Pyrrolo[2,3-d]pyrimidine (7-deazapurine) As a Privileged Scaffold in Design of Antitumor and Antiviral Nucleosides

Overview

Journal Med Res Rev

Publisher Wiley

Specialties General Medicine
Pharmacology

Date 2017 Aug 24

PMID 28834581

Citations 29

Authors

Pavla Perlikova

Michal Hocek

Affiliations

Soon will be listed here.

Abstract

7-Deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides are important analogues of biogenic purine nucleosides with diverse biological activities. Replacement of the N7 atom with a carbon atom makes the five-membered ring more electron rich and brings a possibility of attaching additional substituents at the C7 position. This often leads to derivatives with increased base-pairing in DNA or RNA or better binding to enzymes. Several types of 7-deazapurine nucleosides with potent cytostatic or cytotoxic effects have been identified. The most promising are 7-hetaryl-7-deazaadenosines, which are activated in cancer cells by phosphorylation and get incorporated both to RNA (causing inhibition of proteosynthesis) and to DNA (causing DNA damage). Mechanism of action of other types of cytostatic nucleosides, 6-hetaryl-7-deazapurine and thieno-fused deazapurine ribonucleosides, is not yet known. Many 7-deazaadenosine derivatives are potent inhibitors of adenosine kinases. Many types of sugar-modified derivatives of 7-deazapurine nucleosides are also strong antivirals. Most important are 2'-C-methylribo- or 2'-C-methyl-2'-fluororibonucleosides with anti-HCV activities (several compounds underwent clinical trials). Some underexplored areas of potential interest are also outlined.

Citing Articles

Synthesis and Biological Profiling of Quinolino-Fused 7-Deazapurine Nucleosides.

Fleuti M, Sanchez-Quirante T, Slavetinska L, Tloustova E, Tichy M, Gurska S ACS Omega. 2024; 9(18):20557-20570.

PMID: 38737052 PMC: 11080019. DOI: 10.1021/acsomega.4c02031.

Biosynthesis and function of 7-deazaguanine derivatives in bacteria and phages.

de Crecy-Lagard V, Hutinet G, Cediel-Becerra J, Yuan Y, Zallot R, Chevrette M Microbiol Mol Biol Rev. 2024; 88(1):e0019923.

PMID: 38421302 PMC: 10966956. DOI: 10.1128/mmbr.00199-23.

Tubercidin inhibits PRRSV replication via RIG-I/NF-κB pathways and interrupting viral nsp2 synthesis.

Xu Y, Zhu Z, Zhang M, Chen L, Tian K, Li X Microbiol Spectr. 2024; 12(3):e0347923.

PMID: 38299833 PMC: 10913529. DOI: 10.1128/spectrum.03479-23.

Discovery of New Pyrrolo[2,3-]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers.

AlOtaibi A, Alanazi M, Rahman A Pharmaceuticals (Basel). 2023; 16(9).

PMID: 37765132 PMC: 10536928. DOI: 10.3390/ph16091324.

Non-Covalent Interactions between dUTP C5-Substituents and DNA Polymerase Decrease PCR Efficiency.

Zasedateleva O, Surzhikov S, Kuznetsova V, Shershov V, Barsky V, Zasedatelev A Int J Mol Sci. 2023; 24(17).

PMID: 37686447 PMC: 10487964. DOI: 10.3390/ijms241713643.

References

Davies L, Jamieson D, Kazlauskas R . Halogenated pyrrolopyrimidine analogues of adenosine from marine organisms: pharmacological activities and potent inhibition of adenosine kinase. Biochem Pharmacol. 1984; 33(3):347-55. DOI: 10.1016/0006-2952(84)90225-9. View

Liyanage S, Hurren R, Voisin V, Bridon G, Wang X, Xu C . Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML. Blood. 2017; 129(19):2657-2666. PMC: 5766841. DOI: 10.1182/blood-2016-10-741207. View

De Clercq E, Bernaerts R, Bergstrom D, Robins M, Montgomery J, Holy A . Antirhinovirus activity of purine nucleoside analogs. Antimicrob Agents Chemother. 1986; 29(3):482-7. PMC: 180418. DOI: 10.1128/AAC.29.3.482. View

Gunic E, Girardet J, Pietrzkowski Z, Esler C, Wang G . Synthesis and cytotoxicity of 4'-C- and 5'-C-substituted toyocamycins. Bioorg Med Chem. 2001; 9(1):163-70. DOI: 10.1016/s0968-0896(00)00221-2. View

