Novel sulfonamide-based compounds as dual inhibitors of hCYP1B1 and hCYP19A1 with anticancer activity against breast cancer cells

Cancer remains a critical global health challenge, driven by multifactorial etiologies, including oxidative stress, hormonal imbalances, and procarcinogen bioactivation. The cytochrome P450 enzymes CYP1B1 and CYP19A1 play significant roles in these processes, with CYP1B1 involved in the bioactivation of carcinogens such as DMBA and estrogens, and CYP19A1 being crucial in estrogen biosynthesis, particularly in hormone-dependent cancers. In this study, we synthesized a novel sulfonamide-based 2-indolinone compound (7h) and evaluated its inhibitory activity against human CYP1B1 and CYP19A1 enzymes, along with previously reported 1H-indole-2,3-dione 3-[4-(3sulfamoylphenyl)thiosemicarbazones] (compounds 7-9). Additionally, the cytotoxic effects of these compounds were tested on the MCF-7 human breast cancer cell line. R2 trifluoromethoxy-substituted compound 7c emerged as the most potent inhibitor of both hCYP1B1 (IC50 = 0.97 pM) and hCYP19A1 (IC50 = 6.46 pM) and demonstrated significant cytotoxicity, reducing MCF-7 cell viability to below 70% at 10 pM. R1 methyl- substituted compound 7b, R1 and R2 dimethyl- substituted compound 8b and R2 ethyl- substituted compound 9a reduced MCF-7 cell viability below 60% after 24 hours of incubation at 10 pM. Molecular docking studies revealed key interactions between the compounds and enzyme active sites, correlating with their inhibitory potency. These findings suggest that the sulfonamide-based 2indolinone derivatives, particularly compound 7c, hold promise as dual inhibitors of CYP1B1 and CYP19A1, offering potential therapeutic benefits in the treatment of hormone-dependent and other cancers. Further studies are warranted to explore their full clinical potential.