Antitumor agents. 196. Substituted 2-thienyl-1,8-naphthyridin-4-ones: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization

Citation
Sx. Zhang et al., Antitumor agents. 196. Substituted 2-thienyl-1,8-naphthyridin-4-ones: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization, J MED CHEM, 42(20), 1999, pp. 4081-4087
Citations number
31
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
0022-2623 → ACNP
Volume
42
Issue
20
Year of publication
1999
Pages
4081 - 4087
Database
ISI
SICI code
0022-2623(19991007)42:20<4081:AA1S2T>2.0.ZU;2-E
Abstract
As part of our continuing search for potential anticancer drug candidates i n the 2-aryl-1,8-naphthyridin-4-one series, we have synthesized a series of substituted 8-thienyl-1,8-naphthyridin-4-ones. Most compounds showed signi ficant cytotoxic effects (log GI(50) < -4.0; log molar drug concentration r equired to cause 50% growth inhibition) against a variety of human tumor ce ll lines in the National Cancer Institute's in vitro screen, including cell s derived from solid tumors such as non-small-cell lung, colon, central ner vous system, melanoma, ovarian, prostate, and breast cancers. The most acti ve compounds (31-33, 40) demonstrated strong cytotoxic effects with ED50 va lues in the micromolar or submicromolar range in most of the tumor cell lin es. The most cytotoxic compounds inhibited tubulin polymerization at concen trations substoichiometric to the tubulin concentration. The most potent in hibitors of polymerization (40, 42, 43) had effects comparable to those of the potent antimitotic natural products podophyllotoxin and combretastatin A-4 and to that of NSC 664171, a particularly potent, structurally related analogue. Only compound 40 was a potent inhibitor of the binding of radiola beled colchicine to tubulin, and it was both the most cytotoxic agent and t he most effective inhibitor of polymerization among the newly synthesized c ompounds.