title: Development of C-Methyl Branched Purine Ribonucleoside Analogs: Chemistry, Biological Activity and Therapeutic Potential.
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.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.affiliation: School of Pharmacy Medicinal Chemistry Unit, University of Camerino, Camerino, Italy. mario.grifantini@unicam.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Grifantini
authors.affiliation: loredana.cappellacci@unicam.it.
authors.forename: Loredana
authors.initials: L
authors.lastname: Cappellacci
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D058907:Adenosine A1 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D062105:Molecular Docking Simulation; D009101:Multiple Myeloma / Q000188:drug therapy; D011685:Purine Nucleotides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D043682:Receptor, Adenosine A1 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C569537:2'-C-methyladenosine; D058907:Adenosine A1 Receptor Agonists; D000970:Antineoplastic Agents; D011685:Purine Nucleotides; D043682:Receptor, Adenosine A1; D000241:Adenosine