5’-NORCARBOCYCLIC ANALOGUES OF NUCLEOSIDES AS POTENTIAL CHEMOTHERAPEUTIC AGENTS

Novel types of the 5’-norcarbocyclic analogues of nucleosides have been designed, and new biological targets and mechanisms of action of these compounds have been found. The first group of the analogues are derived from purine nucleosides. N¹-oxide-5’-noraristeromycin derivatives show an antiviral activity in a virus. The isosteric analogues of inosine-5’-monophoshate were weakly inhibitory towards inosine-5’-monophosphate dehydrogenase II and hepatitis C virus, but did not suppress M. Tuberculosis growth. The second group are 1-(4’-hydroxy-2’-cyclopentene-1’-yl)-uracil (HCPU) derivatives having substituents at 4’-hydroxyl and at carbon 3 of the heterocyclic core. The analogues were evaluated as HIV-1 reverse transcriptase inhibitors. It has been shown for the first time that 3,4’-substituted analogues of HCPU can act as the non-nucleoside inhibitors of reverse transcriptase of wild type HIV-1 (Ki 5 to 19 mkM) and HIV-1 mutants L100I (Ki 1 to 11 mkM) and K103N (Ki 8 to 55 mkM) referred to the first generation NNRTI resistant HIV-1 strains. The third group includes HCPU and 1,3-di-(4’-hydroxy-2’-cyclopentene-1’-yl)-uracil derivatives having different substituents (a halogen or 5-arylamine) at carbon 5 of their heterocyclic core. The compounds of this group proved to be potent inhibitors of the laboratory M. Tuberculosis strain H37Rv (MIC90 10 to 40 mg/ml) and the MS-115 strain (MIC90 5 to 20 mkM), which features multiple drug resistance against five first-line anti-tuberculosis: rifampicin, streptomycin, ethambutol, and pyrazinamide. A weak anti-HIV activity of these compounds has also been shown (Ki 60 to 11 mkM). The fourth group of the novel 5’-norcarbocyclic nucleosides are furopyrimidine analogues, which are modified at positions 4 and 5 of their uracil moieties. They were shown to inhibit the growth of different tumor cell lines at IC50 from 3 to 50 mkM.

химиотерапевтические агенты, 5’-норкарбоциклические нуклеозиды, резистентность, chemotherapeutic agents, 5’-norcarbocyclic nucleosides, drug resistance

1. Wang J, Rawal R.K., Chu C.K.Recent Advances in Carbocyclic Nucleosides: Synthesis and Biological Activity // Medicinal Chemistry of Nucleic Acids / Eds. by L.-H. Zhang, Z. Xi and J. Chattopadhyaya.- Hoboken, NJ, USA: John Wiley & Sons, Inc., 2011.- Р. 1-100.- http://online-library.wiley.com/doi/10.1002/9781118092804.ch1/summary.

2. Матюгина Е.С., Сили-Радтке К.Л., Андронова В.Л., Галегов Г.А., Кочетков С.Н., Хандажинская А.Л. Синтез новых производных Ш-оксида-5’-нораристеромицина и их антивирусная оценка в отношении вируса осповакцины // Биоорганическая химия. - 2010.- Т. 36, № 6.- С. 797-801.

3. Braun-Sand S.B., Peetz M. Inosine monophosphate dehydrogenase as a target for antiviral, anticancer, antimicrobial and immunosuppressive therapeutics // Future Med. Chem.- 2010.- № 2.- С. 81-92.

4. Shu Q., Nair V. Inosine Monophosphate Dehydrogenase (IMPDH) as a Target in Drug Discovery // Med. Res. Rev.- 2008.- № 28.- Р. 219-232.

5. Матюгина Е.С., Андреевская С.Н., Смирнова Т.Г., Хандажинская А.Л. Карбоциклические аналоги 5’-монофосфата инозина: синтез и биологическая активность // Acta Naturae.- 2012.- Т. 4, № 15.- С. 75-79.

6. Pedersen O.S., Pedersen E.B. Non-nucleoside reverse transcriptase inhibitors: the NNRTI boom // Antiviral Chem. Chemother.- 1999.- T. 10.- C. 285-314.

7. Hegde V.R., Seley K.L., Schneller S.W.Carbocyclic 5’-noruridine // Nucleosides, Nucleotides Nucleic Acids.- 2000.- № 19.- С. 269-273.

8. Matyugina E.S., Valuev-Elliston V.T., Babkov D.A., Novikov M.S., Ivanov A.V., Kochetkov S.N., Balzarini J., Seley-Radtke K.L., Khandazinskaya A.L. 5’-Nor carbocyclic nucleosides: surprising nonnucleoside inhibitors of HIV-1 reverse transcriptase // Med. Chem. Comm.- 2013.- № 4.- Р. 741-748.

9. Matyugina E.S., Valuev-Elliston V.T., Geisman A.N., Novikov M.S., Chizhov A.O., Kochetkov S.N., Seley-Radtke K.L., Khandazhinskaya A.L. Structure-Activity Evaluation of New Uracil-Containing Non-Nucleoside Inhibitors of HIV Reverse Transcriptase // Med. Chem. Comm.- 2013.- № 4.- Р. 1443-1451.

10. Matyugina E.S., Valuev-Elliston V.T., Chizhov А.О., Kochetkov S.N., Khandazhinskaya A.L. HIV-1 nonnucleoside reverse transcriptase inhibitors: incorporation of benzylphosphonate moiety for solubility improvement //Mendeleev Communication. - 2016.- Vol. 26, № 2.- Р. 114-116.

11. Matyugina E.S., Khandazhinskaya A.L., Chernousova L.N., Andreevskaya S.N., Smirnova T.G., Chizhov A.O., Karpenko I.L, Kochetkov S.N., Alexandrova L.A. The Synthesis and Antituberculosis Activity of 5’-Nor Carbocyclic Uracil Derivatives // Bioorganic and Medicinal Chemistry.- 2012.- Vol. 20, № 22.- Р. 6680-6686.

12. Matyugina E., Novikov M., Babkov D., Ozerov A., Chernousova L., Andreevskaya S., Smirnova T., Karpenko I., Chizhov A.,Murthu P., Lutz S., Kochetkov S., Seley-Radtke K., Khandazhinskaya A. 5-Arylaminouracil derivatives as new inhibitors of M. Tuberculosis // Chem. Biol. Drug. Dеs.- 2015.- Vol. 86, № 6.- Р. 1387-1396.

13. Matyugina E., Logashenko E., Zenkova M., Kochetkov S., Khandazhinskaya A. 5 -Norcarbocyclic analogues of furano[2,3-d]pyrimidine nucleosides // Heterocyclic Communications.- 2015.- Vol. 21, № 5.- Р. 259-262.