title: Pyrimido[4,5-c]quinolin-1(2H)-ones as a novel class of antimitotic agents: Synthesis and in vitro cytotoxic activity.
abstract: Several 2-amino-pyrimido[4,5-c]quinolin-1(2H)-ones variously substituted at positions 3, 5, and 9 were prepared from their corresponding lactones. The target compounds were investigated for in vitro cytotoxic activity against a panel of human cancer cell lines, namely, lung fibrosarcoma HT-1080, colon adenocarcinoma HT-29, and breast carcinoma MDA-MB-231. Analysis of data revealed that the presence of chloro at position 9 has a major positive impact on cytotoxic activity. Additional halogen substitution at the para position of the 3-phenyl group further enhances activity. Furthermore, compound (25) was found to dose-dependently inhibit tubulin polymerization. In accordance, flow cytometric analysis of the most potent compounds (23-26) indicated that the tested compounds induce cell cycle arrest in the G(2)/M phase. The obtained results introduce the rarely described pyrimido[4,5-c]quinolin-1(2H)-one ring system as a new scaffold for promising antimitotic agents.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt. kametwally@hotmail.com
authors.forename: Kamel
authors.initials: K
authors.lastname: Metwally
authors.forename: Harris
authors.initials: H
authors.lastname: Pratsinis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
mesh_terms: D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D012997:Solvents; D013055:Spectrophotometry, Infrared; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D011743:Pyrimidines; D015363:Quinolones; D012997:Solvents; D014404:Tubulin; D050257:Tubulin Modulators