Design, synthesis and evaluation of novel levoglucosenone derivatives as promising anticancer agents

TSAI, Y. H.; BORINI ETICHETT, C. M.; CICETTI, S.; GIRARDINI, J. E.; SPANEVELLO, R.A.; SUÁREZ, A.G.; SAROTTI, A.M.*

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2020 vol. 30 p. 127247 - 127251

0960-894X

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 oxaMichael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. Allof 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 oxaMichael 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 mutantp53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.