| Abstract
| - (−)-Dictyostatin is a sponge-derived, 22-member macrolactone natural product shown to causecells to accumulate in the G2/M phase of the cell cycle, with changes in intracellular microtubules analogousto those observed with paclitaxel treatment. Dictyostatin also induces assembly of purified tubulin morerapidly than does paclitaxel, and nearly as vigorously as does dictyostatin's close structural congener,(+)-discodermolide (Isbrucker et al. (2003), Biochem. Pharmacol. 65, 75−82). We used synthetic (−)-dictyostatin to study its biochemical and cytological activities in greater detail. The antiproliferative activityof dictyostatin did not differ greatly from that of paclitaxel or discodermolide. Like discodermolide,dictyostatin retained antiproliferative activity against human ovarian carcinoma cells resistant to paclitaxeldue to β-tubulin mutations and caused conversion of cellular soluble tubulin pools to microtubules. Detailedcomparison of the abilities of dictyostatin and discodermolide to induce tubulin assembly demonstratedthat the compounds had similar potencies. Dictyostatin inhibited the binding of radiolabeled discodermolideto microtubules more potently than any other compound examined, and dictyostatin and discodermolidehad equivalent activity as inhibitors of the binding of both radiolabeled epothilone B and paclitaxel tomicrotubules. These results are consistent with the idea that the macrocyclic structure of dictyostatinrepresents the template for the bioactive conformation of discodermolide.
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