| Abstract
| - As part of our continuing search for potential anticancer drugcandidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two seriesof 3‘-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compoundsshowedsignificant cytotoxic effects (log GI50< −4.0; logmolar drug concentration required to cause50% growth inhibition) against a variety of human tumor cell lines ofthe National CancerInstitute's in vitro screen, including cells derived fromsolid tumors such as non-small celllung, colon, central nervous system, melanoma, ovarian, prostate, andbreast cancers. All 3‘-substituted compounds demonstrated strong cytotoxic effects in almostall tumor cell lines.Introduction of an aromatic ring at the 2‘- and 3‘-positions alsogenerated compounds withpotent antitumor activity. Incorporation of an aromatic ring atthe 3‘- and 4‘-positions producedcompounds with reduced activity. Interestingly, introduction of ahalogen at the 3‘-positionyielded compounds with different selectivity for the tumor cell linestested. All 3‘-halogenatedcompounds (29−36) and compounds 38and 42−44 were potent inhibitors of tubulinpolymerization with activities nearly comparable to those of the potentantimitotic natural productscolchicine, podophyllotoxin, and combretastatin A-4. Active agentsalso inhibited the bindingof [3H]colchicine to tubulin.
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