Synthetic analogues of the microtubule-stabilizing agent (+)-discodermolide: preparation and biological activity.
A series of seven synthetic discodermolide analogues 2-8, which are minor side products generated during the final stages in the synthesis of (+)-discodermolide (1), have been purified and evaluated for in vitro cytotoxicity against A549, P388, MFC-7, NCI/ADR, PANC-1, and VERO cell lines. These synthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 hydroxy through C-17 hydroxy molecular fragment for potency. Specifically, these analogues suggested the relevance of the C-11 hydroxyl group, the C-13 double bond, and the C-16 (S) stereochemistry for the potency of (+)-discodermolide. The preparation, purification, 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 US 1 North, Fort Pierce, Florida 34946, USA. sgunaseker@hboi.edu
Mickel
Stuart J
SJ
Daeffler
Robert
R
Niederer
Daniel
D
Wright
Amy E
AE
Linley
Patricia
P
Pitts
Tara
T
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; 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; D011753:Pyrones; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; C071229:discodermolide