Title:Development of C-Methyl Branched Purine Ribonucleoside Analogs: Chemistry, Biological Activity and Therapeutic Potential
Volume: 23
Issue: 28
Author(s): Riccardo Petrelli, Mario Grifantini and Loredana Cappellacci
Affiliation:
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.
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.
