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Review
. 2017 Nov;37(6):1429-1460.
doi: 10.1002/med.21465. Epub 2017 Aug 23.

Pyrrolo[2,3-d]pyrimidine (7-deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

Pavla Perlíková  1 , Michal Hocek  1   2
Affiliations
Review

Pyrrolo[2,3-d]pyrimidine (7-deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

Pavla Perlíková et al. Med Res Rev. 2017 Nov.

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.

Keywords: antivirals; cytostatics; deazapurines; nucleosides; nucleotides.

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Figures

Figure 1
Figure 1
Naturally occurring deazapurine nucleosides (1–5) and related compounds
Figure 2
Figure 2
Structure‐activity relationship among cytotoxic 7‐deazapurine ribonucleosides
Figure 3
Figure 3
Cytotoxic C7‐substituted deazapurine ribonucleosides
Figure 4
Figure 4
Scheme of the mechanism of action of AB61 (7a)
Figure 5
Figure 5
Sugar‐modified derivatives of 7‐substituted 7‐deazaadenosines
Figure 6
Figure 6
Structures of sangivamycin‐like molecules
Figure 7
Figure 7
Structures of cytotoxic 6‐(het)aryl‐7‐deazapurine ribonucleosides
Figure 8
Figure 8
Phosphate‐prodrugs of 6‐(het)aryl‐7‐deazapurine ribonucleosides
Figure 9
Figure 9
2‐Modified and sugar‐modified derivatives of 6‐hetaryl‐7‐deazapurine nucleosides
Figure 10
Figure 10
Other examples of cytotoxic 7‐deazapurine ribonucleosides
Figure 11
Figure 11
Structures of triciribine and Janus‐type tricyclic nucleosides
Figure 12
Figure 12
Structures of cytotoxic benzo‐ and thieno‐fused 7‐deazapurine nucleosides
Figure 13
Figure 13
Examples of 7‐deazapurine nucleosides as inhibitors of mammalian ADKs
Figure 14
Figure 14
Examples of 7‐deazapurine nucleosides as inhibitors of Mtb‐ADK
Figure 15
Figure 15
Examples of anti‐HCV 7‐deazapurine ribonucleosides
Figure 16
Figure 16
Examples of sugar‐modified anti‐HCV 7‐deazapurine nucleosides
Figure 17
Figure 17
Examples of anti‐HCV derivatives of 7‐(hetaryl)‐7‐deaza‐2′‐C‐methyladenosines and 7‐deazaneplanocin A
Figure 18
Figure 18
Examples of anti‐DENV 7‐deazapurine nucleosides
Figure 19
Figure 19
Examples of 7‐deazapurine nucleosides and acyclic nucleosides active against other viruses
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