Synthesis and Biological Properties of C-2 Triazolylinosine Derivatives

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• 作者：Mahesh K. Lakshman ; Amit Kumar ; Raghavan Balachandran ; Billy W. Day ; Graciela Andrei ; Robert Snoeck ; Jan Balzarini
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：July 20, 2012
• 年：2012
• 卷：77
• 期：14
• 页码：5870-5883
• 全文大小：543K
• 年卷期：v.77,no.14(July 20, 2012)
• ISSN：1520-6904

文摘

O⁶-(Benzotriazol-1H-yl)guanosine and its 2鈥?deoxy analogue are readily converted to the O⁶-allyl derivatives that upon diazotization with t-BuONO and TMS-N₃ yield the C-2 azido derivatives. We have previously analyzed the solvent-dependent azide路tetrazole equilibrium of C-6 azidopurine nucleosides, and in contrast to these, the O⁶-allyl C-2 azido nucleosides appear to exist predominantly in the azido form, relatively independent of solvent polarity. In the presently described cases, the tetrazole appears to be very minor. Consistent with the presence of the azido functionality, each neat C-2 azide displayed a prominent IR band at 2126鈥?130 cm^鈥?. A screen of conditions for the ligation of the azido nucleosides with alkynes showed that CuCl in t-BuOH/H₂O is optimal, yielding C-2 1,2,3-triazolyl nucleosides in 70鈥?2% yields. Removal of the silyl groups with Et₃N路3HF followed by deallylation with PhSO₂Na/Pd(PPh₃)₄ gave the C-2 triazolylinosine nucleosides. In a continued demonstration of the versatility of O⁶-(benzotriazol-1H-yl)purine nucleosides, one C-2 triazolylinosine derivative was converted to two adenosine analogues via these intermediates, under mild conditions. Products were desilylated for biological assays. The two C-2 triazolyl adenosine analogues demonstrated pronounced antiproliferative activity in human ovarian and colorectal carcinoma cell cultures. When evaluated for antiviral activity against a broad spectrum of DNA and RNA viruses, some of the C-2 triazolylinosine derivatives showed modest inhibitory activity against cytomegalovirus.