Newly synthesized (R)-carvone-derived 1,2,3-triazoles: structural, mechanistic, cytotoxic and molecular docking studies

In the current study, natural (R)-carvone was used as starting material for the efficient synthesis of several 1,2,3-triazole derivatives. The produced products were obtained in good yields and characterized by 1H and 13C NMR and HRMS analysis. The newly synthesized monoterpenic 1,2,3-triazole 4 and derivatives were analyzed by viability tests (MTT) for their cytotoxic activity against three human cancer cells. Product 5 showed a medium antitumor activity, for which the IC50 values against selected cells HT-1080, A-549 and MCF-7 were 29.25 μM, 31.62 μM and 26.02 μM, respectively. The regioselectivity of the condensation reaction and the molecular structure of the title compounds were determined by Density Functional Theory (DFT) using B3LYP calculations at 6-311 + G(d,p) level. The orbitals HOMO and LUMO were studied to determine the electronic properties of the synthesized compounds. In addition, the global reactivity indices were used to explain the regioselectivity for the formation of compound 6, and the theoretical results agree well with the experimental results. Molecular docking and molecular dynamics confirmed the empirical test results and confirmed the stability of the complex during inhibition of the anti-apoptotic protein for killing cancer cells. Communicated by Ramaswamy H. Sarma

本研究以天然(R)-香芹酮为起始原料，高效合成了多种1,2,3-三唑衍生物。目标产物均以优异收率获得，并通过1H核磁共振谱(1H NMR)、13C核磁共振谱(13C NMR)及高分辨质谱(High Resolution Mass Spectrometry, HRMS)完成了结构表征。对新合成的单萜类1,2,3-三唑化合物4及其衍生物，采用MTT细胞活力检测法评价其对三种人癌细胞的细胞毒活性。结果显示，化合物5表现出中等强度的抗肿瘤活性，其对所选细胞HT-1080、A-549及MCF-7的半数抑制浓度(IC50)分别为29.25 μM、31.62 μM和26.02 μM。本研究通过密度泛函理论(Density Functional Theory, DFT)，采用B3LYP泛函结合6-311+G(d,p)基组的计算方法，确定了缩合反应的区域选择性以及目标化合物的分子结构。通过研究最高占据分子轨道(Highest Occupied Molecular Orbital, HOMO)与最低未占据分子轨道(Lowest Unoccupied Molecular Orbital, LUMO)的轨道性质，分析了合成化合物的电子结构特性。此外，借助全局反应性指数阐释了化合物6生成过程中的区域选择性，理论计算结果与实验数据吻合良好。分子对接与分子动力学模拟验证了实验测试结果，并证实了该复合物在抑制抗凋亡蛋白以杀伤癌细胞过程中的稳定性。本文由Ramaswamy H. Sarma转交。