Strategy for designing selective rhamnosidase inhibitors: Synthesis and biological evaluation of L-DMDP cyclic isothioureas

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K08021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: University of Toyama
• Principal Investigator: ADACHI ISAO 富山大学, 附属病院, 教授 (30151070)
• Co-Investigator(Kenkyū-buntansha): 加藤 敦 富山大学, 附属病院, 准教授 (60303236) ; 名取 良浩 東北医科薬科大学, 薬学部, 助教 (50584455)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: ラムノシダーゼ / イミノ糖 / 結核菌 / グリコシダーゼ阻害剤

Outline of Final Research Achievements

This study shows that the cyclization of L-DMDP thioureas to bicyclic L-DMDP isothioureas improved α-L-rhamnosidase inhibition which was further enhanced by increasing the length of the alkyl chain. 3’, 4’-dichlorobenzyl-L-DMDP cyclic isothiourea (3r) was found to display the most potent and selective inhibition of α-L-rhamnosidase, with IC50 value of 0.22 μM,increased by about 46-fold compared to the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ ; IC50 = 10 μM) and occupied the active-site of this enzyme (Ki = 0.11 μM). Bicyclic isothioureas of ido-L-DMDP did not inhibit α-L-rhamnosidase. These new mimics of L-rhamnose may affect other enzymes associated with the biochemistry of rhamnose including enzymes involved in progression of tuberculosis.

Free Research Field

糖質生化学、創薬化学