Synthesis of targeted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines as potential lead molecules with promising anti-breast cancer activity

• Synthesis of targeted tricyclic compounds as conformationally constrained analogues of tamoxifen.
• Evaluation of anti-proliferative activity against MCF-7 (ER + ve) and MDA-MB-231 (ER-ve) breast cancer cells.
• Compound 14b was found to be the most potent, effectively inhibiting both the breast cancer cell lines.
• Compound 14b inhibited cell growth due to G0/G1 arrest in MCF-7 cells and cell inhibition was due to induction of apoptosis.

A targeted library of substituted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines (prototypes I, II and III), and structurally analogous to tamoxifen have been synthesized as a new class of anti-breast cancer agents. All the prototype molecules exhibited potential antiproliferative activity against ER + ve and ER-ve breast cancer cell lines. Dibenzo[b,f]thiepine prototypes were found to be more active. Of all the compound tested, 14b exhibited potent in-vitro antiproliferative activity at 1.33 μM and 5 μM concentration in MCF-7 and MDA-MB-231 cell lines and was devoid of any cytotoxicity in normal HEK cells even at 50 μM. Cell cycle analysis showed that the compound 14b inhibited cell proliferation due to G0/G1 arrest in MCF-7 cells. Annexin-V FITC and PI staining experiments confirmed that the cell inhibition was primarily due to apoptosis and not by necrosis, which was also supported by LDH release assay experiment. Molecular docking studies showed better binding interaction of the new dibenzo[b,f]thiepine analogue 14b with the estrogen receptor (ER) as compared to 4-hydroxy-tamoxifen and this enhanced binding might be responsible for its estrogen antagonistic activity that induces cell cycle arrest, apoptosis and inhibition of breast cancer cells.

Conformationally constrained tricyclic compounds namely, substituted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines (prototypes I, II and III), have been synthesized as new lead molecules exhibiting potential antiproliferative activity against ER + ve & ER-ve breast cancer cell lines.Figure optionsDownload as PowerPoint slide