title: Investigations on the anti-HIV activity of 2',3'-dideoxyadenosine analogues with modifications in either the pentose or purine moiety. Potent and selective anti-HIV activity of 2,6-diaminopurine 2',3'-dideoxyriboside.
abstract: Several 2',3'-dideoxyadenosine analogues with modifications in either the ribose or purine moiety were evaluated for their inhibitory effects on the replication of human immunodeficiency virus (HIV) in MT-4 cell cultures. The 2',3'-dideoxyriboside of 2,6-diaminopurine (ddDAPR) inhibited HIV antigen expression and HIV-induced cytopathogenicity at a 50% effective dose of 2.4-3.8 microM, as compared to 3-6 microM for 2',3'-dideoxyadenosine (ddAdo), whereas 50% inhibition of MT-4 cell viability was noted only at a concentration of 477 and 889 microM, respectively. Both ddDAPR and ddAdo were only weakly inhibitory to the proliferation of a number of T-lymphoblast and T-lymphocyte cell lines, pointing to the selectivity of these compounds as anti-HIV agents. In contrast to ddAdo, ddDAPR was found to be a poor substrate for adenosine deaminase, which may be advantageous from a chemotherapeutic viewpoint. Substitution of an azido or fluoro group at the 2' and 3'-position of the ribose moiety in either "up" or "down" configurations resulted in a decrease of the anti-HIV potency and selectivity of ddAdo. In addition to ddDAPR other purine-modified ddAdo analogues, i.e. several pyrrolo[2,3-d]pyrimidine 2',3'-dideoxynucleosides, were investigated for their anti-HIV activity, but none of these derivatives proved as potent or selective as ddDAPR.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: P
authors.initials: P
authors.lastname: Herdewijn
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: M J
authors.initials: MJ
authors.lastname: Robins
authors.forename: R M
authors.initials: RM
authors.lastname: Zou
authors.forename: D
authors.initials: D
authors.lastname: Madej
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000243:Adenosine Deaminase / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003641:Deamination; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000031:analogs & derivatives; D006678:HIV / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008980:Moloney murine sarcoma virus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003839:Deoxyadenosines; C052692:2,6-diaminopurine 2',3'-dideoxyriboside; D016048:Dideoxyadenosine; D000243:Adenosine Deaminase