A series of novel modifications were performed at the N(4) position of 5-hydroxyisatin thiosemicarbazone (TSC). The structure-activity approach is applied to design and synthesize derivatives by condensing thiosemicarbazides with 5-hydroxy isatin. The TSCs were characterized by various spectroscopic techniques viz. FTIR, 1H NMR, 13C NMR, UV-Vis, HRMS data, CHN elemental analysis, and single crystal X-ray diffraction. Biological evaluation of the synthesized compounds revealed the anticancer potency of the TSC analogues against breast cancer (MD-AMD-231, MCF-7), lung cancer (A549, NCI-H460), prostate cancer (PC3), and skin cancer (A431). The molecules, L2, L3, and L6 showed activity in the micromolar range (IC50; 0.19-2.19 μM). L6 exhibited the highest potency against skin cancer A431 cell line, with an IC50 of 0.19 μM compared to 1.8 μM with triapine and showed low toxicity against PNT-2 cells with an SI index of >100 μM. The mechanistic study revealed that L6 inhibited cancer cell proliferation, colony formation, and 3-dimensional spheroid formation by targeting the Ras/MAPK axis. It induced DNA damage and impaired DNA damage repair machinery, which led to the accumulation of DSB. Also, it lowered the ERK1/2 expression, which affected the caspase 3 activity and showed higher binding affinity compared to the FDA-approved drug Lenalidomide in molecular docking studies. Our findings demonstrated the possible future anticancer drug potency of L6 in the skin cancer A431 cells.
Keywords: 5-Hydroxyisatin; Anticancer potency; DNA Damage Repair; DSB; Molecular docking; Skin cancer; Thiosemicarbazone.
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