1. Overcoming tumor drug resistance with high-affinity taxanes: A SAR study of C2-modified 7-acyl-10-deacetyl cephalomannines
- Author
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Wei-Shuo Fang, Chun-Gang Yang, Dali Yin, Isabel Barasoain, J. Fernando Díaz, Frances J. Sharom, Ronghua Liu, Ruth Matesanz, Xuan Li, Foundation for the Author of National Excellent Doctoral Dissertation of the People's Republic of China, Fok Ying Tong Education Foundation, National Natural Science Foundation of China, Dirección General de Investigación Científica y Técnica, DGICT (España), Comunidad de Madrid, Ministerio de Educación y Ciencia (España), and Canadian Cancer Society
- Subjects
Structure-activity relationships ,Drug resistance ,Pharmacology ,P-glycoprotein ,Biochemistry ,Drug design ,Mannans ,Taxoid ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Humans ,Cytotoxic T cell ,Structure–activity relationship ,General Pharmacology, Toxicology and Pharmaceutics ,Taxane ,Molecular Structure ,biology ,Organic Chemistry ,Cephalomannine ,Paclitaxel ,chemistry ,Drug Resistance, Neoplasm ,biology.protein ,Molecular Medicine ,Taxoids ,β-tubulin - Abstract
A series of C2-modified 10-deacetyl-7-propionyl cephalomannine derivatives was designed, prepared, and biologically evaluated. Some C2 meta-substituted benzoate analogues showed potent activity against both drug-sensitive and drug-resistant tumor cells in which resistance is mediated through either P-gp overexpression or b-tubulin mutation mechanisms. The taxoid 15b and related compounds are of particular interest, as they are much more cytotoxic than paclitaxel, especially against drug-resistant tumor cells; they are able to kill both drug-resistant and drug-sensitive cells (low R/S ratio), and they have high affinity for β-tubulin. Our research results led to an important hypothesis, that is, a taxane with very high binding affinity for β-tubulin is able to counteract drug resistance, which may assist in future taxane-based drug-discovery efforts., The authors thank the Foundation for the Author of National Excellent Doctoral Dissertation of P. R. China (Grant No. 199949), the Fok Ying Tong Education Foundation (Grant No. 91037), and the National Natural Science Foundation (Grant No. 20572135) (to W.-S.F.); the Dirección General de Investigación Científica y Tecnológica (DGICYT, Grant BFU2004-00358), the Comunidad Autonoma de Madrid (Grants CAM200520M061 and BIPPED-CM), the Ministerio de Educación y Ciencia of Spain (Grant BFU-2004-0038) (to J.F.D.); and the Canadian Cancer Society (to F.J.S.) for financial support.
- Published
- 2007