title: Microtubule interactions with chemically diverse stabilizing agents: thermodynamics of binding to the paclitaxel site predicts cytotoxicity.
abstract: The interactions of microtubules with most compounds described as stabilizing agents have been studied. Several of them (lonafarnib, dicumarol, lutein, and jatrophane polyesters) did not show any stabilizing effect on microtubules. Taccalonolides A and E show paclitaxel-like effects in cells, but they were not able to modulate in vitro tubulin assembly or to bind microtubules, which suggests that other factors are involved in their cellular effects. The binding constants of epothilones, eleutherobin, discodermolide, sarcodictyins, 3,17beta-diacetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-triene, and dictyostatin to the paclitaxel site; the critical concentrations of ligand-induced assembly; and their cytotoxicity in carcinoma cells have been measured, and correlations between these parameters have been determined. The inhibition of cell proliferation correlates better with the binding enthalpy change than with the binding constants, suggesting that large, favorable enthalpic contribution to the binding is desired to design paclitaxel site drugs with higher cytotoxicity.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Rubén M
authors.initials: RM
authors.lastname: Buey
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.forename: Evelyn
authors.initials: E
authors.lastname: Jackson
authors.forename: Arndt
authors.initials: A
authors.lastname: Meyer
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
authors.forename: Ian
authors.initials: I
authors.lastname: Paterson
authors.forename: Susan
authors.initials: S
authors.lastname: Mooberry
authors.forename: José M
authors.initials: JM
authors.lastname: Andreu
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008870:Microtubules / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D017239:Paclitaxel / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000187:drug effects; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D014404:Tubulin; D050257:Tubulin Modulators; D017239:Paclitaxel