Synthesis, in-vitro Cytotoxicity, and a Preliminary Structure-Activity Relationship Investigation of Pyrimido[4,5-c]quinolin-1(2H)-ones

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.