Masuda Takeshi, Yoshida Shuku, Arai Masami, Kaneko Satoru, Yamashita Makoto, Honda Takeshi
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Chem Pharm Bull (Tokyo). 2003 Dec;51(12):1386-98. doi: 10.1248/cpb.51.1386.
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.
本文描述了在聚-L-谷氨酰胺主链上带有4-胍基-Neu5Ac2en衍生物的多价唾液酸酶抑制剂。为了使4-胍基-Neu5Ac2en（扎那米韦）在支气管和肺部有更长的保留时间，我们专注于通过不可裂解的烷基醚键在其C-7位结合4-胍基-Neu5Ac2en衍生物的超分子。我们首先发现，唾液酸衍生物8的7-羟基烷基化反应顺利进行，并生成了7-O-烷基-4-胍基-Neu5Ac2en衍生物13，其不仅对甲型流感病毒唾液酸酶具有等效的抑制活性，而且在细胞培养中对甲型流感病毒也有抑制活性。接下来，我们合成了通过酰胺键连接7-O-烷基-4-胍基-Neu5Ac2en衍生物的聚-L-谷氨酰胺26，其对甲型流感病毒显示出增强的抗病毒活性，并且相对于单体唾液酸酶抑制剂在体内具有更强的疗效。
