Novel 1,2-Oxaphosphole- and 1,2-Azaphosphole-Quinolinone Hybrids: Synthesis, Anticancer Activity, Apoptosis, Cell...

A one-pot, three-component reaction involving 4-oxo-1,4-dihydroquinoline-3-carboxaldehyde (1), acyclic or cyclic active methylene compounds, and diethyl phosphite under mild basic conditions afforded nine novel organophosphorus compounds featuring functionalized 1,2-oxaphosphole heterocycles containing 4-quinolinone ring. The 1,2-azaphospholyl quinolinone and diethyl pyrano[3,2-c]quinolinyl phosphonate derivatives were also obtained. The structures of the synthesized compounds were established on the basis of spectral tools. All synthesized compounds were evaluated for their in vitro cytotoxicity against SKOV-3, MCF-7, and HCT-116 cancer cell lines. Compounds 8a and 8b demonstrated superior selectivity by exhibiting potent cytotoxicity against cancer cells while showing significantly lower toxicity against normal HFB4 cells. Furthermore, these two compounds significantly induced early and late apoptosis as well as reduced cell viability in the studied tumor cells. Additionally, both compounds 8a and 8b exhibited significant potential in halting the cell cycle at various stages, including G1, S, and G2 phases. In the absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, compounds 8a and 8b demonstrated improved oral absorption and genetic safety. Compound 8a showed a more favorable with lower chronic toxicity and minimal metabolic interactions, whereas compound 8b exhibited enhanced intestinal and central nervous system (CNS) permeability. Moreover, both products 8a and 8b were subjected to a molecular docking experiment and displayed good interaction with epidermal growth factor receptor (EGFR). These findings suggested that compounds 8a and 8b possess a valuable skeletal structure for the development of novel antitumor agents.