Mechanisms and kinetics of microtubule perturbing agents

摘要: Microtubules are cellular cytoskeletal components that play an integral part in many cell functions. Compounds bind to microtubules and alter their dynamics highly sought as a result of the clinical success paclitaxel docetaxel. A series analogues microtubule stabilizing dictyostatin were examined probe biological biochemical structure-activity relationships. The results consistent with previous reports showing 16-normethyldictyostatin 15Z,16-normethyldictyostatin lose potency pacitaxel-resistant lines have Phe270-to-Val mutation taxoid binding site â-tubulin. 6-epi-Dictyostatin 7-epi-dictyostatin potent dictyostatin, 6-epi-dictyostatin was chosen for milligram scale pre-clinical studies. thalidomide analogue 5HPP-33 identified easily synthesized small perturbing agent, experiments isolated tubulin performed determine its mechanism action. Tubulin polymerization used effect on normal formation. In utilizing associated proteins (MAPs) induce polymer formation, inhibited polymerization, but under different set conditions appeared form stabilize microtubules. imaged using electron microscopy, which showed caused formation spirals rings. Due failing compete known radiolabeled agents respective sites, tritiated version synthesized. [3H]5HPP-33 had slight affinity MAPs, this reason discrepancy between experiments. could not be determined, making it possible novel agent. (-)-Pironetin is inhibitor appears covalent linkage heterodimer. Although immunoflourescent images (-)-pironetin work same manner vinblastine, proved mechanistically from vinblastine. tubulysins destabilizers vinca domain Three effects growth perturbation determined. WZY-111-63C (N14-desacetoxytubulysin H) found 50 times more cytotoxic than vincristine.