Diastereoselective Synthesis of 6″-(Z)- and 6″-(E)-Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers.
Diastereoselective Synthesis of 6″-(Z)- and 6″-(E)-Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers.
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DOI：
10.1021/acs.joc.6b00105
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发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Haraguchi K
中科院分区：
文献类型：
--
作者：
Kumamoto H;Fukano M;Nakano T;Iwagami K;Takeyama C;Kohgo S;Imoto S;Amano M;Kuwata-Higashi N;Aoki M;Abe H;Mitsuya H;Fukuhara K;Haraguchi K
建立了抗乙肝药物恩替卡韦的6“-(Z)-和6”-(E)-氟代类似物的非对映选择性合成方法。目标分子的亚甲基环戊烷骨架的构建是通过自由基介导的5-exo-dig环化反应完成的，这些硒化合物6和15具有苯基硫代乙炔结构作为接受自由基基团。在TBS保护的前体6的自由基反应中，主要产物为(Z)-反-12。另一方面，提示保护的15给了(E)-反12。ANTI-12的硫挤出锡化反应提供了各自的乙烯基锡烷的几何异构体的混合物，而苯甲酰基保护的17则以保留构型的方式进行锡化反应。在XeF2介导的氟化后，引入嘌呤碱并脱氧生成碳环鸟苷，得到脱保护后的目标(E)-和(Z)-3。3的抗病毒活性评价表明，恩替卡韦6“位上的氟取代可降低对HepG2细胞的细胞毒作用，同时保持其抗病毒活性。
A method for the diastereoselective synthesis of 6″-(Z)- and 6″-(E)-fluorinated analogues of the anti-HBV agent entecavir has been developed. Construction of the methylenecyclopentane skeleton of the target molecules has been accomplished by radical-mediated 5-exo-dig cyclization of the selenides 6 and 15 having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor 6, (Z)-anti-12 was formed as a major product. On the other hand, TIPS-protected 15 gave (E)-anti-12. The sulfur-extrusive stannylation of anti-12 furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected 17 underwent the stannylation in the manner of retention of configuration. Following XeF2-mediated fluorination, introduction of the purine base and deoxygenation of the resulting carbocyclic guanosine gave the target (E)- and (Z)-3 after deprotection. Evaluation of the anti-HBV activity of 3 revealed that fluorine-substitution at the 6″-position of entecavir gave rise to a reduction in the cytotoxicity in HepG2 cells with retention of the antiviral activity.
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影响因子：
2.1
作者：
TIUS, MA;KAWAKAMI, JK
通讯作者：
KAWAKAMI, JK
影响因子：
5.4
作者：
WILL, H;REISER, W;SCHALLER, H
通讯作者：
SCHALLER, H
影响因子：
2.1
作者：
Fletcher, Steven;Shahani, Vijay M.;Gunning, Patrick T.
通讯作者：
Gunning, Patrick T.
影响因子：
3.6
作者：
Bogen, S;Fensterbank, L;Malacria, M
通讯作者：
Malacria, M
影响因子：
4.3
作者：
Chatgilialoglu, Chryssostomos
通讯作者：
Chatgilialoglu, Chryssostomos