Total synthesis and biological evaluation of C16 analogs of (-)-dictyostatin.
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.
Jung
Won-Hyuk
WH
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Harrison
Cristian
C
Shin
Youseung
Y
Fournier
Jean-Hugues
JH
Balachandran
Raghavan
R
Raccor
Brianne S
BS
Sikorski
Rachel P
RP
Vogt
Andreas
A
Curran
Dennis P
DP
Day
Billy W
BW
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002417:Cattle; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008870:Microtubules / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
D000970:Antineoplastic Agents; D018942:Macrolides; D014404:Tubulin; C470814:dictyostatin