逆转录反向修饰的HTLV-1蛋白酶抑制剂的引物位点序列的作用

Effect of prime-site sequence of retro-inverso-modified HTLV-1 protease inhibitor.

作者信息

Awahara Chiyuki, Tatsumi Tadashi, Furuta Saki, Shinjoh Gen, Konno Hiroyuki, Nosaka Kazuto, Kobayashi Kazuya, Hattori Yasunao, Akaji Kenichi

机构信息

Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kita-ku, Kyoto 603-8334, Japan.

Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.

出版信息

Bioorg Med Chem. 2014 Apr 15;22(8):2482-8. doi: 10.1016/j.bmc.2014.02.050. Epub 2014 Mar 4.

DOI:10.1016/j.bmc.2014.02.050

PMID:24680060

Abstract

The effects of additional substituents covering the prime-site of retro-inverso (RI)-modified HTLV-1 protease inhibitors containing a hydroxyethylamine isoster were clarified. Stereo-selective construction of the most potent isoster backbone was achieved by the Evans-aldol reaction. Addition of N-acetylated d-amino acid corresponding to the P2' site gave an RI-modified inhibitor showing superior inhibitory activity to the previous inhibitor. Inhibitory activities of the newly synthesized inhibitors suggest that partially modified RI inhibitors would interact with HTLV-1 protease in the same manner as the parent hydroxyethylamine inhibitor.

摘要

阐明了覆盖含有羟乙胺类似物的逆转化（RI）修饰的HTLV-1蛋白酶抑制剂主要位点的额外取代基的作用。通过埃文斯-羟醛反应实现了最有效类似物骨架的立体选择性构建。添加与P2'位点对应的N-乙酰化d-氨基酸得到一种RI修饰的抑制剂，其抑制活性优于先前的抑制剂。新合成抑制剂的抑制活性表明，部分修饰的RI抑制剂与HTLV-1蛋白酶的相互作用方式与母体羟乙胺抑制剂相同。