Journal
CHINESE CHEMICAL LETTERS
Volume 33, Issue 11, Pages 4891-4895Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cclet.2022.02.075
Keywords
Multicomponent reaction; Domino reaction; Biginelli reaction; Bridged polyheterocycles; Reaction mechanism; Anti-tumor activities
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Funding
- National Natural Science Foundation of China [21901067, 22171075]
- Ministry of Human Resource and Social Security of China
- NSFC of Guangxi Province [91122032, 2017GXNSFDA198040]
- BAGUI talent program [2019AC26001]
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This study investigated the low-cost CuBr-promoted domino Biginelli reaction under solvothermal conditions and successfully synthesized novel bridged polyheterocycles. The reaction mechanism was elucidated, and the antitumor activity of the synthesized compounds was evaluated. The findings suggest that the synthesized polyheterocycles have potential medicinal value and provide fragmentation rules for rapid structural identification.
The low-cost CuBr-promoted domino Biginelli reaction among readily available ketones, salicylaldehyde derivatives and 3-amino-1,2,4-triazole was studied under solvothermal conditions, giving the novel bridged polyheterocycles bearing two or three stereocenters depending on the starting ketones. This multicomponent reaction proceeded with high diastereoselectivity (dr > 20:1) based on a combined H-1 NMR, crystallographic and supercritical fluid chromatographic (SFC) analysis of the product. Time-dependent high-resolution mass spectrometry (HRMS) was performed to track the reaction process, and several key intermediates were identified, leading to the drawing of a plausible reaction mechanism. Density functional theory (DFT) calculation was supplemented, and two reaction pathways were differentiated. Moreover, in vitro antitumor activity was evaluated using HeLa and HepG2 cell lines, and two of these polyheterocycles demonstrated promising activities against HepG2 cells with EC50 down to 10 mu mol/L. Additionally, ESI-MS/MS studies on all the polyheterocycles suggest a common fragmentation pathway (loss of one molecule of amino-triazole) they shared, providing the first-hand fragmentation rules for future rapid structural identification of them. The multicomponent domino reaction presented here may offer prospects for future design of more efficient strategies to access medicinally important bridged polyheterocycles. (C) 2022 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
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