Pyrimido[4,5-c]quinolin-1(2H)-ones as a novel class of antimitotic agents: Synthesis and in vitro cytotoxic activity

Tubulin represents an attractive target of anticancer natural products, either microtubule-destabilizing agents, such as the vinca alkaloids and colchicines, or microtubule-stabilizing ones, such as the taxanes. However, development of resistance to the currently available agents, and their side effects have led to a worldwide search for new classes of drugs acting by the same mechanism yet enjoying better pharmacological profile. There has been a growing interest in 2-phenyl-4-quinolones, the aza bioisosteric analogues of flavones, as potent cytotoxic antimitotic agents interacting with microtubules. Likewise, natural flavonoids have been reported to display potent cytotoxic activity through inhibition of tubulin polymerization. Furthermore, 2-phenyl-4-anilinoquinolines and related condensed heterocyclic compounds were found to exhibit appreciable cytotoxic activities, not only as a result of the coplanar polycyclic core but also of peripheral substituents.

In this context, we have prepared several 2-amino-pyrimido[4,5-c]quinolin-1(2H)-ones variously substituted at positions 3, 5, and 9 from their corresponding lactones. The target compounds were investigated for in vitro cytotoxic activity against a panel of human cancer cell lines, derived from fibrosarcoma, colon adenocarcinoma, and breast carcinoma, and it was 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. The most potent compounds were found to dose-dependently inhibit tubulin polymerization, inducing cell cycle arrest in the G2/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.