Abstract
Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide–alkyne cycloaddition reaction using CuSO4,5H2O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC50 values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC50 value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.
Highlights
Cancer is a significant public health issue and has become the leading cause of death worldwide [1]
All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines
The high chemoselectivity of this CuAAC reaction was examined by means of DFT mechanistic studies which show that the terminal alkyne is the most reactive of all the dipolarophiles of 7
Summary
Cancer is a significant public health issue and has become the leading cause of death worldwide [1]. One of the hallmarks of cancer is the ability of some tumor cells to evolve during the epithelial mesenchymal transition and to acquire both migration and invasion properties These two characteristics are the most important key factors in metastasis [2] and often lead to poor prognosis and treatment failure. Natural compounds have been and are the main source for the development of several anticancer agents [6,7,8,9,10] Terpenes and their functionalized derivatives, especially heterocyclic analogues, are often used as a source for the preparation of new semi-synthetic compounds displaying various biological properties including anticancer activity [11,12]. Terpenes and their functionalized derivatives, especially heterocyclic analogues, are often used as a source for the preparation of new semi-synthetic compounds displaying various biological properties including anticancer activity [11,12]. 1,2,3-Triazole derivatives of such terpenes have been shown to present a broad spectrum
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