Chemo-Enzymatic Synthesis and Biological Evaluation of 5,6-Disubstituted Benzimidazole Ribo- and 2′-Deoxyribonucleosides

Irina D. Konstantinova; Olga M. Selezneva; Ilja V. Fateev; Tamara A. Balashova; Svetlana K. Kotovskaya; Zoya M. Baskakova; Valery N. Charushin; Alexander V. Baranovsky; Anatoly I. Miroshnikov; Jan Balzarini; Igor A. Mikhailopulo

doi:10.1055/s-0032-1317782

Synthesis, Table of Contents

Synthesis 2013; 45(2): 272-280
DOI: 10.1055/s-0032-1317782

paper

Chemo-Enzymatic Synthesis and Biological Evaluation of 5,6-Disubstituted Benzimidazole Ribo- and 2′-Deoxyribonucleosides

Irina D. Konstantinova

^aShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 GSP, Moscow B-437, Russian Federation

,

Olga M. Selezneva

^aShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 GSP, Moscow B-437, Russian Federation

,

Ilja V. Fateev

^aShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 GSP, Moscow B-437, Russian Federation

,

Tamara A. Balashova

^aShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 GSP, Moscow B-437, Russian Federation

,

Svetlana K. Kotovskaya

^bI. Ya. Postovsky Institute of Organic Synthesis, the Ural Branch of the Russian Academy of Sciences, Sophia Kovalevskaya/Academicheskaya St. 22/20, 620041 Yekaterinburg, Russian Federation

,

Zoya M. Baskakova

^bI. Ya. Postovsky Institute of Organic Synthesis, the Ural Branch of the Russian Academy of Sciences, Sophia Kovalevskaya/Academicheskaya St. 22/20, 620041 Yekaterinburg, Russian Federation

,

Valery N. Charushin

^bI. Ya. Postovsky Institute of Organic Synthesis, the Ural Branch of the Russian Academy of Sciences, Sophia Kovalevskaya/Academicheskaya St. 22/20, 620041 Yekaterinburg, Russian Federation

,

Alexander V. Baranovsky

^cInstitute of Bioorganic Chemistry, National Academy of Sciences, Acad. Kuprevicha 5/2, 220141 Minsk, Belarus Fax: +375(17)2678761 Email: imikhailopulo@gmail.com

,

Anatoly I. Miroshnikov

^aShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 GSP, Moscow B-437, Russian Federation

,

Jan Balzarini*

^dRega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium

,

Igor A. Mikhailopulo*

^cInstitute of Bioorganic Chemistry, National Academy of Sciences, Acad. Kuprevicha 5/2, 220141 Minsk, Belarus Fax: +375(17)2678761 Email: imikhailopulo@gmail.com

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Abstract

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Abstract

A number of new 5,6-disubstituted benzimidazoles have been prepared and their substrate properties for recombinant E. coli purine nucleoside phosphorylase (PNP; the product of the deoD gene) in the transglycosylation reaction were investigated. The heterocyclic bases showed good substrate activity for PNP and the ribo- and 2′-deoxyribonucleosides were synthesized. The predominant (OMe and OEt) or exclusive (Oi-Pr, morpholino, and N-methylpiperazino) formation of the 5-substituted 6-fluoro-1-(β-d-ribofuranosyl)benzimidazoles was observed. The formation of the regioisomeric 6- methoxy-, 6-ethoxy-, or 6-isopropoxy-substituted 1-(2-deoxy-β-d-ribofuranosyl)-5-fluorobenzimidazoles was observed in the trans-2-deoxyribosylation reaction of the corresponding bases. The predominant or exclusive formation of the regioisomeric N ¹-nucleosides with bulky 5-substituents of 6-fluorobenzimidazole points to a large hydrophobic pocket in the E. coli PNP active site that can accommodate these groups. The biological activity of the synthesized nucleosides was studied and revealed no inhibitory activity against a broad variety of DNA and RNA viruses. The compounds also lacked significant cytotoxicity.

