Vanillin-Based Indolin-2-one Derivative Bearing a Pyridyl Moiety as a Promising Anti-Breast Cancer Agent via Anti-Estrogenic Activity

The structure-based design introduced indoles as an essential motif in designing new selective estrogen receptor modulators employed for treating breast cancer. Therefore, here, a series of synthesized vanillin-substituted indolin-2-ones were screened against the NCI-60 cancer cell panel followed by in vivo, in vitro, and in silico studies. Physicochemical parameters were evaluated with HPLC and SwissADME tools. The compounds demonstrated promising anti-cancer activity for the MCF-7 breast cancer cell line (GI = 6-63%). The compound with the highest activity (6j) was selective for the MCF-7 breast cancer cell line (IC50 = 17.01 mu M) with no effect on the MCF-12A normal breast cell line supported by real-time cell analysis. A morphological examination of the used cell lines confirmed a cytostatic effect of compound 6j. It inhibited both in vivo and in vitro estrogenic activity, triggering a 38% reduction in uterine weight induced by estrogen in an immature rat model and hindering 62% of ER-alpha receptors in in vitro settings. In silico molecular docking and molecular dynamics simulation studies supported the stability of the ER-alpha and compound 6j protein-ligand complex. Herein, we report that indolin-2-one derivative 6j is a promising lead compound for further pharmaceutical formulations as a potential anti-breast cancer drug.

Automated summary

The study focused on using indoles as a key group in the design of selective estrogen receptor modulators for breast cancer treatment. A series of vanillin-substituted indolin-2-one compounds were synthesized and tested against cancer cells, with physicochemical parameters evaluated. The compound 6j showed promising anti-cancer activity specifically against the MCF-7 breast cancer cell line, without affecting normal breast cells. In vivo and in vitro studies confirmed its ability to inhibit estrogenic activity and its stability in complex with the ER-alpha receptor.