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

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• 作者：Shota Miyawaki^a ; Yuki Hirokami^a ; Kyoko Kinami^a ; Masako Hoshino^a ; Daisuke Minehira^a ; Daiki Miyamoto^b ; Robert J. Nash^c ; George W.J. Fleet^d ; Isao Adachi^a ; Naoki Toyooka^b ; Atsushi Kato^a ;
• 关键词：α-l-Rhamnosidase ; l-DMDP cyclic isothiourea ; Iminosugars ; Structure&ndash ; activity relationships ; Glycosidase inhibitor ; Mycobacterium tuberculosis
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：25
• 期：1
• 页码：107-115
• 全文大小：1422 K
• 卷排序：25

文摘

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. The addition of a long alkyl chain, such as decyl or dodecyl, to the nitrogen led to the production of highly potent inhibitors of α-l-rhamnosidase; it also caused broad inhibition spectrum against β-glucosidase and β-galactosidase. In contrast, the corresponding N-benzyl-l-DMDP cyclic isothioureas display selective inhibition of α-l-rhamnosidase; 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, about 46-fold better than 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.