Journal
JOURNAL OF MOLECULAR STRUCTURE
Volume 1290, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.molstruc.2023.135889
Keywords
Indolic cannabinoids; Triazoles; Molecular hybridization; Antitumoral compounds; Structure-activity relationship
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Twenty-two novel hybrid compounds of indolic cannabinoids and 1,2,3-triazoles were synthesized with high yields. These compounds showed antiproliferative activity against breast tumor cells, with 12 compounds exhibiting significant cytotoxicity. Derivative 18j and 18a were the most active compounds, with promising ADME parameters for further development as anticancer agents.
Twenty-two novel hybrid compounds of indolic cannabinoids and 1,2,3-triazoles were obtained in yields greater than 69%. To this aim, we employed a 1,3-dipolar cycloaddition between terminal alkynes attached to a cannabinoid core and organic azides. These compounds evaluated in vitro for their antiproliferative activity against MCF7 and MDA-MB-231 mammary tumor cells. Also, cytotoxicity towards the normal cell line MCF10A was assessed to estimate selectivity. Twelve compounds showed cytotoxic activity IC50<100 mu M. Derivative 18j, which bears an alkyl chain at N-1 triazole ring, was found to be the most active compound, displaying IC50 of 2.8 mu M and 4.4 mu M against MCF7 and MDA-MB-231 cell lines, respectively, and displaying 3.0-fold less cytotoxic towards normal cell line MCF10A. The best result combining activity and selectivity was found for derivative 18a (benzyl triazole substituted), which showed high cytotoxicity against tumor cell lines (MCF7-IC50 = 8.3 +/- 0.4 mu M; MDA-MB-231-IC50 = 7.1 +/- 0.1 mu M) and was not active against the tested normal cell line. QSAR models and molecular docking using Mitogen-activated protein kinase (MAPK) revealed that the triazole ring plays an important role in the antiproliferative activity displayed by the novel compounds, suggesting molecular hybridization as a successful approach. In addition to their high cytotoxicity, the most active derivatives 18a and 18j might also present drug like properties according to predicted ADME parameters, becoming promising compounds for further development of anticancer agents.
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