Enzyme-catalyzed aldol condensation for asymmetric synthesis of azasugars: synthesis, evaluation, and modeling of glycosidase inhibitors

Abstract

6187 determination summary of [TTF] [(CHz),Tcbiim] including tables of bond lengths and bond angles, tables of atomic positions and thermal parameters, and additional crystal-packing diagrams and an ORTEP plot of [TTF][(CH2)zTcbiim] (14 pages): tables of structure factors for C18HsNsS4 (10 pages). Ordering information is given on any current masthead page. helpful discussions and suggestions. We especially thank Professor A. H. Francis and S. Sibley for luminescence spectroscopy measurements. We also thank Dr. J. Kampf for the X-ray crystallography.Abstract: A combined fructose 1,6diphosphate aldolase reaction and catalytic reductive amination has been used in the asymmetric synthesis of azasugars structurally corresponding to N-acetylglucosamine, N-acetylmannosamine, and deoxyhexoses. The 6-deoxyazasugars were prepared by direct hydrogenolysis of the aldolase product without removal of the 6-phosphate group.Both (R)and (S)-3-azido-2-acetamidopropanal used as substrates in the aldolase reactions were prepared from the corresponding lipase-resolved 2-hydroxy species followed by formation of an aziridine intermediate and opening of the aziridine with azide. Evaluation of these azasugars and their diastereomerically pure tertiary amine oxides as well as 5-thioglucose and its sulfoxide derivatives as glycosidase inhibitors was carried out. It was found that all synthetic azasugars and 5-thioglucose were strong inhibitors, but oxidation of the ring heteroatom weakened the inhibition. With the aid of molecular modeling and inhibition analysis, a structure-K; relation of inhibitors was established which provides useful information for the design of new glycosidase inhibitors.Many pyranoses and furanoses with the ring oxygen replaced by an imino group are natural products and useful as potent glycosidase inhibitorse2 This discovery has stimulated interests in the development of effective procedures for the synthesis of various azasugars' and analogues4 for the investigation of glycosidase reactions5 and the development of specific glycosidase ~ ~~ ~~~ ____ (1) Supported by the NIH (GM44154). (2) (a) Paulsen, H.; Tcdt, K. Petursson, S.; Campbell, A. L.; Mueller, R. A.; Behling, J. R.; Babiak, K. A,; Ng, J. S.; Scaros, M. G. J. Chem. Soc., Perkin Trans. 1989,665. (I) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Merino, P.

Synthesis and Biological Activity of Novel Deoxynojirimycin Derivatives as Potent α-Glucosidase Inhibitors

“…In our α-glucosidase inhibitory activity assay system, the observed IC 50 of acarbose was 3.44 × 10 −4 M, which was consistent with the reference data of 3.36 × 10 −4 M and 2.90 × 10 −4 M [24,25]. However, under the present conditions, the IC 50 of DNJ was determined to be 4.51 × 10 −4 M, which was much higher than the sole published data of 1.0 × 10 −5 M [27]. This phenomenon may be attributed to the complexity of the enzyme assay or the unidentified differences between the source and purity of DNJ.…”

Chiron approaches to polyhydroxylated piperidines: promising glycosidase inhibitors

“…2 Amongst these azasugars, nojirimycin (1) and 1-deoxynojirimycin (2) are the first naturally occurring alkaloids with promising glycosidase inhibitory activity. 3 In order to examine the structure-activity relationship, a number of synthetic analogues of 1 and 2 have been synthesized and evaluated for glycosidase inhibition in the treatment of various diseases such as diabetes, cancer, AIDS and viral infections. 4 This study established the correlation between the α/β-glycosidase inhibitory activity with the positions,and the configurations of -OH groups as well as various substituents (in lieu of -OH groups).…”

Stereospecific synthesis of N-tosyl derivatives of dihydroconduramine E-2 and ent-F-2

“…16 Inhibitors of glycoside-processing enzymes share structural homology with the natural enzymatic substrates that are often aminohydroxy-substituted five or six-membered heterocyclic rings. 17,18 Conduramines, dihydroconduramines and structurally related compounds belong to an important class of glycosidase inhibitors which are essential elements of many biologically active compounds. [19][20][21][22][23][24][25][26][27] In particular, conduramines 1-3 and dihydroconduramines 4-6 apart from their use as probes for biological functions of oligosaccharides have also served as important synthetic precursors of amino-and diaminocyclitols and many other biologically active compounds ( Figure 1).…”