Offering novel scaffolds targeting estrogen receptor creates huge necessity to overcome the evolving resistance developed by tumors. Structure-based drug design coupled with ring opening strategy of the steroids skeleton revealed the potential of indole-based analogs to be synthesized targeting the ligand binding domain of estrogen receptor-α. In vitro studies revealed the potential of the total sub-classes of the synthesized analogs to show anti-proliferative activity against estrogen receptor-dependent cancer cell lines at IC50 ranging from 28.23 to 57.13⯵M. This was further validated by evaluating the potential of the synthesized analogs to compete along with estradiol via ER-α ELISA assay to show inhibitory profile at IC50 ranging from 1.76 to 204.75â¯nM. Two analogs (YMA-005 and YMA-006) showed significant reduction in tumor size at two dose levels with extensive degeneration and necrosis. Both YMA-005 and YMA-006 showed in-situ reduction of ER-α Immunohistochemical expression at both dose levels. Ultimately, novel analogs of indole-based biomimetic of estrone scaffolds were offered as estrogen receptor-α inhibitors.
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Biomimetic Materials/chemical synthesis , Biomimetic Materials/pharmacology , Drug Design , Estrogen Receptor alpha/antagonists & inhibitors , Indoles/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Biomimetic Materials/chemistry , Biomimetic Materials/metabolism , Cell Line, Tumor , Chemistry Techniques, Synthetic , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/metabolism , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Conformation