discodermolide and Leukemia-P388

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.

Topics: Alkanes; Animals; Antineoplastic Agents; Carbamates; Drug Screening Assays, Antitumor; Humans; Lactones; Leukemia P388; Mice; Microtubules; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pyrones; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured

Discodermolide (1) and five new discodermolide analogues trivially named 2-epi-discodermolide (2), 2-des-methyldiscodermolide (3), 5-hydroxymethyldiscodermolate (4), 19-des-aminocarbonyldiscodermolide (5), and 9(13)-cyclodiscodermolide (6) have been isolated from marine sponges belonging to the genus Discodermia collected from the Caribbean Sea. The isolation, structure elucidation, and biological activities of 2-6 are described. The natural analogues, which were isolated in trace amounts, exhibited significant variation of cytotoxicity against the cultured murine P-388 leukemia and A-549 human adenocarcinoma cells and suggested the importance of the C(7) through C(17) moiety for potency against cultured tumor cell lines.

Topics: Adenocarcinoma; Animals; Caribbean Region; Drug Screening Assays, Antitumor; Humans; Lactones; Leukemia P388; Mice; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Porifera; Structure-Activity Relationship; Tumor Cells, Cultured

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.

Topics: Adenocarcinoma; Alkanes; Animals; Antineoplastic Agents; Carbamates; Drug Screening Assays, Antitumor; Humans; Lactones; Leukemia P388; Mice; Microtubules; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Porifera; Pyrones; Structure-Activity Relationship; Tumor Cells, Cultured

A series of eight discodermolide acetates have been prepared using natural (+)-discodermolide and evaluated for in vitro cytotoxicity against the cultured murine P-388 leukemia cells. The acetylated analogues showed a significant variation of cytotoxicity and suggested the importance of C-11 and C-17 hydroxyl groups for potency. The preparation and structure elucidation of the new analogues are described.

Topics: Acetylation; Alkanes; Animals; Antineoplastic Agents; Carbamates; Lactones; Leukemia P388; Magnetic Resonance Spectroscopy; Mice; Microtubules; Models, Chemical; Porifera; Pyrones