Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives |
| |
Authors: | Masuda Takeshi Yoshida Shuku Arai Masami Kaneko Satoru Yamashita Makoto Honda Takeshi |
| |
Affiliation: | Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. takemd@shia.sankyo.co.jp |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|