Potent and selective activity of 3'-azido-2,6-diaminopurine-2',3'-dideoxyriboside, 3'-fluoro-2,6-diaminopurine-2',3'-dideoxyriboside, and 3'-fluoro-2',3'-dideoxyguanosine against human immunodeficiency virus.
Several sugar-modified 2,6-diaminopurine and guanine 2',3'-dideoxyribosides were synthesized and evaluated in vitro for their ability to inhibit the cytopathic effect and replication of human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS). 3'-Azido-2,6-diaminopurine-2',3'-dideoxyriboside (AzddDAPR), 3'-fluoro-2,6-diaminopurine-2',3'-dideoxyriboside (FddDAPR), and 3'-fluoro-2',3'-dideoxyguanosine emerged as potent and selective anti-HIV agents in MT4 cells (50% effective antiviral dose: 0.3-4.5 microM). Their selectivity indexes, based on the ratio of the 50% cytotoxic dose to the 50% antiviral effective dose, were 157, 80, and 96, respectively, as compared to 106 for 2,6-diaminopurine-2',3'-dideoxyriboside (ddDAPR) and 132 for 2',3'-dideoxyadenosine (ddAdo), two other potent anti-HIV agents. The 9-beta-D-arabinoside and 9-beta-D-2'-deoxyxyloside derivatives of 2,6-diaminopurine were devoid of any antiretrovirus activity. Both AzddDAPR and FddDAPR, like the parent compounds ddDAPR and ddAdo, proved susceptible to deamination by beef intestine adenosine deaminase (Km, 11, 148, 29, and 73 microM, respectively). 2'-Deoxycoformycin, a potent inhibitor of adenosine deaminase, decreased the antiretrovirus and cytostatic activity of ddDAPR and FddDAPR to a greater extent than that of AzddDAPR. This suggests that ddDAPR and FddDAPR are primarily active as their guanine analogues, whereas AzddDAPR may be potentially active as a 2,6-diaminopurine derivative as well.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Baba
M
M
Pauwels
R
R
Herdewijn
P
P
Wood
S G
SG
Robins
M J
MJ
de Clercq
E
E
D000243:Adenosine Deaminase / Q000032:analysis; D000963:Antimetabolites / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000494:pharmacology; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000031:analogs & derivatives*; D015224:Dideoxynucleosides; D006678:HIV / Q000187:drug effects*; D015649:Pentostatin; D011355:Prodrugs / Q000494:pharmacology; D012995:Solubility; D014779:Virus Replication / Q000187:drug effects
D000963:Antimetabolites; D000998:Antiviral Agents; D003839:Deoxyadenosines; D015224:Dideoxynucleosides; D011355:Prodrugs; C052692:2,6-diaminopurine 2',3'-dideoxyriboside; D003070:Coformycin; C055319:3'-azido-2,6-diaminopurine-2',3'-dideoxyriboside; C055320:3'-fluoro-2,6-diaminopurine-2',3'-dideoxyriboside; D015649:Pentostatin; D016048:Dideoxyadenosine; C055315:3'-fluoro-2',3'-dideoxyguanosine; D000243:Adenosine Deaminase; D003849:Deoxyguanosine