Development Of C-Methyl Branched Purine Ribonucleoside Analogs: Chemistry, Biological Activity And Therapeutic Potential

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 N-6-substituted and 5', N-6-disubstituted 2'-C-methyladenosine derivatives that were synthetized in our laboratory and evaluated as A(1) adenosine receptor agonists. 2-Chloro-2'-C-methyl-N-6-cyclopentyladenosine (2'-Me-CCPA), 5'-chloro-5'-deoxy-N-6-(+/-)-(endo-norborn-2-yl) adenosine (5'Cl5'd-(+/-)-ENBA) and 2'-C-methyl-5'-chloro-5'-deoxy-N-6 -(+/-)-(endonorborn-2-yl) adenosine (2'-Me-5'Cl5'd-(+/-)-ENBA) displayed high hA(1)AR affinity and selectivity. 2'-Me-CCPA and 5'Cl5'd-(+/-)-ENBA showed significant analgesic properties.