Discodermolide, A Cytotoxic Marine Agent That Stabilizes Microtubules More Potently Than Taxol^,

Abstract

Computer-assisted structure analysis indicated (+)-discodermolide, a polyhydroxylated alkatetraene lactone marine natural product, was an antimitotic compound, and we confirmed this prediction. Previous work had shown an accumulation of discodermolide-treated cells in the G2/M portion of the cell cycle, and we have now found that discodermolide arrests Burkitt lymphoma cells in mitosis. Discodermolide-treated breast carcinoma cells displayed spectacular rearrangement of the microtubule cytoskeleton, including extensive microtubule bundling. Microtubule rearrangement that occurred with 10 nM discodermolide required 1 microM taxol. Discodermolide had equally impressive effects on tubulin assembly in vitro. Near-total polymerization occurred at 0 degree C with tubulin plus microtubule-associated proteins (MAPs) under conditions in which taxol at an identical concentration was inactive. Without MAPs and/or without GTP, tubulin assembly was also more vigorous with discodermolide than with taxol under every reaction condition examined. Discodermolide-induced polymer differed from taxol-induced polymer in that it was completely stable at 0 degree C in the presence of high concentrations of Ca2+. In a quantitative assay designed to select for agents more effective than taxol in inducing assembly, discodermolide had an EC50 value of 3.2 microM versus 23 microM for taxol.

Relationship between Beta-Tubulin Mutations and Taxol Resistance in Breast Cancer Cells

“…This idea also came at a time when the initial observation on tubulin mutations in cancer patients failed to be repeated. In a group of breast cancer patients treated with Taxol, no ß-mutations were observed [3].…”

Structural and chemical basis for anticancer activity of a series of²-tubulin ligands: molecular modeling and 3D QSAR studies

“…These physicochemical and biological characteristics have qualified discodermolide as a lead compound for the development of new, more effective and safer anticancer agents. [13][14][15][16] An important strategy in the design of new β-specific tubulin modulators is to identify key properties of the chemical structure related to their ability to induce a cytotoxic response as a consequence of modulation of microtubule functions through tubulin-binding. Structure and ligand-based drug design approaches have become fundamental components of modern drug discovery.…”

“…694 an overlapping binding site in the β-tubulin cavity, which can accommodate a variety of structurally diverse MSAAs in unique and independent ways. [11][12][13][14][15] The marine polyketide discodermolide is one of the most potent MSAAs known. In addition to its potent antiproliferative and apoptosis-inducing activities, discodermolide is more water soluble than paclitaxel and retains substantial activity against taxane-resistant cell lines.…”

Mechanism Targeted Discovery of Antitumor Marine Natural Products

“…Hamel and coworkers at the NCI used a computer-assisted search for novel compounds with structural homology to colchicine-site inhibitors. They discovered that the marine natural product (+)-discodermolide (previously isolated from the sponge Discodermia dissolute) enhanced tubulin nucleation reactions more potently than paclitaxel and inhibited the growth of paclitaxel-resistant cells [256]. The structure of (+)-discodermolide is shown in Fig.…”