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

Despite 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 mu M, respectively. These values indicated higher potency than free curcumin (IC50>100 mu M). Molecular docking studies of curcumin and three derivatives 1-3 with two estrogen receptor alpha (ER alpha) 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 ER alpha. 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.