Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups
| Autor: | José Fernando Díaz, Gonzalo Sáez-Calvo, Federico Gago, Shao-Rong Wang, Pedro A. Sánchez-Murcia, James P. Snyder, Wei-Shuo Fang, Chun-Gang Yang, Ning Yan |
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| Přispěvatelé: | National Natural Science Foundation of China, Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Wang, Shao-Rong [0000-0003-1746-7400], Sánchez-Murcia, Pedro A. [0000-0001-8415-870X], Díaz, José Fernando [0000-0003-2743-3319], Gago, Federico [0000-0002-3071-4878], Wang, Shao-Rong, Sánchez-Murcia, Pedro A., Díaz, José Fernando, Gago, Federico |
| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Paclitaxel Stereochemistry macromolecular substances Biochemistry Microtubules Tubulin binding chemistry.chemical_compound Structure-Activity Relationship Microtubule Ethers Cyclic Structure–activity relationship Hydroxymethyl Physical and Theoretical Chemistry Cytotoxicity Nuclear Magnetic Resonance Biomolecular Taxane biology Molecular Structure Organic Chemistry Tubulin chemistry biology.protein Protein Binding |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1523-7052 |
| Popis: | 4 p.-1 fig.-1 tab.-6 schem. To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepared from paclitaxel 1a. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane 5e is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than 1a on tubulin polymerization promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and molecular modeling studies. From these results, we draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects. S.R.W. and W.S.F. thank the National Natural Science Foundation of China (Grant Nos. 30930108 and 81202434)for financial support. F.G. is grateful to the Spanish Ministerio de Economıa y Competitividad (SAF2012-39760-C02-02) and Comunidad Autónoma de Madrid (S2010-BMD-2457). |
| Databáze: | OpenAIRE |
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