aigialomycin-d and Breast-Neoplasms

A program currently ongoing in our laboratory envisions natural macrolide radicicol-based inhibitors targeting the molecular chaperone Hsp90. Such inhibitors can be potential anticancer agents due to their ability to induce the breakdown of a variety of oncogenic proteins. In this account, we first concern ourselves with a vastly important total synthesis of such an inhibitor. We accomplished this via a new approach, which we term the "ynolide method", directed to the synthesis of resorcinylic macrolides, including cycloproparadicicol and aigialomycin D. The key features of the syntheses involve cobalt-complexation-promoted ring-closing metathesis (RCM) to generate ynolides, followed by Diels-Alder reaction with dimedone-derived bis-siloxy dienes to elaborate the benzo system. A number of interesting analogues were synthesized using this protocol. They were evaluated for their inhibitory activity against the growth of breast cancer cell line, MCF-7. The potency of their cytotoxicity was found to be consistent with their ability to degrade the oncogenic protein, Her2. From these assays, cycloproparadicicol was identified as a most promising candidate for further development.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cobalt; Cyclopropanes; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Lactones; Macrolides; Molecular Chaperones; Molecular Structure; Resorcinols

Aigialomycins A-E (2-6), new 14-membered resorcylic macrolides, were isolated together with a known hypothemycin (1) from the mangrove fungus, Aigialus parvus BCC 5311. Structures of these compounds, including absolute configuration, were elucidated by spectroscopic methods, chemical conversions, and X-ray crystallographic analysis. Hypothemycin and aigialomycin D (5) exhibited in vitro antimalarial activity with IC(50) values of 2.2 and 6.6 microg/mL, respectively, while other analogues were inactive. Cytotoxicities of these compounds were also evaluated.

Topics: Animals; Anti-Bacterial Agents; Antimalarials; Antineoplastic Agents; Antiprotozoal Agents; Ascomycota; Botrytis; Breast Neoplasms; Chlorocebus aethiops; Chromatography, High Pressure Liquid; Colonic Neoplasms; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Female; Humans; Inhibitory Concentration 50; KB Cells; Kidney; Leukemia; Leukemia P388; Macrolides; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plasmodium falciparum; Tetrahymena; Thailand; Ustilago; Vero Cells; Zearalenone