Total synthesis and biological evaluation of potent analogues of dictyostatin: Modification of the C2–C6 dienoate region

By exploiting a Still–Gennari olefination of a common C11–C26 aldehyde with a C4–C10 or C1–C10 β-ketophosphonate, three modified C2–C6 region analogues of the 22-membered macrolide dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the Taxol-resistant NCI/ADR-Res cell line. 6-Desmethyldictyostatin and 2,3-dihydrodictyostatin displayed potent (low nanomolar) antiproliferative activity, intermediate between dictyostatin and discodermolide, while 2,3,4,5-tetrahydrodictyostatin showed activity comparable to discodermolide. As with dictyostatin, these simplified analogues act through a mechanism of microtubule stabilisation, G2/M arrest and apoptosis.