Chemoenzymatic Synthesis of Modified 2′-Deoxy-2′-fluoro-β- d -arabinofuranosyl Benzimidazoles and Evaluation of Their Activity Against Herpes Simplex Virus Type 1 / Kharitonova M.I., Dntonov K.V., Fateev I.V., Berzina D.Y., Kaushin A.L., Paramonov A.S., Kotovskaya S.K., Dndronova V.L., Konstantinova I.D., Galegov G.A., Charushin V.N., Miroshnikov A.I. // Synthesis (Germany). - 2017. - V. 49, l. 5. - P. 1043-1052.

ISSN:
00397881
Type:
Article
Abstract:
1-(2′-Deoxy-2′-fluoro-β-d-arabinofuranosyl)benzimidazoles containing 4,6-difluoro-, 4,5,6-trifluoro-, 5-fluoro-6-methoxy-, and 5-methoxy-4,6-difluorobenzimidazole fragments were synthesized by using purine nucleoside phosphorylase-catalyzed chemoenzymatic approach. As expected, enzymatic synthesis of nucleosides proceeds in lower yields of target compounds in comparison with the synthesis of ribo- and 2′-deoxyribobenzimidazoles (40-55% vs 60-90%). The compounds obtained were tested against the herpes simplex virus type 1, by using the Vero E6 cells. 5-Methoxy-4,6-difluoro-1-β-d-(2′-deoxy-2′-fluoroarabinofuranosyl)benzimidazole did not show any antiviral activity, when used in nontoxic concentration. All other nucleosides proved to exhibit a selective antiherpes activity. In contrast, it was shown that benzimidazole-β-d-arabinofuranosides of both di- and trisubstituted derivatives, having substituents in positions 4-6 of the benzene ring, as well as unsubstituted compounds, cannot be synthesized by enzymatic transglycosylation. 1-(β-d-Arabinofuranosyl)benzimidazole was obtained through glycosylation of N-trimethylsilylbenzimidazole with 1-chloro-2,3,5-O-methoxymethyl-d-arabinose. The behavior of this compound, as inhibitor of purine nucleoside phosphorylase (PNP) E. N oli, was investigated. 1-(β-d-Arabinofuranosyl)benzimidazole was found to belong to a mixed type of inhibitors of PNP. This fact explains why all attempts to perform enzymatic arabinosylation of 4,6-di-, 5,6-di-, and 4,5,6-trisubstituted benzimidazoles failed.
Author keywords:
drug discovery; fluorine; herpes simplex virus; nucleosides
Index keywords:
Biomolecules; Drug products; Fluorine; Glycosylation; Phosphorylation; Viruses; Chemo-enzymatic synthesis; Chemoenzymatic approaches; Drug discovery; Enzymatic transglycosylation; Herpes simplex virus
DOI:
10.1055/s-0036-1588625
Смотреть в Scopus:
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84992107673&doi=10.1055%2fs-0036-1588625&partnerID=40&md5=fec8b9e712e42f7a1eca0dbab3f1f63c
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Art. No. ss-2016-t0488-op
Link https://www.scopus.com/inward/record.uri?eid=2-s2.0-84992107673&doi=10.1055%2fs-0036-1588625&partnerID=40&md5=fec8b9e712e42f7a1eca0dbab3f1f63c
Affiliations Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St. 16/10, 117997 GSP, Moscow, Russian Federation; Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, S. Kovalevskaya/Academicheskaya St. 22/20, Ekaterinburg, Russian Federation; Ural Federal University, Named after the First President of Russia, B. N. Yeltsin Mira St. 19, Ekaterinburg, Russian Federation; D. I. Ivanovsky Institute of Virology, Gamaleya St. 18, Moscow, Russian Federation
Author Keywords drug discovery; fluorine; herpes simplex virus; nucleosides
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Correspondence Address Dndronova, V.L.; D. I. Ivanovsky Institute of Virology, Gamaleya St. 18, Russian Federation; email: kharitonova-mari@rambler.ru
Publisher Georg Thieme Verlag
CODEN SYNTB
Language of Original Document English
Abbreviated Source Title Synthesis
Source Scopus