Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III beta-tubulin.
Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III beta-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All novel C-seco-taxoids exhibited remarkable potency against A2780TC1 and A2780TC3 cell lines, and no cross resistance to cisplatin- and topotecan-resistant cell lines, A2780CIS and A2780TOP. Four of those C-seco-taxoids exhibit much higher activities than IDN5390 against paclitaxel-resistant cell lines, A2780ADR, A2780TC1 and A2780TC3. SB-CST-10202 possesses the best all-round high potencies across different drug-resistant cell lines. Molecular modeling studies, including molecular dynamics simulations, on the drug-protein complexes of class I and III beta-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III beta-tubulin.
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA.
Antonella
A
Pepe
Liang
L
Sun
Ilaria
I
Zanardi
Xinyuan
X
Wu
Cristiano
C
Ferlini
Gabriele
G
Fontana
Ezio
E
Bombardelli
Iwao
I
Ojima
D045744:Cell Line, Tumor; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000235:genetics
D043823:Taxoids; D014404:Tubulin; D017239:Paclitaxel