title: Synthesis, in-vitro cytotoxicity, and a preliminary structure-activity relationship investigation of pyrimido[4,5-c]quinoline-1(2H)-ones.
abstract: As part of our ongoing research effort to develop new antimitotic agents based on the recently reported pyrimido[4,5-c]quinoline-1(2H)-one ring skeleton, we were interested in identifying structural elements that contribute to the cytotoxicity of this class of compounds. The effect of several quinoline-ring substituents was examined and the new compounds were evaluated in vitro for cytotoxicity against three human cancer cell lines namely, lung fibrosarcoma HT-1080, colon adenocarcinoma HT-29, and breast carcinoma MDA-MB-231. Most of the compounds showed cytotoxic activity in the low micromolar and sub-micromolar range. Structure-activity relationship information revealed that a combination of electronic and steric factors may be involved. Flow cytometric cell cycle analysis performed on HT-1080 cells revealed that the most cytotoxic compounds 48, 50, 54, 59, and 63 inhibit the S-phase and arrest the cells in the G2/M phase of the cell cycle suggesting an antimitotic action of these compounds.
authors.affiliation: Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia. kametwally@hotmail.com
authors.forename: Kamel
authors.initials: K
authors.lastname: Metwally
authors.forename: Ashraf
authors.initials: A
authors.lastname: Khalil
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; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D050256:Antimitotic Agents; D011743:Pyrimidines; D011804:Quinolines