PHARMACOLOGICAL AND STRUCTURE-ACTIVITY RELATIONSHIP EVALUATION OF MICROTUBULE-STABILIZING AGENTS

[摘要] PHARMACOLOGICAL AND STRUCTURE-ACTIVITY RELATIONSHIP EVALUATION OF MICROTUBULE-STABILIZING AGENTSCharitha Madiraju, M.S.University of Pittsburgh, 2005Microtubules are composed of alpha- and beta-tubulin subunits and are highly dynamic elements of the cytoskeleton that help maintain fidelity during cell division. This aspect of microtubules makes them a very useful target for the treatment of tumors. The potent microtubule-stabilizing agent (+)-discodermolide is a sponge-derived polyketide natural product and is a polyhydroxylated and polymethylated, C24:4 fatty acid lactone carbamate. The microtubule-stabilizing action of discodermolide was predicted by computational chemistry. Biochemical, pharmacological, and antiproliferative activity studies with discodermolide showed it to have potent hypernucleating, microtubule-stabilizing and microtubule bundling properties. Synthetic analogues of discodermolide were made to establish a structure-activity relationship (SAR) for discodermolide. The library consisted of analogues with modifications made on the lactone and carbamate/diene portions, with altered stereochemistry on C-11 and C-17, conformational analogues based on the solution structure of discodermolide, and macrocyclic analogues of discodermolide. Biological evaluation of the analogues suggested the diene, the carbamate on C-19 and the stereochemistry on C-11 and C-17 to be important for the activity of the parent molecule, and that the lactone moiety is amenable to modifications. Of interest were the conformational and macrocyclic analogues that showed promising microtubule-targeting activities. Furthermore, these studies paved way for the discovery of the related natural product dictyostatin as a potent microtubule stabilizer. Dictyostatin is a macrocycle with stereochemistry very much like discodermolide. Intensive biochemical and pharmacological studies showed dictyostatin to have comparable, or superior in some respects, properties to those of discodermolide and paclitaxel. Biological analyses of structural analogues of dictyostatin suggested that the macrolactone and the bottom half of dictyostatin have a critical role in the biological activity of the parent molecule. The top portion of the molecule was amenable for modifications without much loss of activity; however, this half of the molecule seemed crucial for the microtubule binding property of the parent molecule. These studies identified dictyostatin to be the most potent of the microtubule stabilizers studied. One interesting analogue, C16-normethyldictyostatin, was identified to have promising activity comparable to the parent molecule.

[发布机构] the University of Pittsburgh

[效力级别] microtubule-stabilizing agents