Synthesis and Comparative Evaluation of Polymethoxy Substituted 1,4-Naphthoquinones and their Acetyl-O-glucosides as Cytotoxic Agents

Abstract

Twenty five hydroxy-, chloro-and methoxy derivatives of natural and synthetic naphthazarins and their acetylated O-glycosides were synthesized. Targeted compounds were screened as cytotoxic agents on mouse Ehrlich ascites carcinoma cells using MTT test. Chloro-and methoxy-substituted naphthoquinones as well as naphthoquinone O-acetylglucosides were the most potent with IC 50 in low micromolar concentration range. Glucosidation of hydroxynaphthoquinones was shown to enhance cytotoxicity, whereas methoxylation yielded both more active and less active derivatives depending on the number and position of methoxy groups. Evaluation using a phenotypic sea urchin embryo assay suggested that naphthazarins exerted their cytotoxic effects through tubulin-unrelated mechanism.

Multi-target bioactivity of summer quinones production in the Persian Gulf burrowing black-type sea urchin

“…(2018) displayed that 1,4-Naphthoquinone derivatives at low dosages (0.8–31.2 mg/L), show no toxicity toward zebrafish embryos. However, previous studies have shown that naphthoquinones and their acetyl-o-glucosides could act as cytotoxic agents through unrelated tubulin mechanisms ( Sabutskia et al., 2017 ). Naphthoquinones have also been suggested to act as harmful or very toxic compounds against zebrafish ( Song et al., 2010 ).…”

Untitled

“…The glycosylated naphthoquinones were found to be highly potent, with conjugate 42 being the best with an IC50 of 5.1 M compared to cisplatin's IC50 of 50.1 M as a standard cytotoxic drug. These findings suggested that glycosylation significantly impacts the cytotoxic capacity of the glycosylated derivatives compared with the corresponding parent compounds [45]. Wang et al synthesized several albocarbon-based compounds grafted to the indole heterocycle using a chalcone linker.…”