Design, synthesis, and biological evaluation of selective estrogen receptor modulators (SERMs) as anticancer agents...

Globally, breast cancer stands as one of the primary causes of cancer related deaths. Among the types of breast cancer, estrogen receptor- positive (ER+) breast cancer accounts for the highest incidence and mortality worldwide. The present study emphasizes the design, synthesis, and biological evaluation of a series of novel triphenylethylene (TPE) based selective estrogen receptor modulators (SERMs) for their antiproliferative activity against ER+ breast cancer. All the synthesized compounds were well characterized using spectroscopic and chromatographic techniques. Favorable druglike properties indicating acceptable permeability through membrane and oral bioavailability were observed in in-silico physicochemical, ADME, and toxicity profiling. Further, biological evaluation of the synthesized compounds against MCF-7 breast cancer cells demonstrated significant antiproliferative nature of the synthesized compounds. Compounds 5g and 5o showed antiproliferative activity comparable to the standard metabolite 4-hydroxytamoxifen (4-OH TAM) and the IC₅₀ of compounds 5g and 5o were found to be 4.350 ± 0.373 and 3.562 ± 0.466 μM respectively. Subsequently, the cell death pathway was revealed through caspase-3/7 assay and immunoblotting analysis and the compounds were found to cause cell death through activation of apoptosis-related proteins such as cleaved PARP and cleaved caspase-7. The molecular docking studies on the target protein ERα (PDB ID: 3ERT) exhibited favorable docking interactions between the compounds 5g and 5o with key amino acid residues such as Asp351, Thr347, Leu346, and His524. Similar interactions with amino acid residues were observed in the case of 4-OH TAM. Comprehensively, the results of the study highlight the promising anticancer potential of the synthesized compounds 5g and 5o as TPE-based SERM for selective ER+ breast cancer.