Halogenated quinolinone-aziridines: Substituent-controlled diastereodivergent synthesis and geometry-dependent antiproliferative activity.

A series of halogenated quinolinone-aziridine hybrids (±)-14-20 inspired by marinoaziridine scaffolds was synthesized through an eight-step racemic route starting from two achiral fragments and convergently assembled via a sulfur ylide-imine aziridination reaction. The reaction afforded cis and trans aziridine derivatives in good yields (51-81%), with diastereoselectivity strongly dependent on the fluorine substitution pattern. Remarkably, complete stereoselectivity was observed for two derivatives, with the meta-fluorinated analogue (±)-17 obtained exclusively as the cis isomer and the di-ortho-fluorinated analogue (±)-19 exclusively as the trans isomer, highlighting the decisive role of substituent effects in controlling the stereochemical outcome of the reaction. The synthesized compounds were evaluated for antiproliferative activity against H460 and MCF-7 cancer cell lines and for cytotoxicity toward non-tumor HEK293T cells. Several derivatives displayed pronounced stereochemistry-dependent biological activity. In particular, selected cis isomers exhibited enhanced selectivity toward MCF-7 cells, whereas some trans analogues showed higher overall antiproliferative potency. Structure-activity relationship analysis revealed that both aziridine stereochemistry and fluorine substitution pattern play roles in determining biological response. Zebrafish embryotoxicity studies additionally demonstrated marked stereochemistry-dependent effects however with no direct correlation between antiproliferative selectivity and developmental toxicity. In silico target prediction suggested the possible involvement of proliferation-related signalling pathways, including kinase-associated targets. Overall, the results identify fluorine positioning is a critical determinant governing the stereochemical outcome of the synthesis, while both fluorine positioning and aziridine stereochemistry strongly influence antiproliferative activity, cellular selectivity, and embryotoxicity within this series of marine-inspired quinolinone-aziridine hybrids.