1. Design, synthesis and evaluation of novel levoglucosenone derivatives as promising anticancer agents
- Author
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Alejandra G. Suárez, Javier Girardini, Soledad Cicetti, Yi-hsuan Tsai, Ariel M. Sarotti, Carla M. Borini Etichetti, and Rolando A. Spanevello
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Humans ,Molecular Biology ,Cell Proliferation ,Mda mb 231 ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Isoxazoles ,Triazoles ,Bridged Bicyclo Compounds, Heterocyclic ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Glucose ,Design synthesis ,Drug Design ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53. The results highlighted the importance of the introduction of the flexible spacer as well as the higher activity of oxa-Michael isoxazole-derivatives. The most prominent compounds also showed anti-proliferative activities against lung and colon cancer cell lines. The compounds showed enhanced cytotoxic effects in the presence of mutant p53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.
- Published
- 2020
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