Cyclobut-A and cyclobut-G, carbocyclic oxetanocin analogs that inhibit the replication of human immunodeficiency virus in T cells and monocytes and macrophages in vitro.
Two newly synthesized carbocyclic oxetanocin analogs, (+/-)-9-[(1 beta,2 alpha,3 beta)-2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine (cyclobut-A) and (+/-)-9-[(1 beta,2 alpha,3 beta)-2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine (cyclobut-G) were tested for activity against the infectivity of human immunodeficiency virus (HIV) in vitro. A number of other carbocyclic oxetanocin analogs failed to exert good antiretroviral effects. Both cyclobut-A and cyclobut-G protected CD4+ ATH8 cells against the infectivity and cytopathic effect of HIV type 1 (HIV-1) and suppressed proviral DNA synthesis in ATH8 cells exposed to HIV-1 in vitro at concentrations of 50 to 100 microM. These compounds also inhibited the in vitro infectivity of another human pathogenic retrovirus, HIV-2. Furthermore, both compounds completely suppressed the replication of a monocytotropic strain of HIV-1 in monocytes and macrophages at concentrations as low as 0.5 microM, as assessed by inhibition of HIV-1 p24 gag protein production. We also found that 2'-deoxyguanosine readily reversed the antiretroviral activity of cyclobut-G in our system, whereas the activity of cyclobut-A was hardly reversed by 2'-deoxyadenosine or 2'-deoxycytidine. We noted, however, that these compounds inhibited the proliferation of peripheral blood mononuclear cells at concentrations of greater than or equal to 100 microM in vitro. Although both cyclobut-A and cyclobut-G appear to have a certain level of in vitro toxicity, our observations may have theoretical and clinical implications in understanding the structure-activity relationships of antiretroviral agents active against HIV.
Hayashi
S
S
Clinical Oncology Program, National Cancer Institute, Bethesda, Maryland 20892.
Norbeck
D W
DW
Rosenbrook
W
W
Fine
R L
RL
Matsukura
M
M
Plattner
J J
JJ
Broder
S
S
Mitsuya
H
H
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D015139:Blotting, Southern; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology*; D008934:Mitogens / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000382:microbiology*; D009705:Nucleosides / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000382:microbiology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D008934:Mitogens; D009705:Nucleosides; C051061:oxetanocin; C062353:cyclobut A; D006147:Guanine; C063638:lobucavir; D000225:Adenine