Synthesis and biological evaluation of 10,11-dihydrodictyostatin, a potent analogue of the marine anticancer agent dictyostatin.
By employing a diverted total synthesis strategy with late-stage intermediates, 10,11-dihydrodictyostatin ( 5) was prepared and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the NCI/ADR Taxol-resistant cell line. This novel dictyostatin analogue was found to retain potent antimitotic activity, with a comparable profile to discodermolide and Taxol, functioning by microtubule stabilization and G2/M arrest. These SAR studies provide further insight into the interaction between dictyostatin ( 1) and its tubulin target.
Paterson
Ian
I
University Chemical Laboratory, Cambridge, UK. ip100@cam.ac.uk
Gardner
Nicola M
NM
Poullennec
Karine G
KG
Wright
Amy E
AE
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry; D013237:Stereoisomerism; D014404:Tubulin / Q000378:metabolism
C529251:10,11-dihydrodictyostatin; D000970:Antineoplastic Agents; D018942:Macrolides; D014404:Tubulin; C470814:dictyostatin; D017239:Paclitaxel