Enhancement of anticancer potential of novel β-carboline derivatives by ACS81 hybridization

Natural β-carboline alkaloids are currently under extensive scrutiny for their antitumor properties. To improve the antitumor efficacy of β-carboline, a range of β-carboline-ACS81 hybrids were created through molecular hybridization with diallyl disulfide derivatives, and preliminary structure-activity relationships (SAR) were established. Furthermore, the newly synthesized hybrids (12a-c, 13a-d, 14a-d, and 15a-d) were evaluated for in vitro cytotoxicity against a panel of six human cancer cell lines (HL-60, U937, HepG2, HCT-116, A375, and A549), as well as one normal human hepatic cell line (L-02). Among them, hybrid 12c exhibited the strongest inhibitory activity against the HL-60 cell line, with an IC₅₀ value of 1.52 μM, surpassing the efficacy of the positive control drug 5-FU. Moreover, this compound displayed minimal cytotoxicity against L-02 cells (IC₅₀ > 30 μM), indicating a favorable selectivity profile between tumor cells and normal cells. Comprehensive investigations revealed that 12c induced apoptosis by arresting the cell cycle at the G2/M phase. This effect was achieved by inducing alterations in nuclear morphology and the collapse of mitochondrial membrane potential. These findings suggested that 12c exerted an antiproliferative impact by triggering apoptosis through the mitochondrial pathway. Given these observations, 12c may represent a promising anti-leukemia agent and warrants further investigation.