Overcoming tumor drug resistance with high-affinity taxanes: a SAR study of C2-modified 7-acyl-10-deacetyl cephalomannines.
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.
Yang
Chun-Gang
CG
Department of Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China.
Barasoain
Isabel
I
Li
Xuan
X
Matesanz
Ruth
R
Liu
Ronghua
R
Sharom
Frances J
FJ
Yin
Da-Li
DL
Díaz
J Fernando
JF
Fang
Wei-Shuo
WS
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*
D008351:Mannans; D043823:Taxoids