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. 2023 Jan 6;12(1):139.
doi: 10.3390/antiox12010139.

Seleno-Analogs of Scaffolds Resembling Natural Products a Novel Warhead toward Dual Compounds

Affiliations

Seleno-Analogs of Scaffolds Resembling Natural Products a Novel Warhead toward Dual Compounds

Nora Astrain-Redin et al. Antioxidants (Basel). .

Abstract

Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer's disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD50 values below 9.2 µM. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 × 10-6 cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.

Keywords: Alzheimer’s disease; NSAIDs; acetylcholinesterase; allyl; cancer; garlic; natural; propargyl; selenium; selenoester.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Allylic and propargylic molecules from natural products.
Figure 2
Figure 2
Structures of synthesized compounds (1a19a and 1b19b).
Scheme 1
Scheme 1
Synthesis procedure to yield 1a19a and 1b19b derivatives. Reagents and conditions: (i) H2O, 20 min, and room temperature; (ii) THF/H2O, 60 min, and room temperature; (iii) ClCOCOCl, CH2Cl2, 12 h, and room temperature; (iv) BrCH2CH=CH2 or BrCH2C≡CH, THF/H2O, 90 min, and room temperature.
Figure 3
Figure 3
Analysis of DPPH radical scavenging activity for compound 13a at different concentrations and different time points. Data correspond to at least three independent experiments.
Figure 4
Figure 4
Antiproliferative effect of synthesized compounds 1a6a (A), 7a12a (B), 13a19a (C) from series a (allyl motif) and 1b6b (D), 7b12b (E), 13b19b (F) from series b (propargyl motif). Data correspond to at least three independent experiments.
Figure 4
Figure 4
Antiproliferative effect of synthesized compounds 1a6a (A), 7a12a (B), 13a19a (C) from series a (allyl motif) and 1b6b (D), 7b12b (E), 13b19b (F) from series b (propargyl motif). Data correspond to at least three independent experiments.
Figure 5
Figure 5
Representation of GI50 (A,B), TGI (C,D), and LC50 (E,F) values of compounds 14a (A,C,E) and 17a (B,D,E) in the 60 cancer cell lines tested and grouped by cancer type. Values over 100 µM are represented as 100 µM. The LC50 values of some cell lines were not determined. Blue lines represent mean value in each cancer type.
Figure 5
Figure 5
Representation of GI50 (A,B), TGI (C,D), and LC50 (E,F) values of compounds 14a (A,C,E) and 17a (B,D,E) in the 60 cancer cell lines tested and grouped by cancer type. Values over 100 µM are represented as 100 µM. The LC50 values of some cell lines were not determined. Blue lines represent mean value in each cancer type.
Figure 6
Figure 6
Dose-inhibition curve for AChE inhibition by compound 14a (green) compared to galantamine (blue).
Figure 7
Figure 7
Interactive models of compounds 14a (A,B) and 14b (C,D) with the residues in the binding pocket of AChE (code PDB 4BD7).

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