Antiproliferative Activity and Acute Toxicity of α,β‐Bis(diphenylphosphine Oxide)ethanes Obtained by Bisphosphorylation of Acetylenes: Electrosynthesis Under Mild Conditions Versus Improved Superbasic Medium Synthesis

A series of vicinal bis(diphenylphosphine oxide)ethanes were synthesized via the α,β-bisphosphorylation of aryl-substituted acetylenes. Optimized reaction conditions were established, affording the desired compounds in moderate to good yields. The synthesized derivatives were evaluated for cytotoxic activity against a panel of cancer cell lines (M-HeLa, MCF-7, HuTu 80, A549), and nonmalignant cells (WI-38 and Chang Liver). The highest efficacy was observed against the M-HeLa cell line, with IC50 values ranging from 1.4 to 3.9 μM, which is 9-25 times more potent than the activity of sorafenib, a reference drug. Lead compounds 3g and 3d demonstrated selectivity toward M-HeLa cells compared to Chang liver cells, suggesting their potential therapeutic value. Mechanistic investigations revealed that 3g and 3d induce dose-dependent apoptosis via the mitochondrial pathway. Key findings indicate G2/M phase cell cycle arrest independent of the p53 pathway. Furthermore, a significant decrease in tubulin polymerization-promoting protein (TPPP) levels was observed, indicating tubulin depolymerization and antimitotic activity. Additionally, compound 3d exhibited inhibitory activity against cyclin-dependent kinase 2 (CDK2). These results position bis(diphenylphosphine oxide) derivatives as a promising scaffold for the development of novel anticancer agents.