Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly

• DOI: 10.1124/mol.106.027847
• Publication Date: 2006-08-04T00:44:38Z
• Authors: Ernest Hamel; Billy W. Day; John H. Miller; M. Katherine Jung; Peter T. Northcote; Arun K. Ghosh; Dennis P. Curran; Mark Cushman; K.C. Nicolaou; Ian Paterson; Erik J. Sorensen
• Keywords: Taxoid; Epothilones; Taxane; Epothilones

Previous studies on the drug content of pelleted tubulin polymers suggest that peloruside A binds in laulimalide site, which is distinct from taxoid site. In a assembly system containing microtubule-associated proteins and GTP, however, was significantly less active than laulimalide, inducing manner most similar to sarcodictyins B. Because thus far seems be only compound mimics action we examined combinations microtubule-stabilizing agents for synergistic effects assembly. We found showed no synergism but both compounds could act synergistically with number site [paclitaxel, epothilones A/B, discodermolide, dictyostatin, eleutherobin, steroid derivative 17β-acetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-trien-3-ol, cyclostreptin]. None any each other. From an initial study cyclostreptin, conclude phenomenon derives, at least part, apparent lowering critical concentration compared single drugs. The binding led us attempt construction pharmacophore model based superposition energy-minimized structure crystal laulimalide. Although different sizes macrocycles limited our ability superimpose two molecules, atom correspondences were observed consistent difficulty so experienced creation fully analogs