New neplanocin analogues. VIII. Synthesis and biological activity of 6'-C-ethyl, -ethenyl, and -ethynyl derivatives of neplanocin A.
New neplanocin analogues. VIII. Synthesis and biological activity of 6'-C-ethyl, -ethenyl, and -ethynyl derivatives of neplanocin A.
复制标题
新奈普兰菌素类似物。
DOI：
10.1248/cpb.45.1163
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发表时间：
1997
影响因子：
1.7
通讯作者：
A. Matsuda
中科院分区：
文献类型：
--
作者：
S. Shuto;T. Obara;Y. Saito;K. Yamashita;M. Tanaka;T. Sasaki;G. Andrei;R. Snoeck;J. Neyts;E. Padalko;J. Balzarini;E. De Clercq;A. Matsuda
本报告描述了奈普拉诺星A的（6 'R）-6'-C-乙炔基、-乙烯基和-乙基衍生物（分别为7a、8a和9a）和相应的6'S-非对映体（分别为7 b、8b和9 b）的合成和抗病毒作用，作为6 '-C-取代的奈普拉诺星A类似物的实例。容易从奈普拉诺星A制备的6 ′-甲酰基衍生物4与乙炔基溴化镁的格氏反应得到相应的1，2-加成产物5a和5 b的非对映体混合物。除去保护基后，分离（6 ′ R）-和（6 ′ S）-6 ′-C-乙炔基新霉素A（7a，7 b）。分别通过催化氢化7a和7 b制备相应的乙烯基衍生物8a和8b以及乙基衍生物9a和9 b。与neplanocin A相比，新的neplanocin A衍生物对S-腺苷-L-高半胱氨酸水解酶的抑制作用弱得多，R-非对映体比S-非对映体更具有抑制作用。活性大小顺序为7a > 8a > 7 b> 9a > 8b > 9 b。细胞毒性（对于CEM细胞）遵循完全相同的顺序。在这些化合物中，（6 ′ R）-6 ′-C-乙炔基新霉素A（7a，RENPA）显示出与新霉素A相当的抗病毒活性谱，并且抗病毒特异性高于新霉素A。RENPA对那些已知对Hcy水解酶抑制剂高度敏感的病毒（即牛痘病毒、水泡性口炎病毒）特别有效。
This report describes the synthesis and antiviral effects of (6'R)-6'-C-ethynyl, -ethenyl, and -ethyl derivatives of neplanocin A (7a, 8a, and 9a, respectively) and the corresponding 6'S-diastereomers (7b, 8b, and 9b, respectively), as examples of 6'-C-substituted analogues of neplanocin A. Grignard reaction of the 6'-formyl derivative 4, which was readily prepared from neplanocin A, with ethynylmagnesium bromide gave a diastereomeric mixture of the corresponding 1,2-addition products 5a and 5b. After removal of the protecting groups, (6'R)- and (6'S)-6'-C-ethynylneplanocin A's (7a, 7b) were separated. The corresponding ethenyl derivatives 8a and 8b and ethyl derivatives 9a and 9b were prepared by catalytic hydrogenation of 7a and 7b, respectively. As compared to neplanocin A, the new neplanocin A derivatives were much weaker inhibitors of S-adenosyl-L-homocysteine hydrolase, the R-diastereomers being more inhibitory than the S-diastereomers. The decreasing order of activity was 7a > 8a > 7b > 9a > 8b > 9b. The cytotoxicity (for CEM cells) followed exactly the same order. Of these compounds, (6'R)-6'-C-ethynylneplanocin A (7a, RENPA) showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. RENPA was particularly active against those viruses (i.e. vaccinia virus, vesicular stomatitis virus) that are known to be highly sensitive to AdoHcy hydrolase inhibitors.