N(6)-取代腺苷衍生物的抗疟活性。第3部分。

Antimalarial activity of N(6)-substituted adenosine derivatives. Part 3.

作者信息

Herforth Claudia, Wiesner Jochen, Heidler Philipp, Sanderbrand Silke, Van Calenbergh Serge, Jomaa Hassan, Link Andreas

机构信息

Institut für Pharmazie, Abteilung für Pharmazeutische Chemie, Universität Hamburg, Bundesstrasse 45, D-20146 Hamburg, Germany.

出版信息

Bioorg Med Chem. 2004 Feb 15;12(4):755-62. doi: 10.1016/j.bmc.2003.11.008.

DOI:10.1016/j.bmc.2003.11.008

PMID:14759735

Abstract

A series of novel 3'-amido-3'-deoxy-N(6)-(1-naphthylmethyl)adenosines was synthesized applying a polymer-assisted solution phase (PASP) protocol and was tested for anti-malarial activity versus the Dd2 strain of Plasmodium falciparum. Further, this series and 62 adenosine derivatives were analyzed regarding 1-deoxy-d-xylulose 5-phosphate (DOXP) reductoisomerase inhibition. Biological evaluations revealed that the investigated 3',N(6)-disubstituted adenosine derivatives displayed moderate but significant activity against the P. falciparum parasite in the low-micromolar range. On the molecular level, DOXP reductoisomerase utilizing an adenosyl-containing substrate was identified as a promising metabolic target for ligands of adenosine binding motifs.

摘要

采用聚合物辅助溶液相（PASP）方法合成了一系列新型的3'-氨基-3'-脱氧-N(6)-(1-萘甲基)腺苷，并对其针对恶性疟原虫Dd2株的抗疟活性进行了测试。此外，对该系列化合物和62种腺苷衍生物进行了1-脱氧-D-木酮糖-5-磷酸（DOXP）还原异构酶抑制作用分析。生物学评价表明，所研究的3'，N(6)-二取代腺苷衍生物在低微摩尔范围内对恶性疟原虫表现出中等但显著的活性。在分子水平上，利用含腺苷底物的DOXP还原异构酶被确定为腺苷结合基序配体的一个有前景的代谢靶点。