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
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.