%A WH Jung
%A C Harrison
%A Y Shin
%A JH Fournier
%A R Balachandran
%A BS Raccor
%A RP Sikorski
%A A Vogt
%A DP Curran
%A BW Day
%J Journal of Medicinal Chemistry
%T Total synthesis and biological evaluation of C16 analogs of (-)-dictyostatin
%X The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy was used to prepare milligram quantities of 16-normethyldictyostatin, 16-epi-dictyostatin, and the C16-normethyl-C15Z isomer. Along the way, a number of other E/Z isomers and epimers were prepared, and a novel lactone ring contraction to make iso-dictyostatins with 20-membered macrolactones (instead of 22-membered macrolactones) was discovered. The synthesis of 16-normethyl-15,16- dehydrodictyostatin is the first of any dictyostatin by a maximally convergent route in which three main fragments are assembled, coupled in back-to-back steps, and then processed through refunctionalization and macrolactonization. Cell-based and biochemical evaluations showed 16-normethyl-15,16- dehydrodictyostatin and 16-normethyldictyostatin to be the most potent of the new agents, only 2- and 5-fold less active than (-)-dictyostatin itself. This data and that from previously generated dictyostatin analogs are combined to produce a picture of the structure-activity relationships in this series of anticancer agents. ? 2007 American Chemical Society.
%N 13
%P 2951 - 2966
%V 50
%D 2007
%R 10.1021/jm061385k
%L pittir18236