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Pure Appl. Chem., 2009, Vol. 81, No. 2, pp. 169-180

Total synthesis of novel dictyostatin analogs and hybrids as microtubule-stabilizing anticancer agents

Ian Paterson, Nicola M. Gardner and Guy J. Naylor

University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK

Abstract: Structural modification of the dictyostatin macrolide template through adaptation of our total synthesis has led to the identification of a number of potent analogs of this novel microtubule-stabilizing agent. A common synthetic strategy was exploited, employing a (Z)-selective Still-Gennari olefination between various advanced C11-C26 aldehyde and C4-C10 (or C1-C10) β-ketophosphonate intermediates. In vitro evaluation of the growth inhibitory activity of these analogs against both Taxol-sensitive and -resistant human cancer cell lines has provided a foundation for structure-activity relationship (SAR) studies to help define the pharmacophore region.