SYNTHESIS AND IN VITRO ANTI-HIV ACTIVITY OF LIPOPHILIC DIDEOXYNUCLEOSIDES

亲脂性双脱氧核苷的合成及其体外抗HIV活性

• 批准号: 3838140
• 负责人: H MITSUYA
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838140
• 关键词: 2'3' dideoxyinosine; 2'3' dideoxynucleoside; HIV infections; adenosine deaminase; antiAIDS agent; antiviral agents; drug design /synthesis /production; drug resistance; drug screening /evaluation; enzyme substrate; halogens; human immunodeficiency virus 1; human immunodeficiency virus 2; lipids; nucleoside analog; virus infection mechanism; virus replication; zidovudine

2-Amino-6-halo-2',3'-dideoxypurine ribofuranosides (6-halo-ddGs) and 6- halo-ddPs (6-halo-ddls) have been shown to suppress the infectivity, replication and cytopathic effect of HIV (Shirasaka et al. Proc. Natl. Acad. Sci. USA. 87:9426-9430, 1990). 2-Amino-6-fluoro-, 2-- amino-6-chloro-, and 6-fluoro-ddPs showed a potent activity against HIV comparable to that of 2',3'-dideoxyinosine (ddl) or 2',3'-dideoxyguanosine (ddG), and completely blocked the infectivity of HIV without affecting the growth of target cells. These compounds have also shown a potent activity against HIV-2 and AZT-resistant HIV-1 variants in vitro. Several of the 6-halogen-containing ddPs have been found to have substantial lipophilic character. The lipophilicity order was: 2-amino-6-iodo is greater than 2-amino-6-bromo is greater than 2-amino-6-chloro is greater than 2-amino-6-fluoro is much greater than ddG is greater than ddI with a log P range from +0.5 to -1.2. All eight 6-halogen-containing ddPs were substrates for adenosine deaminase (ADA). In the presence of an ADA-inhibitor, 2'deoxycoformycin, all 6-halogen-containing ddPs failed to exert their in vitro antiretroviral effects.

2-氨基-6-卤代-2 '，3'-二脱氧嘌呤呋喃核糖苷（6-卤代-ddGs）和6- 卤代-ddPs（6-卤代-ddls）已经显示出抑制感染性， HIV的复制和细胞病变效应（Shirasaka等人，Proc.Natl. Acad. Sci. USA. 87：9426-9430，1990）。2-氨基-6-氟-，2- 氨基-6-氯-和6-氟-DDP显示出较强的抗HIV活性 与2 ′，3 ′-双脱氧肌苷（DDL）或 2 '，3'-双脱氧鸟苷（ddG），并完全阻断了 不影响靶细胞的生长。 这些化合物具有 也显示出对HIV-2和AZT抗性HIV-1的有效活性 在体外的变体。 几种含6-卤素的ddp已经被 发现具有显著的亲脂性。 亲脂性顺序 为：2-氨基-6-碘大于2-氨基-6-溴大于 2-氨基-6-氯大于2-氨基-6-氟， ddG大于ddI，log P范围为+0.5至-1.2。所有八 含6-卤素的ddPs是腺苷脱氨酶（ADA）的底物。 在ADA抑制剂2 '脱氧共福霉素的存在下， 含6-卤素的DDP不能发挥其体外抗逆转录病毒作用， 方面的影响.