Design and Synthesis of Novel Benzoazepinone Derivatives as Potent Estrogen Receptor Alpha Inhibitors

Background Selective estrogen receptor modulators (SERMs) block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. If a SERM is in the estrogen receptor, estrogen can't attach to the cancer cell and the cell doesn't receive estrogen's signals to grow and multiply. The goal of this research is to develop small drug-like molecules of novel Benzoazepinone derivatives that mimic the ability of the SERM (Tamoxifene and Raloxifene) to binds with estrogen receptor protein. Methods 2-Phenylethyl bromide undergoes amino alkylation through mannich reaction with CH ₃ NH ₂ and chloro acetyl chloride, gives 2-chloro-N-methyl-N-phenethylacetamide, which is further undergoing cyclization gives 3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.2-phenylethyl bromide. 1-amino-3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.di-p-toluoyl-1-tartaric acid and 1-amino-3-methyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one. HCl was obtained by treatment with di-p-toluoyl-l-tartaric acid and con. HCl respectively. Finally, this intermediate undergoes nucleophilic addition reactions with different substituted aldehydes. All the compounds were screened for their in-vitro cytotoxicity activity using Vero and MDA MB 231 cell lines by MTT assay. Results IC50 values from Cytotoxicity studies by MTT assay ranges from 11µg/ml to 153µg/ml. A total of 15 compounds were synthesized by using a diverse scheme and the title compounds have exhibited low to high in-vitro anticancer activity with MDA MB 231 cells. Compared to the standard (Raloxifene 6 µg/ml), the developed compounds T2 (35µg/ml), T10 (36µg/ml), T14 (11µg/ml) and T15 (22 µg/ml). Conclusion Finally, four compounds might be used as a lead molecule for future development into a therapeutically viable anti-ER positive breast cancer drug from the benzoazepinone derivatives family.