title: Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit tubulin polymerization.
abstract: As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed significant cytotoxic effects (log GI50 < -4.0; log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breast cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ring at the 2'- and 3'-positions also generated compounds with potent antitumor activity. Incorporation of an aromatic ring at the 3'- and 4'-positions produced compounds with reduced activity. Interestingly, introduction of a halogen at the 3'-position yielded compounds with different selectivity for the tumor cell lines tested. All 3'-halogenated compounds (29-36) and compounds 38 and 42-44 were potent inhibitors of tubulin polymerization with activities nearly comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Active agents also inhibited the binding of [3H]colchicine to tubulin.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599, USA.
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.forename: S C
authors.initials: SC
authors.lastname: Kuo
authors.forename: M C
authors.initials: MC
authors.lastname: Hsieh
authors.forename: A
authors.initials: A
authors.lastname: Mauger
authors.forename: C M
authors.initials: CM
authors.lastname: Lin
authors.forename: E
authors.initials: E
authors.lastname: Hamel
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D046911:Macromolecular Substances; D008297:Male; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D046911:Macromolecular Substances; D009287:Naphthyridines; D014404:Tubulin; D003078:Colchicine