Combinatorial library of five-membered iminocyclitol and the inhibitory activities against glyco-enzymes.
BACKGROUND
Oligosaccharide processing enzymes are important classes of catalysts involved in synthesizing specific oligosaccharide structures on proteins and sphingolipids. Development of specific inhibitors of such enzymes is of current interest as these inhibitors may be used to control cellular functions. Five-membered iminocyclitols have been shown to be potent inhibitors of such enzymes. Since a rational design and synthesis of inhibitors is often extremely difficult due to the limited information regarding the structure of the active site, we carried out a combinatorial library approach.


RESULTS
To create diversity, we decided to use an aldehyde group of a protected iminocyclitol for reductive amination and the Strecker reaction. After transformation of the nitrile group introduced by the Strecker reaction into an amine and amide and complete deprotection, a small library of five-membered iminocyclitols consisting of 27 compounds was synthesized. A series of compounds obtained by reductive amination was first screened as potential inhibitors of glycosidases and glycosyltransferases. Among them, compounds carrying a C(10)-alkyl group showed marked enhancement of inhibitory activity against alpha-mannosidase at 10 microM concentration when compared with its parent compound and deoxymannojirimycin. Furthermore, compounds having the phenylethyl group showed an extremely strong inhibitory effect against alpha-galactosaminidase at a K(i) value of 29.4 nM. Compounds with an aminomethyl and amide group at the C-1' position of these two molecules showed a decrease in inhibitory activities.


CONCLUSIONS
A combinatorial approach based on five-membered iminocyclitols with a galacto-configuration was exploited. The potential usefulness of the library as a source of inhibitors of glycoenzymes is clearly shown in this study.
Saotome
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Mitsubishi Kagaku Institute of Life Science (MITILS), Machida-shi, Tokyo, Japan.
Wong
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Kanie
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D000606:Amino Sugars / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013402:Sugar Alcohols / Q000737:chemistry* / Q000494:pharmacology
D000606:Amino Sugars; D004791:Enzyme Inhibitors; D007097:Imines; D013402:Sugar Alcohols; D006602:Hexosyltransferases; D006026:Glycoside Hydrolases