Key words

5,6-disubstituted benzimidazoles - purine nucleoside phosphorylase - substrate properties - transglycosylation reaction - nucleosides

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References

References
1 For a review, see: De Clercq E. Adv. Virus Res. 2009; 73: 1

2a Krosky PM, Borysko KZ, Nassiri MR, Devivar RV, Ptak RG, Davis MG, Biron KK, Townsend LB, Drach JC. Antimicrob. Agents Chemother. 2002; 46: 478
2b Evers DL, Komazin G, Shin D, Hwang DD, Townsend LB, Drach JC. Antiviral Res. 2002; 56: 61
2c Gudmundsson KS, Tidwell J, Lippa N, Koszalka GW, van Draanen N, Ptak RG, Drach JC, Townsend LB. J. Med. Chem. 2000; 43: 2464
2d Sharma D, Narasimhan B, Kumar P, Judge V, Narang R, De Clercq E, Balzarini J. J. Enzyme Inhib. Med. Chem. 2009; 24: 1161

3a Prichard MN. Rev. Med. Virol. 2009; 19: 215
3b Williams SL, Hartline CB, Kushner NL, Harden EA, Bidanset DJ, Drach JC, Townsend LB. Antimicrob. Agents Chemother. 2003; 47: 2186
3c Hwang JS, Kregler O, Schilf R, Bannert N, Drach JC, Townsend LB, Bogner E. J. Virol. 2007; 81: 11604
3d Hwang JS, Schilf R, Drach JC, Townsend LB, Bogner E. Antimicrob. Agents Chemother. 2009; 53: 5095

For reviews, see:

4a Trofe J, Pote L, Wade E, Blumberg E, Bloom RD. Ann. Pharmacother. 2008; 42: 1447
4b Drugs R D . 2007. 8. 188 Maribavir: 1263W94, Benzimidavir, GW 1263, GW 1263W94, VP41263
4c Chou S, Marousek GI. J. Virol. 2008; 82: 246

For reviews, see:

5a Galmarini CM, Popowycz F, Joseph B. Curr. Med. Chem. 2008; 15: 1072
5b Mathe C, Gosselin G. Antiviral Res. 2006; 71: 276
5c Biron KK. Antiviral Res. 2006; 71: 154

6 Mikhailopulo IA. Curr. Org. Chem. 2007; 11: 317
7 Mikhailopulo IA, Zinchenko AI, Bokut SB, Dudchik NV, Barai VN, Kalinichenko EN, Rosemeyer H, Seela F. Biotechnol. Lett. 1992; 14: 885
8 Mikhailopulo IA, Kazimierczuk Z, Zinchenko AI, Barai VN, Romanova VV, Eroshevskaya LA. Nucl. Acids Symp. Ser. 1994; 31: 83
9 Mikhailopulo IA, Kazimierczuk Z, Zinchenko AI, Barai VN, Romanova VV, Eroshevskaya LA. Nucleosides Nucleotides 1995; 14: 477
10 Bentancor L, Trelles JA, Nóbile M, Lewkowicz ES, Iribarren AM. J. Mol. Catal. B: Enzym. 2004; 29: 3
11 Esipov RS, Gurevich AI, Chuvikovsky DV, Chupova LA, Muravyova TI, Miroshnikov AI. Protein Expression Purif. 2002; 24: 56
12 Kotovskaya SK, Perova NM, Baskakova ZM, Romanova SA, Charushin VN, Chupakhin ON. Russ. J. Org. Chem. 2001; 37: 564
13 Kotovskaya SK, Charushin VN, Chupakhin ON, Kozhevnikova EO. Russ. J. Org. Chem. 1998; 34: 369 ; Chem. Abstr. 1999, 130, 25028
14 Berger S, Braun S, Kalinowski H.-O. ¹⁹F NMR-Spektroskopie . In NMR Spektroskopie von Nichtmetallen . Vol. 4. Georg Thieme Verlag; Stuttgart: 1994
15 Roivainen J, Elizarova T, Lapinjoki S, Mikhailopulo IA, Esipov RS, Miroshnikov AI. Nucleosides, Nucleotides Nucleic Acids 2007; 26: 905
16 Kulikovskiy AI, Esipov RS, Miroshnikov AI, Mikhailopulo IA. Collect. Symp. Ser. 2011; 12: 397
17 Konstantinova ID, Antonov KV, Fateev IV, Miroshnikov AI, Stepchenko VA, Baranovsky AV, Mikhailopulo IA. Synthesis 2011; 1555
18 Mikhailopulo IA, Miroshnikov AI. Acta Naturae 2010; 2: 36