title: Strategy for designing selective α-l-rhamnosidase inhibitors: Synthesis and biological evaluation of l-DMDP cyclic isothioureas.
abstract: 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 IC50value of 0.22μM, about 46-fold better than the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ; IC50=10μM) and occupied the active-site of this enzyme (Ki=0.11μM). 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.
authors: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Shota
authors: S
authors: Miyawaki
authors: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Yuki
authors: Y
authors: Hirokami
authors: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Kyoko
authors: K
authors: Kinami
authors: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Masako
authors: M
authors: Hoshino
authors: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Daisuke
authors: D
authors: Minehira
authors: Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
authors: Daiki
authors: D
authors: Miyamoto
authors: Institute of Biological, Environmental and Rural Sciences/Phytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, United Kingdom.
authors: Robert J
authors: RJ
authors: Nash
authors: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, United Kingdom.
authors: George W J
authors: GW
authors: Fleet
authors: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Isao
authors: I
authors: Adachi
authors: Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
authors: Naoki
authors: N
authors: Toyooka
authors: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Atsushi
authors: A
authors: Kato
mesh_terms: D000818:Animals; D003500:Cyclization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010407:Penicillium / Q000201:enzymology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C540241:3,4-dihydroxypyrrolidine; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D006026:Glycoside Hydrolases; C022525:alpha-L-rhamnosidase; D013890:Thiourea
keywords: Glycosidase inhibitor; Iminosugars; Mycobacterium tuberculosis; Structure–activity relationships; l-DMDP cyclic isothiourea; α-l-Rhamnosidase