MULTI-TARGETED EFFECTS OF NOVEL MELATONIN ANALOGUES: AROMATASE INHIBITION, ER ANTAGONISM AND CYP1 INHIBITORY ACTIVITY

Objective: This study aimed to synthesize and evaluate novel chlorophenyl-substituted melatonin analogues for their potential multi-target effects in hormone-dependent breast cancer. Their inhibitory activity on aromatase (CYP19A1), antagonistic potential on estrogen receptor (ER), inhibition of CYP1 enzymes, and selective cytotoxicity on cancer cells were investigated.Material and Method: Two groups of novel indole-based melatonin analogues (non-benzylated and benzylated) were synthesized and structurally characterized. Aromatase inhibition was assessed using a cell-free fluorescence-based assay. ER antagonism was evaluated in MCF-7 BUS cells using the E-Screen assay. CYP1 enzyme inhibition was determined via EROD assay using rat liver microsomes. Cytotoxicity was evaluated in MCF-7 BUS and MCF-10A cells using the MTT assay.Result and Discussion: Non-benzylated new compounds (2a–2f) showed higher aromatase and CYP1 inhibition compared to benzylated derivatives (4a–4e). Compound 2f exhibited the highest aromatase (78.5%) and CYP1 (79%) inhibition, and significant ER antagonism. New benzylated compounds displayed stronger cytotoxicity in MCF-7 BUS cells but less enzymatic inhibition. Compound 2f showed a favorable multi-target profile with selective cytotoxicity.