ER alpha selective chromone, isoxazolylchromones, induces ROS‐mediated cell death without autophagy. (7th May 2019)

• Record Type: Journal Article
• Authors: Kaushik, Swati; Sanawar, Rahul; Lekshmi, Asha; Chandrasekhar, Leena; Nair, Mydhily; Bhatnagar, Seema; Santhoshkumar, Thankayyan Retnabai
• Is Part Of: Chemical biology & drug design. Volume 94:Number 1(2019)
• Page Start: 1352
• Page End: 1367
• Publication Date: 2019-05-07
• Subjects: autophagy -- Caspase -- cell cycle -- estrogen receptor -- isoxazolylchromones -- ROS -- SERM -- transactivation; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13510
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: Chromones are recognized as privileged structures and useful templates for the design of novel compounds with promising pharmacological activity. Several reports implicate chromone scaffold as an antitumor agent. The present study highlights synthesis, docking, and potential activity of isoxazolylchromones, 3(a–f), a new class of compounds as potential agents exhibiting ERα antagonism and ERβ agonism. Molecular docking studies determined the binding site of compounds3(a–f) in ERα and ERβ. All the analogues synthesized showed preferential cytotoxicity in ERα+ cell line (MCF‐7) compared to ERα‐ cell line (MDA‐MB‐231). Among the analogues synthesized, analogue3d exhibited increased cytotoxicity. ERα silencing experiments confirmed the ERα selective nature of ligands. Transactivation assay on compound3d indicated the down‐regulation of ERα luciferase reporter gene expression and induction of ERβ GFP in the treated cells. Cell cycle analysis revealed an increase in sub‐G0/G1 population on treatment with analogue3d as compared to control. Similar to tamoxifen, 3d ‐induced cell death is mediated through an increase in ROS as evidenced by change in roGFP ratio. Interestingly, the compound3d induced mitochondrial trans‐membrane potential loss and caspase activation without indication of autophagy compared to tamoxifen that induced autophagy in the treated cells. Lack of significant autophagy and induction of ERβ signaling by the new compound place them as a better ERα antagonist. Abstract : The article describes the discovery of a new ER alpha selective chromone with unique functional properties such as autophagy independent caspase‐dependent cell death primarily involving ROS. Molecular docking studies determined the binding site of compound3d in ERα and ERβ. Similar to tamoxifen, 3d‐ induced cell death is mediated by an increase in ROS via inducing a significant mitochondrial trans‐membrane potential loss and caspase activation.