Ugarkar B, DaRe J, Kopcho J, Browne 3rd C, Schanzer J, Wiesner J . Adenosine kinase inhibitors. 1. Synthesis, enzyme inhibition, and antiseizure activity of 5-iodotubercidin analogues. J Med Chem. 2000; 43(15):2883-93. DOI: 10.1021/jm000024g. View

Shi J, Zhou L, Zhang H, McBrayer T, Detorio M, Johns M . Synthesis and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5'-triphosphates. Bioorg Med Chem Lett. 2011; 21(23):7094-8. PMC: 3242417. DOI: 10.1016/j.bmcl.2011.09.089. View

Smith K, Lai V, Prigaro B, Ding Y, Gunic E, Girardet J . Synthesis of new 2'-beta-C-methyl related triciribine analogues as anti-HCV agents. Bioorg Med Chem Lett. 2004; 14(13):3517-20. DOI: 10.1016/j.bmcl.2004.04.067. View

Bourdin C, McGuigan C, Brancale A, Chamberlain S, Vernachio J, Hutchins J . Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2'-C-methyl-6-O-methyl guanosine nucleoside and L-Alanine ester phosphoramidates. Bioorg Med Chem Lett. 2013; 23(7):2260-4. DOI: 10.1016/j.bmcl.2012.12.004. View

Seela F, Zulauf M, Chen S . Pyrrolo[2,3-d]pyrimidine nucleosides: synthesis and antitumor activity of 7-substituted 7-deaza-2'-deoxyadenosines. Nucleosides Nucleotides Nucleic Acids. 2000; 19(1-2):237-51. DOI: 10.1080/15257770008033006. View

10.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

11.

Pudlo J, Nassiri M, Kern E, Wotring L, DRACH J, Townsend L . Synthesis, antiproliferative, and antiviral activity of certain 4-substituted and 4,5-disubstituted 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidines. J Med Chem. 1990; 33(7):1984-92. DOI: 10.1021/jm00169a028. View

12.

Schul W, Liu W, Xu H, Flamand M, Vasudevan S . A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. J Infect Dis. 2007; 195(5):665-74. DOI: 10.1086/511310. View

13.

Chen Y, Yin Z, Lakshminarayana S, Qing M, Schul W, Duraiswamy J . Inhibition of dengue virus by an ester prodrug of an adenosine analog. Antimicrob Agents Chemother. 2010; 54(8):3255-61. PMC: 2916325. DOI: 10.1128/AAC.00397-10. View

14.

Davies L, Marwood J . Studies on several pyrrolo[2,3-d]pyrimidine analogues of adenosine which lack significant agonist activity at A1 and A2 receptors but have potent pharmacological activity in vivo. Biochem Pharmacol. 1986; 35(18):3021-9. DOI: 10.1016/0006-2952(86)90381-3. View

15.

Olsen D, Eldrup A, Bartholomew L, Bhat B, Bosserman M, Ceccacci A . A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob Agents Chemother. 2004; 48(10):3944-53. PMC: 521892. DOI: 10.1128/AAC.48.10.3944-3953.2004. View

16.

Thiaville J, Kellner S, Yuan Y, Hutinet G, Thiaville P, Jumpathong W . Novel genomic island modifies DNA with 7-deazaguanine derivatives. Proc Natl Acad Sci U S A. 2016; 113(11):E1452-9. PMC: 4801273. DOI: 10.1073/pnas.1518570113. View

17.

Chung F, Schram K, Panzica R, Earl R, Wotring L, Townsend L . Synthesis of certain [6:5:6] linear tricyclic nucleosides as potential antitumor agents. J Med Chem. 1980; 23(11):1158-66. DOI: 10.1021/jm00185a002. View

18.

Balasis M, Forinash K, Chen Y, Fulp W, Coppola D, Hamilton A . Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice. Clin Cancer Res. 2011; 17(9):2852-62. PMC: 3156694. DOI: 10.1158/1078-0432.CCR-10-2544. View

19.

Daigle S, Olhava E, Therkelsen C, Majer C, Sneeringer C, Song J . Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011; 20(1):53-65. PMC: 4046888. DOI: 10.1016/j.ccr.2011.06.009. View

20.

Renau T, Wotring L, DRACH J, Townsend L . Synthesis of non-nucleoside analogs of toyocamycin, sangivamycin, and ++thiosangivamycin: influence of various 7-substituents on antiviral activity. J Med Chem. 1996; 39(4):873-80. DOI: 10.1021/jm950444j. View