies, the complex chemical structure of the dictyostatins presents a major obstacle for their development into novel antineoplastic therapies. We recently reported a streamlined synthesis of 16-desmethyl-25,26-dihydrodictyostatins and found several agents that, when compared with 6-<i>epi</i>-dictyostatin, retained nanomolar activity in cellular microtubule-bundling assays but had lost activity against paclitaxel-resistant cells with mutations in β-tubulin. Extending these studies, we applied the new, highly convergent synthesis to generate 25,26-dihydrodictyostatin and 6-<i>epi</i>-25,26-dihydrodictyostatin. Both compounds were potent microtubule-perturbing agents that induced mitotic arrest and microtubule assembly <i>in vitro</i> and in intact cells. <i>In vitro</i> radioligand binding studies showed that 25,26-dihydrodictyostatin and its C6-epimer were capable of displacing [<sup>3</sup>H]paclitaxel and [<sup>14</sup>C]epothilone B from microtubules with potencies comparable to (−)-dictyostatin and discodermolide. Both compounds inhibited the growth of paclitaxel- and epothilone B–resistant cell lines at low nanomolar concentrations, synergized with paclitaxel in MDA-MB-231 human breast cancer cells, and had antiangiogenic activity in transgenic zebrafish larvae. These data identify 25,26-dihydrodictyostatin and 6-<i>epi</i>-25,26-dihydrodictyostatin as candidates for scale-up synthesis and further preclinical development. <i>Mol Cancer Ther; 10(6); 994–1006. ©2011 AACR</i>.</p></div>