title: Overcoming tumor drug resistance with high-affinity taxanes: a SAR study of C2-modified 7-acyl-10-deacetyl cephalomannines.
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 beta-tubulin mutation mechanisms. The taxoid 15 b 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 beta-tubulin. Our research results led to an important hypothesis, that is, a taxane with very high binding affinity for beta-tubulin is able to counteract drug resistance, which may assist in future taxane-based drug-discovery efforts.
authors: Department of Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China.
authors: Chun-Gang
authors: CG
authors: Yang
authors: Isabel
authors: I
authors: Barasoain
authors: Xuan
authors: X
authors: Li
authors: Ruth
authors: R
authors: Matesanz
authors: Ronghua
authors: R
authors: Liu
authors: Frances J
authors: FJ
authors: Sharom
authors: Da-Li
authors: DL
authors: Yin
authors: J Fernando
authors: JF
authors: Díaz
authors: Wei-Shuo
authors: WS
authors: Fang
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008351:Mannans / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008351:Mannans; D043823:Taxoids