Development of C-Methyl Branched Purine Ribonucleoside Analogs: Chemistry, Biological Activity and Therapeutic Potential

Author(s): Riccardo Petrelli, Mario Grifantini, Loredana Cappellacci.

Journal Name: Current Medicinal Chemistry

Volume 23 , Issue 28 , 2016

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Abstract:

In this review, we first highlighted on C-methyl-branched nucleosides and nucleotides approved as anti-hepatitis C infection (HCV) drugs, their mechanism of action and recent progress in the development of new clinical candidates. Then, we report on our attempt to develop several C-methyl nucleosides/tides potentially useful for treatment of various diseases such cancer, pain, epilepsy and glaucoma. Design, synthesis and pharmacological screening of 1′-C-, 2′-C-, 3'-C-methyladenosine or other purine/pyrimidine nucleosides allowed us to discover some promising new molecules. 3'-C-Methyladenosine showed antitumor activity against several human tumor cell lines. We have investigated the mechanism of action of 3'-C-methyladenosine that proved to be an effective inhibitor of ribonucleotide reductase. Moreover, we will also summarize the chemical and biological properties of some of the recent N6-substituted and 5', N6-disubstituted 2'-C-methyladenosine derivatives that were synthetized in our laboratory and evaluated as A1 adenosine receptor agonists. 2-Chloro-2'- C-methyl-N6-cyclopentyladenosine (2'-Me-CCPA), 5′-chloro-5′-deoxy-N6-(±)-(endo-norborn- 2-yl)adenosine (5′Cl5′d-(±)-ENBA) and 2'-C-methyl-5'-chloro-5'-deoxy-N6-(±)-(endonorborn- 2-yl)adenosine (2'-Me-5′Cl5′d-(±)-ENBA) displayed high hA1AR affinity and selectivity. 2'-Me-CCPA and 5′Cl5′d-(±)-ENBA showed significant analgesic properties.

Keywords: 2'-C-methyl and 3'-C-methyl branched nucleosides/tides, hepatitis C virus, antitumor nucleosides, adenosine receptors, A1AR agonists, P2Y1 and P2Y2 receptor ligands, IMPDH inhibitors, NAD analogs.

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Article Details

VOLUME: 23
ISSUE: 28
Year: 2016
Page: [3118 - 3135]
Pages: 18
DOI: 10.2174/0929867323666160627100755
Price: $58

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