Design, Synthesis, Cytotoxic Evaluation, and Molecular Docking of New Alkyl Triphenylphosphonium Curcumin Derivatives

Abstract

AbstractDespite the previous anticancer effects of curcumin against various cancer cell lines, in vitro, pre–clinical, and clinical studies have faced constraints, particularly at high doses. Therefore, the mitochondria–targeted approach represents a promising trend in cancer drug development. This study successfully synthesized three new alkyl triphenylphosphonium ester curcumin derivatives (1–3) with good yield. They demonstrated cytotoxicity against MCF‐7 cells with IC50 values of 49.72, 62.57, and 91.73 μM, respectively. These values indicated higher potency than free curcumin (IC50>100 μM). Molecular docking studies of curcumin and three derivatives 1–3 with two estrogen receptor α (ERα) ligand binding domains, 3ERT (antagonist recognition and antiproliferative function), and 1GWR (agonist recognition and pro–proliferative function), were carried out. These domains are important targets in hormone–dependent anticancer strategies. The favourable docking scores and key residue interactions suggested that these derivatives could be the potential antagonists. Three synthesized alkyl–TPP+ curcumin ester derivatives (1–3) demonstrated more potent cytotoxic efficacy than curcumin, particularly against the human MCF‐7 breast cancer cell line. In addition, molecular docking studies suggested their potential as antagonists of ERα. The in silico ADMET data of three derivatives (1–3) showed compliance with the Lipinski rule and demonstrated their absorption, distribution, metabolism, and excretion properties.