Semisynthetic analogues of the microtubule-stabilizing agent discodermolide: preparation and biological activity.
A series of 12 semisynthetic discodermolide analogues, 2-13, have been prepared using natural (+)-discodermolide (1) and evaluated for in vitro cytotoxicity against cultured murine P-388 leukemia and A-549 human adenocarcinoma cells. These semisynthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 through C-19 molecular fragment for potency. Specifically, these analogues suggested the importance of the C-11 and C-17 hydroxyl groups and the C-13 double bond for the potency of discodermolide. The preparation, structure elucidation, and biological activity of these new analogues are described.
Gunasekera
Sarath P
SP
Division of Biomedical Marine Research, Harbor Branch Oceanographic Institution, 5600 U.S. 1 North, Fort Pierce, FL 34946, USA. sgunaseker@hboi.edu
Longley
Ross E
RE
Isbrucker
Richard A
RA
D000230:Adenocarcinoma; D000473:Alkanes; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007941:Leukemia P388; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011161:Porifera / Q000737:chemistry; D011753:Pyrones; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; C071229:discodermolide