Ligand-based drug design: Synthesis and biological evaluation of substituted benzoin derivatives as potential antitumor agents

Background: Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target for anticancer drug design. Objectives: Target compounds were designed to investigate the effect of the p-OCH₃ motifs on ligand/PI3Ka complex interaction and antiproliferative activity. Methods: Synthesis of the proposed compounds, biological examination tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, along with Glide docking studies. Results: A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized by means of FT-IR, ¹H and ¹³C NMR, and by elemental analysis. Biological investigation demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines possibly via inhibition of PI3Ka and estrogen receptor alpha (ERa). Additionally, results revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position. Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against T47D. Glide docking studies against PI3Ka and ERa demonstrated that the series accommodate binding to PI3Kα and/or ERα. Conclusion: The series exhibited a potential antitumor activity in human carcinoma cell lines encoding PI3Kα and/or ERα.