N-(3-Trifluoromethylphenyl)sulfonyl-indole-3-carbaldehyde thiosemicarbazones induce apoptosis and modulate p53-associated signaling in prostate cancer: integrated experimental and computational studies.

Prostate cancer continues to be an important therapeutic challenge that demands the development of new apoptosis-inducing agents. In the present study, a series of N-(3-trifluoromethylphenyl)sulfonyl-indole-3-carbaldehyde thiosemicarbazone derivatives (5a-s) was synthesized and evaluated for their biological activity against the LNCaP prostate cancer cell line. Among the synthesized compounds, 5a and 5g showed strong antiproliferative activity and favorable selectivity toward non-malignant HEK293 cells, with IC50 values of 7.56 and 5.81 μM, respectively. Compound 5g increased the expression of TP53, CDKN1A, BBC3, and BAX, whereas compound 5a significantly reduced the expression of the anti-apoptotic BCL2 gene. Both compounds also modulated the expression of cancer- and DNA damage response-related genes, including c-MYC, KRAS, PTEN, ATM, and ATR. Molecular docking studies predicted favorable interactions of compound 5g with MDM2 (IFD score = -7.951 kcal/mol; ΔG_bind = -56.75 kcal/mol) and compound 5a with BCL-2 (IFD score = -8.636 kcal/mol; ΔG_bind = -59.55 kcal/mol). 500-nanosecond molecular dynamics simulations further supported the dynamic stability and persistence of the proposed ligand-protein interactions. ADME and DFT analyses further indicated favorable pharmacokinetic and electronic properties of the lead compounds. Overall, the integrated experimental and computational findings identify compounds 5a and 5g as promising lead candidates for further investigation as apoptosis-inducing agents against prostate cancer.