Synthesis, Cytotoxic Activity Evaluation and Quantitative Structure-Activity Analysis of Substituted 5,8-Dihydroxy-1,4-Naphthoquinones and their O- and S-Glycoside Derivatives Tested Against Neuro-2a Cancer Cells.

ABSTRACT: Based on 6,7-substituted 2,5,8-trihydroxy-1,4-naphtoquinones (1,4-NQs) derived from sea urchins, five new acetyl-O-glucosides of NQs were prepared. A new method of conjugation of per-O-acetylated 1-mercaptosaccharides with 2-hydroxy-1,4-NQs through a methylene spacer was developed. Methylation of 2-hydroxy group of quinone core of acetylthiomethylglycosides by diazomethane and deacetylation of sugar moiety led to 28 new thiomethylglycosidesof 2-hydroxy- and 2-methoxy-1,4-NQs. The cytotoxic activity of starting 1,4-NQs (13 compounds) and their O- and S-glycoside derivatives (37 compounds) was determined by the MTT method against Neuro-2a mouse neuroblastoma cells. Cytotoxic compounds with EC₅₀ = 2.7-87.0 ?M and nontoxic compounds with EC₅₀ > 100 ?M were found. Acetylated O- and S-glycosides 1,4-NQs were the most potent, with EC₅₀ = 2.7-16.4 ?M. Methylation of the 2-OH group innaphthoquinone core led to a sharp increase in the cytotoxic activity of acetylated thioglycosidesof NQs, which was partially retained for their deacetylated derivatives. Thiomethylglycosides of 2-hydroxy-1,4-NQs with OH and MeO groups in quinone core at positions 6 and 7, resprectively formed a nontoxic set of compounds with EC₅₀ > 100 ?M. A quantitative structure-activity relationship (QSAR) model of cytotoxic activity of 22 1,4-NQ derivatives was constructed and tested. Descriptors related to the cytotoxic activity of new 1,4-NQ derivatives were determined. The QSAR model is good at predicting the activity of 1,4-NQ derivatives which are unused for QSAR models and nontoxic derivatives.

SUBMITTER: Polonik S 

PROVIDER: S-EPMC7761386 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature