Tran Tu H, Le Tho H, Nguyen Thu-Ha T, Vong Long B, Nguyen Mai T T, Nguyen Nhan T, Dang Phu H
Faculty of Chemistry, University of Science, Ho Chi Minh City, 72711, Vietnam.
Vietnam National University, Ho Chi Minh City, 71300, Vietnam.
J Comput Aided Mol Des. 2025 Jul 12;39(1):46. doi: 10.1007/s10822-025-00631-2.
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 (IC, 1.84-24.72 µM), compared to dipterocarpol (IC > 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 (IC, 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.
龙脑香二萜醇具有细胞毒性；然而，其疏水性导致生物利用度降低。本研究成功合成了六种产率良好的新型烷基三苯基鏻龙脑香二萜醇衍生物（1 - 6）。与龙脑香二萜醇（IC＞100 μM）相比，这些衍生物对雌激素受体α阳性（ERα +）乳腺癌细胞系MCF - 7表现出增强的细胞毒性效力（IC，1.84 - 24.72 μM）。为揭示其作用机制，对ERα进行了分子对接分析，ERα是治疗ER +乳腺癌的治疗靶点。此外，对与两种ERα形式复合的两种最有效的化合物（2和4）进行分子动力学模拟表明，这些化合物可作为良好的拮抗剂。基于计算机模拟研究，化合物4显示比化合物2更有效，这与细胞毒性数据一致（4的IC为1.84 μM，2的IC为2.13 μM）。基于对Lipinski规则、logD、TPSA、人体肠道吸收潜力、分布体积和Tox21的评估进行的计算机模拟药代动力学预测表明，化合物2和4可能是潜在的药物候选物。
