Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III β-tubulin

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• 作者：Antonella Pepe ; Liang Sun ; Ilaria Zanardi ; Xinyuan Wu ; Cristiano Ferlini ; Gabriele Fontana ; Ezio Bombardelli ; Iwao Ojima
• 关键词：C-seco-taxoid ; Taxane ; β ; -Tubulin ; Paclitaxel-resistance
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：15 June 2009
• 年：2009
• 卷：19
• 期：12
• 页码：3300-3304
• 全文大小：562 K

文摘

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 β-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 β-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III β-tubulin.