Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives
Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives
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DOI：
10.1248/cpb.51.1386
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发表时间：
2003-12-01
影响因子：
1.7
通讯作者：
Honda, T
中科院分区：
文献类型：
--
作者：
Masuda, T;Yoshida, S;Honda, T
描述了在多L-谷氨酰胺主链上含有4-胍-Neu5Ac2en衍生物的多价唾液酸酶抑制剂。为了延长4-胍-Neu5Ac2en(扎那米韦)在支气管和肺部的保留时间，我们重点研究了含4-胍-Neu5Ac2en衍生物的超分子通过不可切割的烷基醚键合在其C-7位。我们首次发现唾液酸衍生物8的7-羟基的烷基化反应进展顺利，得到了7-O-烷基-4-胍基-Neu5Ac2en衍生物13，它们在细胞培养中不仅对甲型流感病毒唾液酸酶具有同等的抑制活性，而且对甲型流感病毒也具有相同的抑制活性。接下来，我们合成了通过酰胺键连接的含7-O-烷基-4-胍-Neu5Ac2en的聚L-谷氨酰胺衍生物，26，与单体唾液酸酶抑制剂相比，它具有更强的抗甲型流感病毒活性和更强的体内疗效。
Polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives on a poly-L-glutamine backbone are described. Aiming for a longer retention time of 4-guanidino-Neu5Ac2en (zanamivir) in bronchi and lungs, we focused on supermolecules bearing 4-guanidino-Neu5Ac2en derivatives bound at their C-7 position through noncleavable alkyl ether linkages. We first found that alkylation of the 7-hydroxyl group of sialic acid derivative 8 proceeded smoothly, and produced 7-O-alkyl-4-guanidino-Neu5Ac2en derivatives 13, which exhibited equipotent inhibitory activity against not only influenza A virus sialidase but also influenza A virus in the cell culture. Next, we synthesized poly-L-glutamine bearing 7-O-alkyl-4-guanidino-Neu5Ac2en derivatives linked by amide bonds, 26, which showed enhanced antiviral activity against influenza A virus and more potent efficacy in vivo relative to a monomeric sialidase inhibitor.