Adefovir based acyclic nucleoside phosphonates were previously shown to modulate bacterial and, to a certain extent, human adenylate cyclases (mACs). In this work, a series of 24 novel 7-substituted 7-deazaadefovir analogues were synthesized in the form of prodrugs. Twelve analogues were single-digit micromolar inhibitors of Bordetella pertussis adenylate cyclase toxin with no cytotoxicity to J774A.1 macrophages. In HEK293 cell-based assays, compound 14 was identified as a potent (IC50 = 4.45 μM), non-toxic, and selective mAC2 inhibitor (vs. mAC1 and mAC5). Such a compound represents a valuable addition to a limited number of small-molecule probes to study the biological functions of individual endogenous mAC isoforms.

• Keywords
• 7-Deazapurine, Acyclic nucleoside phosphonates, Adefovir, Adenylate cyclase, Prodrugs,
• MeSH
• Adenylate Cyclase Toxin MeSH
• Adenylyl Cyclases * MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Nucleosides chemistry   MeSH
• Organophosphonates * pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• 7-deazapurine MeSH Browser
• adefovir MeSH Browser
• Adenylate Cyclase Toxin MeSH
• Adenylyl Cyclases * MeSH
• Nucleosides MeSH
• Organophosphonates * MeSH

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,
• MeSH
• Antiviral Agents chemical synthesis   chemistry   pharmacology   MeSH
• A549 Cells MeSH
• Hep G2 Cells MeSH
• HeLa Cells MeSH
• Humans MeSH
• Nucleosides chemical synthesis   chemistry   pharmacology   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Purines chemistry   MeSH
• Drug Design MeSH
• Drug Screening Assays, Antitumor MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• 7-deazapurine MeSH Browser
• Antiviral Agents MeSH
• Nucleosides MeSH
• Antineoplastic Agents MeSH
• Purines MeSH

Three types of sugar modified pyrimido[4,5-b]indole nucleosides (2'-deoxy-2'-fluororibo-, 2'-deoxy-2'-fluoroarabino- and arabinonucleosides) were synthesized by glycosylation of 4,6-dichloropyrimido[4,5-b]indole followed by modification of sugar moiety and introduction of substituents into position 4 by cross-coupling reactions or nucleophilic substitutions. Some 2'-fluororibo- and 2'-fluoroarabinonucleosides displayed interesting anti-HCV activities (IC50 = 1.6-20 μM) and the latter compounds also some anti-dengue activities (IC50 = 10.8-40 μM).

• Publication type
• Journal Article MeSH