SYNTHESIS AND ANTI-HIV ACTIVITY OF 4'-AZIDO-METHOXYNUCLEOSIDES AND 4'-METHOXYNUCLEOSIDES
SYNTHESIS AND ANTI-HIV ACTIVITY OF 4'-AZIDO-METHOXYNUCLEOSIDES AND 4'-METHOXYNUCLEOSIDES
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DOI：
10.1021/jm00086a013
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发表时间：
1992-04-17
影响因子：
7.3
通讯作者：
PRISBE, EJ
中科院分区：
文献类型：
--
作者：
MAAG, H;RYDZEWSKI, RM;PRISBE, EJ
合成了一系列核苷，其中的4'-氢被一个叠氮基或甲氧基取代。合成4-叠氮类似物的关键步骤是在4'-不饱和核苷前体上立体选择性和区域选择性地加成碘叠氮，然后氧化辅助置换5'-碘基团。4′-甲氧基核苷是由4′-不饱和核苷用甲醇原位开孔环氧化而成。反应机理考虑、经验构象规则、基于核磁共振的构象计算和NOE实验表明，4'-叠氮核苷倾向于呋喃糖部分的3'-端（n型）构象。当在A3.01细胞培养中评估其对HIV的抑制作用时，所有4'-叠氮-2'-脱氧- β -d -核苷都表现出有效的活性。4′-叠氮-2′-脱氧尿苷（6c）的IC50为0.80 mu- m， 4′-叠氮-2′-脱氧鸟苷（6e）的IC50为0.003 mu- m。在该系列中，细胞毒性检测为IC50的50-1500倍。4'-甲氧基-2'-脱氧- β -d -核苷的活性和毒性比它们的叠氮基对应物低2-3个数量级。在4'-取代-2'-脱氧核苷的2'-或3'-位置上的修饰倾向于降低活性。对感染HIV的H9、PBL和MT-2细胞中4′-叠氮胸苷（6a）的进一步评估显示，其抑制作用与AZT相似。然而，4′-叠氮thymidine （6a）对抗AZT的HIV突变体保持了活性。
A series of nucleosides were synthesized in which the 4'-hydrogen was substituted with either an azido or a methoxy group. The key steps in the syntheses of the 4-azido analogues were the stereo- and regioselective addition of iodine azide to a 4'-unsaturated nucleoside precursor followed by an oxidatively assisted displacement of the 5'-iodo group. The 4'-methoxynucleosides were made via epoxidation of 4'-unsaturated nucleosides with in situ epoxide opening by methanol. Reaction-mechanism considerations, empirical conformation rules, NMR-based conformational calculations, and NOE experiments suggest that the 4'-azidonucleosides prefer a 3'-endo (N-type) conformation of the furanose moiety. When evaluated for their inhibitory effect on HIV in A3.01 cell culture, all the 4'-azido-2'-deoXY-beta-D-nucleosides exhibited potent activity. IC50's ranged from 0.80-mu-M for 4'-azido-2'-deoxyuridine (6c) to 0.003-mu-M for 4'-azido-2'-deoxyguanosine (6e). Cytotoxicity was detected at 50-1500 times the IC50's in this series. The 4'-methoxy-2'-deoXy-beta-D-nucleosides were 2-3 orders of magnitude less active and less toxic than their azido counterparts. Modifications at the 2'- or 3'-position of the 4'-substituted-2'-deoxynucleosides tended to diminish activity. Further evaluation of 4'-azidothymidine (6a) in H9, PBL, and MT-2 cells infected with HIV demonstrated a similar inhibitory profile to that of AZT. However, 4'-azidothymidine (6a) retained its activity against HIV mutants which were resistant to AZT.