Design, synthesis, and mechanistic evaluation of alepterolic acid derivatives incorporating indole and piperazine moieties as anticancer agents targeting breast cancer
摘要
Breast cancer represents the most prevalent malignancy worldwide and persists as the principal contributor to cancer mortality in women. Natural origins supply invaluable bioactive constituents demonstrating potential antitumor properties with improved safety. In this investigation, a sequence of alepterolic acid derivatives bearing indole or indazole functionality coupled with piperazine substituents were conceived and synthesized. Validation of molecular structures employed ESI-MS, ¹H NMR, and ¹³C NMR spectroscopic techniques. Experimental outcomes established that derivatives 14n and 14t manifested IC50 readings of 4.29 ± 0.25 µM and 4.15 ± 0.01 µM, correspondingly, in MCF-7 cellular models. Extended evaluations disclosed that both derivatives provoked morphological modifications and restrained proliferative capacity following concentration- and duration-based patterns. Western blot demonstrated that exposure to compound 14t evoked substantial upregulation of critical apoptosis indicators—specifically activated caspases 9, 8, 6 and cleaved PARP—concomitant with an elevated Bax/Bcl-2 ratio within MCF-7 cell populations. Treatment with 14t additionally instigated mitochondrial anomalies, characterized by marked depolarization of mitochondrial transmembrane potential and augmented reactive oxygen species (ROS) generation. Furthermore, administration of 14n enhanced concentrations of activated caspase 8, caspase 6, and cleaved PARP in MCF-7 cells. These observations imply that apoptosis induction by 14t in MCF-7 systems operates through dual intrinsic and extrinsic cascades, whereas 14n principally initiates apoptotic mechanisms via the extrinsic route. Conclusively, integration of indole-piperazine moieties into alepterolic acid scaffolds constitutes a viable tactical framework for generating innovative therapeutic candidates.