CYCLOBUT-A AND CYCLOBUT-G, CARBOCYCLIC OXETANOCIN ANALOGS THAT INHIBIT THE REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS IN T-CELLS AND MONOCYTES AND MACROPHAGES INVITRO

被引:86
作者
HAYASHI, S
NORBECK, DW
ROSENBROOK, W
FINE, RL
MATSUKURA, M
PLATTNER, JJ
BRODER, S
MITSUYA, H
机构
[1] NCI,CLIN ONCOL PROGRAM,BETHESDA,MD 20892
[2] ABBOT LABS,ANTIINFECT RES DEPT,ABBOTT PK,IL 60064
[3] DUKE UNIV,VET ADM HOSP,MED CTR,DIV HEMATOL ONCOL,DURHAM,NC 27705
关键词
D O I
10.1128/AAC.34.2.287
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Two newly synthesized carbocyclic oxetanocin analogs, (±)-9-[(1β,2α,3β)-2,3-bis(hydroxymethyl)-1cyclobutyl]adenine (cyclobut-A) and (±)-9-[(1β,2α,3β)-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 DsNA synthesis in ATH8 cells exposed to HIV-1 in vitro at concentration of 50 to 100 μM. 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 μM, 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 harly reversed by 2'-deoxyadenosine or 2'-deoxycytidine. We noted, however, that these compounds inhibited the proliferation of peripheral blood mononuclear cells at concentrations of ≥100 μM 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.
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页码:287 / 294
页数:8
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