Diacetate Naphthoquinone Derivatives Tethered to 1,2,3-Triazoles: Synthesis and Cytotoxicity Evaluation in Caco-2 Cells

Acetylated compounds prepared from naphthoquinones have been reported as antitumoral prodrugs. Exploring the synthetic versatility of the naphthoquinone and triazolic nuclei, herein we report a simple and efficient synthetic route to prepare a series of sixteen prodrugs prototype of 1,2,3-triazoles-naphthoquinodoic acetyl derivatives. The compounds 10a-10h and 11a-11h were obtained by oxidative cycloaddition reaction between lawsone and 4-vinyl-1H-1,2,3-triazoles promoted by ceric ammonium nitrate (CAN) in alkaline medium followed by reductive acetylation of the quinones in excess of metallic zinc and acetic anhydride in yields up to > 98%. All derivatives revealed to be hemocompatible and the compound 11e exhibited the most promising profile against Caco-2 cells showing the higher selectivity index. Molecular docking suggests that these compounds could exert their cytotoxic activity through inhibition of one topoisomerase II isoform, at least.

Keywords:
naphthoquinones; lapachones; cancer; human epithelial colorectal adenocarcinoma cells; molecular docking; topoisomerase