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. 2022 Mar 30;15(4):421.
doi: 10.3390/ph15040421.

Design, Synthesis, and Biological Evaluation of Novel Tomentosin Derivatives in NMDA-Induced Excitotoxicity

Mohamed Zaki  1   2   3 , Mohammed Loubidi  1   3 , Tuğçe Bilgiç  4 , Derviş Birim  5 , Mohamed Akssira  3 , Taner Dagcı  4 , Sabine Berteina-Raboin  1 , Luciano Saso  6 , Mostafa Khouili  7 , Güliz Armagan  5
Affiliations

Design, Synthesis, and Biological Evaluation of Novel Tomentosin Derivatives in NMDA-Induced Excitotoxicity

Mohamed Zaki et al. Pharmaceuticals (Basel). .

Abstract

N-methyl-D-aspartate (NMDA) receptor stimulation may lead to excitotoxicity, which triggers neuronal death in brain disorders. In addition to current clinical therapeutic approaches, treatment strategies by phytochemicals or their derivatives are under investigation for neurodegenerative diseases. In the present study, novel amino and 1,2,3-triazole derivatives of tomentosin were prepared and tested for their protective and anti-apoptotic effects in NMDA-induced excitotoxicity. Amino-tomentosin derivatives were generated through a diastereoselective conjugate addition of several secondary amines to the α-methylene-γ-butyrolactone function, while the 1,2,3-triazolo-tomentosin was prepared by a regioselective Michael-type addition carried out in the presence of trimethylsilyl azide (TMSN3) and the α-methylene-γ-lactone function. The intermediate key thus obtained underwent 1,3-dipolar Huisgen cycloaddition using a wide range of terminal alkynes. The possible effects of the derivatives on cell viability and free-radical production following NMDA treatment were measured by Water-Soluble Tetrazolium Salts (WST-1) and Dichlorofluorescein Diacetate (DCF-DA) assays, respectively. The alterations in apoptosis-related proteins were examined by Western blot technique. Our study provides evidence that synthesized triazolo- and amino-tomentosin derivatives show neuroprotective effects by increasing cellular viability, decreasing ROS production, and increasing the Bcl-2/Bax ratio in NMDA-induced excitotoxicity. The findings highlight particularly 2e, 2g, and 6d as potential regulators and neuroprotective agents in NMDA overactivation.

Keywords: 1,2,3-triazolo-tomentosin; amino-tomentosin; apoptosis; excitotoxicity; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of various amino-tomentosins.
Scheme 2
Scheme 2
Synthesis of 1,2,3-triazole-tomentosins.
Figure 1
Figure 1
The alteration in ROS production following (A) triazolo- and (B) amino-tomentosin treatments at indicated concentrations in NMDA (2 mM)-treated SH-SY5Y cells. The concentration of each derivative was 0.1 µM, except for 2b, 2e, and 2g, whose concentrations were 1 µM. * p < 0.05 significant difference from untreated cells; ** p < 0.01 significant difference from NMDA-treated cells; # p < 0.05 significant difference from NMDA-treated cells.
Figure 2
Figure 2
The alteration in Bax and Bcl-2 protein levels following 0.1 µM triazolo-tomentosin derivative treatments in NMDA-treated cells. Quantified band values were normalized to the corresponding β-actin signal. Bar graph data represent the mean ± SD; n = 3 independent experiments. * p < 0.01 significant difference from untreated cells; ** p < 0.001 significant difference from NMDA-treated cells.
Figure 3
Figure 3
The alteration in Bax and Bcl-2 protein levels following amino-tomentosin derivative treatments in NMDA-treated cells. The concentration of 2c and 2d was 0.1 µM and the concentration of 2b, 2e, and 2g was 1 µM. Quantified band values were normalized to the corresponding β-actin signal. Bar graph data represent the mean ± SD; n = 3 independent experiments. * p < 0.05 significant difference from untreated cells; ** p < 0.01 significant difference from NMDA-treated cells.
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