New alkyl triphenylphosphonium dipterocarpol derivatives with cytotoxicity against the MCF-7 breast cancer cell line

Dipterocarpol exhibited cytotoxic properties; however, its hydrophobic nature resulted in decreased bioavailability. This study successfully synthesized six new alkyl triphenylphosphonium dipterocarpol derivatives (1–6) with good yield. These derivatives demonstrated enhanced cytotoxic potency against MCF-7, an estrogen receptor α-positive (ERα+) breast cancer cell line (IC₅₀, 1.84–24.72 µM), compared to dipterocarpol (IC₅₀ > 100 µM). To unveil their mechanism of action, molecular docking analyses were performed with ERα, a therapeutic target for the treatment of ER + breast cancers. Furthermore, molecular dynamics simulations of the two most potent compounds (2 and 4) complexed with both ERα forms indicated that these compounds could function as favourable antagonists. Based on the in silico studies, compound 4 was showed to be more potent than compound 2, which was consistent with the cytotoxicity data (IC₅₀, 1.84 µM for 4 and 2.13 µM for 2). In silico pharmacokinetic predictions, informed by assessments of Lipinski compliance, logD, TPSA, human intestinal absorption potential, volume of distribution, and Tox21, suggested that compounds 2 and 4 may serve as potential drug candidates.