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Evaluation of N-Hydroxy-, N-Metoxy-, and N-Acetoxybenzoyl-Substituted Derivatives of Thymine and Uracil as New Substances for Prevention and Treatment of Long-Term Complications of Diabetes Mellitus

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Abstract

New uracil and thymine derivatives, N1-,N3- and N1,N3-(RO-benzoyl)-(1H,3H)-pyrimidine- 2,4-diones, were synthesized (RO- is hydroxy, acetoxy- or methoxy-group). The compounds were studied in a complex of in vitro tests for the ability to inhibit the development of long-term complications of diabetes. Their ability to cleave cross-links of proteins has been evaluated. The most significant ways of pharmacological correction of thrombosis, angio-, nephro-, encephalo-, and cardiopathy, antiglycation, chelating, and antiplatelet activities, have been established. The most active compound in terms of antiplatelet action, N1- hydroxybenzoyluracil, exceeded acetylsalicylic acid by ~44%. In terms of their ability to chelate copper (II) cations, all compounds (with the exception of 1,3-bis(3-hydroxybenzoyl)-(1H,3H)-pyrimidine-2,4-dione that was not not studied in this test) showed the activity, whose IC50 fell in the range between that for pioglitazone (44.1 μM) and pyridoxamine (136.7 μM) comparison drugs. The best antiglycation effect at the 1 mM concentration was observed for N1,N3-bismethoxy- and N1,N3-bisacetoxybenzoyl derivatives of thymine. The maximum activity to cleave cross-links of proteins (C = 1 mM), comparable to that of alagebrium, was established for 1,3-bis(4-methoxybenzoyl)uracil, for which also high rates of other estimated activities were noted. Thus, the N1-,N3- and N1,N3-(RO-benzoyl) derivatives of uracil and thymine are promising basiсs for creating drugs that suppress the development of long-term complications of diabetes.

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Abbreviations

DM:

diabetes mellitus

ROS:

reactive oxygen species

GEP:

glycation-end products

NMR:

nuclear magnetic resonance

BSA:

bovine serum albumin

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Authors and Affiliations

  1. Volgograd State Medical University, Volgograd, 400131, Russia

    A. A. Spasov, A. K. Brel, R. A. Litvinov, S. V. Lisina, A. F. Kucheryavenko, Yu. N. Budaeva, O. A. Salaznikova, A. I. Rashchenko, D. D. Shamshina, V. V. Batrakov & A. V. Ivanov

  2. Volgograd Medical Scientific Center, Volgograd, 400081, Russia

    A. A. Spasov

  3. Scientific Institute of Pharmacology of VSMU, Antioxidant Lab., Volgograd, 400001, Russia

    A. A. Spasov & R. A. Litvinov

Authors
  1. A. A. Spasov
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  2. A. K. Brel
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  3. R. A. Litvinov
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  4. S. V. Lisina
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  5. A. F. Kucheryavenko
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  6. Yu. N. Budaeva
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  7. O. A. Salaznikova
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  8. A. I. Rashchenko
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  9. D. D. Shamshina
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  10. V. V. Batrakov
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  11. A. V. Ivanov
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Correspondence to R. A. Litvinov.

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Spasov, A.A., Brel, A.K., Litvinov, R.A. et al. Evaluation of N-Hydroxy-, N-Metoxy-, and N-Acetoxybenzoyl-Substituted Derivatives of Thymine and Uracil as New Substances for Prevention and Treatment of Long-Term Complications of Diabetes Mellitus. Russ J Bioorg Chem 44, 769–777 (2018). https://doi.org/10.1134/S1068162019010163

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