Interaction of Epothilone Analogs with the Paclitaxel Binding Site: Relationship between Binding Affinity, Microtubule Stabilization, and Cytotoxicity
| Autor: | Martínez Buey, Rubén, Díaz, José Fernando, Andreu, José Manuel, O´Brate, Aurora M., Giannakakou, Paraskevi, Nicolaou, K.C., Sasmal, Pradip K., Ritzen, Andreas, Namoto, Kenji |
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| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 2001-1725 |
| Popis: | 12 páginas, 4 figuras, 3 tablas -- PAGS nros. 225-236 The interactions of epothilone analogs with the paclitaxel binding site of microtubules were studied. The influence of chemical modifications in the C15 side chain and in C12 on binding affinity and microtubule elongation was characterized. Modifications favorable for binding affinity are (1) a thiomethyl group at C21 of the thiazole side chain, (2) a methyl group at C12 in S configuration, (3) a pyridine side chain with C15 in S configuration, and (4) a cyclopropyl moiety between C12 and C13. The same modification in different ligands has similar effect on affinity, allowing good structure-affinity characterization. The correlation between binding, microtubule stabilization, and cytotoxicity of the compounds has been determined, showing differential effects of the modifications. The binding constants correlate well with IC50 values, demonstrating that affinity measurements are a useful tool for drug design This work was supported in part by grants BIO2001-1725 from MCyT to J.F.D., 07B/0026/2002 from Comunidad de Madrid to J.M.A., and the Avon Foundation with funds raised through the Avon Breast Cancer Crusade and NIH Prostate Cancer SPORE Grant CA-58236 to P.G. R.M.B. was supported by a MECD FPU predoctoral fellowship. K.C.N. acknowledges the Skaggs Institute for Chemical Biology, the National Institutes of Health, and Novartis for their financial support |
| Databáze: | OpenAIRE |
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