The selective toxic effect of dialdehyde derivatives of pyrimidine nucleosides on human ovarian cancer cells

Ефремова, А.; Shram, S. I.; Drenichev, Mikhail S.; Посыпанова, Г. А.; Myasoedov, N. F.; Mikhailov, Sergey N.

doi:10.1134/s1990750814040027

Cited by 3 publications

(4 citation statements)

References 17 publications

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“…Recently, a novel group of Tdp1 inhibitors effective in the submicromolar range of concentrations was found among disaccharide nucleosides with lipophilic groups [ 19 ]. The current work represents a continuation of our earlier studies on the inhibition of DNA repair enzymes by nucleoside compounds [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 84%

“…It has been shown earlier that disaccharide nucleosides with lipophilic groups inhibit Tdp1 in a submicromolar range of concentrations and are only weakly toxic to cancerous and healthy cells [ 19 ]. On the other hand, disaccharide nucleosides tend to inhibit PARP1 [ 20 , 22 ], and this activity may reduce their selectivity toward Tdp1 in the cell. Therefore, we focused on nucleoside inhibitors of Tdp1, which are structurally modified previously described disaccharide inhibitors of Tdp1.…”

Section: Discussionmentioning

confidence: 99%

“…It has been previously reported that disaccharide nucleosides [ 20 , 22 ] and nucleoside derivatives with modified nitrogen bases [ 29 , 30 ] inhibit PARP1. Therefore, in addition to the effect on Tdp1, a possible effect of the lipophilic nucleosides on DNA break sensors PARP1 and PARP2 was tested.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides

et al. 2020

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Inhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose)polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied here. New effective Tdp1 inhibitors were found in a series of nucleoside derivatives possessing 2′,3′,5′-tri-O-benzoyl-d-ribofuranose and 5-substituted uracil moieties and have half-maximal inhibitory concentrations (IC50) in the lower micromolar and submicromolar range. 2′,3′,5′-Tri-O-benzoyl-5-iodouridine manifested the strongest inhibitory effect on Tdp1 (IC50 = 0.6 μM). A decrease in the number of benzoic acid residues led to a marked decline in the inhibitory activity, and pyrimidine nucleosides lacking lipophilic groups (uridine, 5-fluorouridine, 5-chlorouridine, 5-bromouridine, 5-iodouridine, and ribothymidine) did not cause noticeable inhibition of Tdp1 (IC50 > 50 μM). No PARP1/2 inhibitors were found among the studied compounds (residual activity in the presence of 1 mM substances was 50–100%). Several O-benzoylated uridine and cytidine derivatives strengthened the action of topotecan on HeLa cervical cancer cells.

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Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides

et al. 2020

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“…Recently it was shown, that some pyrimidine disaccharide derivatives inhibit poly(ADP-ribose)polymerase-1 (PARP-1), a key enzyme of DNA repair 28 , 29 . Moreover, in the studies 30 , 31 series of nicotinamide adenine dinucleotide (NAD + ) mimetics, which comprise morpholino analogues of nucleosides were synthetised to inhibit PARP-1 enzyme.…”

Section: Introductionmentioning

confidence: 99%

Novel group of tyrosyl-DNA-phosphodiesterase 1 inhibitors based on disaccharide nucleosides as drug prototypes for anti-cancer therapy

Komarova

Drenichev

Dyrkheeva

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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A new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors based on disaccharide nucleosides was identified. TDP1 plays an essential role in the resistance of cancer cells to currently used antitumour drugs based on Top1 inhibitors such as topotecan and irinotecan. The most effective inhibitors investigated in this study have IC50 values (half-maximal inhibitory concentration) in 0.4–18.5 µM range and demonstrate relatively low own cytotoxicity along with significant synergistic effect in combination with anti-cancer drug topotecan. Moreover, kinetic parameters of the enzymatic reaction and fluorescence anisotropy were measured using different types of DNA-biosensors to give a sufficient insight into the mechanism of inhibitor’s action.

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Synthesis and In Vitro Anticancer Activity of 6-Ferrocenylpyrimidin-4(3H)-one Derivatives

Grabovskii

Muhammadiev²,

Валиуллин³

et al. 2019

COS

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Aim and Objective: Some ferrocenyl derivatives are active in vitro and in vivo against cancer. Generally, ferrocenyl derivatives for cancer research have three key components: a ferrocene moiety, a conjugated linker that lowers the oxidation potential and some derivative (peptide, nucleobase and others) that can interact with biomolecules. Since the pyrimidine fragment can easily pass through the membrane into the cells and become involved in metabolism; it appears to be promising. Furthermore, this fragment is an electron-acceptor group, so a spacer can be excluded. Therefore, the synthesis of 6-ferrocenylpyrimidin-4(3H)-one derivatives and the study of their anticancer activity have scientific and practical interest. </P><P> Methods: The syntheses of 6-ferrocenylpyrimidin-4(3H)-one derivatives were performed by the condensation of ethyl 3-ferrocenyl-3-oxopropionate with thiourea or acetamidine or guanidine. The cytotoxicity of four 6- ferrocenylpyrimidin-4(3H)-one derivatives was evaluated by using the MTT assay in vitro against Human breast adenocarcinoma MCF-7 and normal human skin fibroblast HSF cells. The tested derivatives induced a concentration-dependent cytotoxic response in cell lines. </P><P> Results: A study of the cytotoxic activity of 6-ferrocenylpyrimidin-4(3H)-one derivatives by the MTT test has found that all compounds have a dose-dependent toxic effect on the lines of breast cancer cells (MCF-7) and normal human fibroblast cells (HSF). The most pronounced cytotoxic effect is exhibited by 2-methyl-6-ferrocenylpyrimidin- 4(3H)-one (MCF-7, IC50 17 ± 1 µM). Conclusion: The experimental results confirm the importance of investigation and design of ferrocenylpyrimidin- 4(3H)-one derivatives as anticancer agents. Compounds where the pyrimidine derivatives are directly linked to the ferrocene unit rather than via a spacer group also may be of interest for antiproliferative drug design.

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The selective toxic effect of dialdehyde derivatives of pyrimidine nucleosides on human ovarian cancer cells

Cited by 3 publications

References 17 publications

Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides

Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides

Novel group of tyrosyl-DNA-phosphodiesterase 1 inhibitors based on disaccharide nucleosides as drug prototypes for anti-cancer therapy

Synthesis and In Vitro Anticancer Activity of 6-Ferrocenylpyrimidin-4(3H)-one Derivatives

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