University of Hawai'i

Wayne State University

Richard E. Moore

Marcus A. Tius

Jian Liang

Russell A. Barrow

Thomas K. Hemscheidt

Frederick A. Valeriote

Thomas H. Corbett

Trimurtulu Golakoti

Thomas K Hemscheidt

Thomas Hughes Corbett

Richard E Moore

Susan L Mooberry

Frederick A Valeriote

Jian Wen Liang

Marcus A Tius

Russell A Barrow

Thomas H Corbett

In accordance with the present invention, there have been identified extracts from a tropical plant that initiate paclitaxel-like microtubule bundling. Bioassay-directed purification yields the steroid taccalonolide A. Taccalonolide, like paclitaxel, initiates the formation of abnormal interphaes and mitotic microtubules. Cells treated with taccalonolide exhibit thick bundles of microtubules that appear to nucleate independent of the microtubule organizing center. Abnormal mitotic spindles consisting of multi-polar spindles are initiated by taccalonolide and resemble abnormal mitotic spindles found in the presence of paclitaxel. Like paclitaxel, taccalonolide causes the breakdown of the nucleus into micronuclei. Taccalonolide causes G2/M arrest, Bc1-2 phosphorylation and initiates an apoptotic cascade that includes the activation of caspase 3. Taccalonolide is an effective inhibitor of proliferation against both SK-OV-3 and MDA-MB-435 cell with ICvalues of 2.3 &#x3bc;M and 2.1 &#x3bc;M respectively. In contrast to paclitaxel, taccalonolide is effective against the multidrug resistant SKVLB-1 cellline and thus appears to be a poor substrate for P-glycoprotein-mediated transport. Although taccalonolide is almost equipotent with paclitaxel in its effects on cellular microtubules, it is much less potent than paclitaxel in its ability to initiate the polymerization of purified tubulin and microtubule protein. Taccalonolide A is the first microtubule stabilizing agent to be discovered from a plant since identification of the mechanism of action of paclitaxel and it is the first natural product steroid identified to have these cellular effects.

Taccalonolide microtubule stabilizing agents

A cryptophycin compound is provided having the structure: ##STR1## Further provided are methods of producing cryptophycins by total synthesis and methods of using cryptophycins in pharmaceuticals. It is a further object of this invention to use cryptophycins to inhibit the proliferation of mammalian cells. Moreover, methods of using cryptophycins to treat neoplasia is also provided.

Cryptophycins from synthesis

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Honolulu, HI, United States of America

Thomas K Hemscheidt