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Mar Drugs
2020 Nov 29;1812:. doi: 10.3390/md18120602.
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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.
Polonik S
,
Likhatskaya G
,
Sabutski Y
,
Pelageev D
,
Denisenko V
,
Pislyagin E
,
Chingizova E
,
Menchinskaya E
,
Aminin D
.
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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 μM and nontoxic compounds with EC50 > 100 μM were found. Acetylated O- and S-glycosides 1,4-NQs were the most potent, with EC50 = 2.7-16.4 μM. 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 μM. 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.
Figure 1. Natural hydroxynaphthazarins: 1,3,4: naphthazarins from terrestrial plants; 2,5–10: from sea urchins.
Figure 2. 3,4,6-Tri-O-acetyl-α-d-glucopyranose 1,2-(tert-butoxy orthoacetate) 11 and related hydroxynaphthazarin O-glucosides 12–17.
Figure 3. Acetylated tris-O-glucoside echinochrome 14 (U-133) and its simplified analogues 18–21 and 23.
Scheme 1. Acid-catalyzed condensation of tetra-O-acetyl-1-mercapto-d-glucose 27 with 6,7-substituted 2-hydroxynaphthazarines 2, 22, 24–26 and paraformaldehyde.
Scheme 2. Synthesis of thiomethylglucosides 38–52.
Figure 4. Per-O-acetyl-1-mercaptoderivatives of d-glucose 27, d-galactose 53, d-mannose 54, d-xylose 55 and thiomethyl glycosides 56–63 derived from spinochrome D 8.
Figure 5. Cytotoxic activity of 5,8-dihydroxy-1,4-naphthoquinone derivatives on mouse Neuro-2a cells. Dose-dependent representative curves of cytotoxic action of some studied 5,8-dihydroxy-1,4-naphthoquinone derivatives on Neuro-2a mouse neuroblastoma cells: high toxic compounds (A,B); moderate toxic compounds (C,D); low toxic compounds (E,F). Ratio of tested cytotoxic and nontoxic 1,4-NQs (G).
Figure 6. Predicted cytotoxic activity of 5,8-dihydroxy-1,4-naphthoquinone derivatives as a function of experimental values for Neuro-2a cell line.
Figure 7. The relative importance of descriptors (RID) used for QSAR model of cytotoxic activity of 5,8-dihydroxy-1,4-NQ derivatives.
Figure 8. Molecular surface of 1,4-NQs of nontoxic 2 (U-139) and its derivatives of mono-, di- and tris-O-acetylglycosides: compounds 12 (U-127), 13 (U-136) and 14 (U-133), respectively. Molecular surface colors are pink (H-bonding), green (hydrophobic) and blue (mild polar).
Figure 9. The structure of the pharmacophores of high toxic 43 (U-634) and nontoxic 28 (U-633) compounds. A pharmacophore annotation scheme: Hyd—hydrophobe (green), Acc—H-bond acceptor (turquoise), Don—H-bond donor (pink), Aro—aromatic (orange) (A,B); a heat map of high, moderate, low toxic and nontoxic compounds describing the contribution of substituent compositions of 1,4-NQ main core to the cytotoxic activity (C); structure of S-glycoside of 1,4-NQ pharmacophore where the green spots indicate hydrophobic substituent positions required for high cytotoxicity (D).
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