A Versatile Synthetic Strategy for the Preparation and Discovery of New Iminocyclitols as Inhibitors of Glycosidases (original) (raw)
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Bioorganic & Medicinal Chemistry, 2013
The design and synthesis of a small library of pyrrolidine iminocyclitol inhibitors with a structural similarity to 1,4-dideoxy-1,4-imino-D-arabitol (DAB-1) is reported. This library was specifically designed to gain a better insight into the mechanism of inhibition of glycosidases by polyhydroxylated pyrrolidines or iminocyclitols. Pyrrolidine-3,4-diol 15a and pyrrolidine-3,4-diol diacetate 15b had emerged as the most potent a-glucosidase inhibitors in the series. Docking studies performed with an homology model of a-glucosidase disclosed binding poses for compounds 15a, 15b, 16a, and 16a 0 occupying the same region as the NH group of the terminal ring of acarbose and suggest a closer and stronger binding of compound 15a and 15b with the enzyme active site residues. Our studies indicate that 2 or 5-hydroxyl substituents appear to be vital for high inhibitory activity.
Chemistry & Biology, 2001
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. Fivemembered 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 glycosyltrans-ferases. Among them, compounds carrying a C 10-alkyl group showed marked enhancement of inhibitory activity against Kmannosidase at 10 WM concentration when compared with its parent compound and deoxymannojirimycin. Furthermore, compounds having the phenylethyl group showed an extremely strong inhibitory effect against K-galactosaminidase at a K i value of 29.4 nM. Compounds with an aminomethyl and amide group at the C-1P 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.
Synthesis of Pyrrolidine-Based Imino Sugars as Glycosidase Inhibitors
European Journal of Organic Chemistry, 2007
Two pyrrolidine-based imino sugars have been synthesized in an efficient manner, using regiospecific amination, ring closing metathesis, and diastereospecific dihydroxylations as key steps. These azasugars are found to be moderate inhibitors of glycosidases.
Synthesis and evaluation of sulfamide-type indolizidines as glycosidase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2008
A practical synthesis of reducing sulfamide-derived iminosugar glycomimetics related to the indolizidine glycosidase inhibitor family is reported. The polyhydroxylated bicyclic system was built from readily accessible hexofuranose derivatives through a synthetic scheme that involves 5,6-cyclic sulfamides. Further intramolecular nucleophilic addition of the sulfamide nitrogen atom to the masked aldehyde group of the monosaccharide in the open chain form afforded the target sugar mimics. By starting from D D-glucose and D D-mannose precursors, 2-aza-3,3-dioxo-3-thiaindolizidine derivatives with hydroxylation profiles that matched those of (+)-castanospermine and 6-epi-(+)-castanospermine were obtained. In vitro screening against a panel of glycosidases evidenced a high selectivity towards a-mannosidase.
The Journal of Organic Chemistry, 2012
The Jocic−Reeve and Corey−Link type reaction of dichloromethyllithium with suitably protected 5-ketohexofuranoses followed by treatment with sodium azide and sodium borohydride reduction gave 5-azido-5-hydroxylmethyl substituted hexofuranoses 7a−c with required geminal dihydroxymethyl group. Removal of protecting groups and converting the C-1 anomeric carbon into free hemiacetal followed by intramolecular reductive aminocyclization with in situ generated C5-amino functionality afforded corresponding 5C-dihydroxymethyl piperidine iminosugars 2a−c. Alternatively, removal of protecting groups in 7b and 7c and chopping of C1-anomeric carbon gave C2-aldehyde that on intramolecular reductive aminocyclization with C5-amino gave 4C-dihydroxymethyl pyrrolidine iminosugars 1b and 1c, respectively. On the basis of the 1 H NMR studies, the conformations of 2a/2b were assigned as 4 C 1 and that of 2c as 1 C 4 . The glycosidase inhibitory activities of all five iminosugars were studied with various glycosidase enzymes and compared with natural D-gluco-1-deoxynojirimycin (DNJ). All the five compounds were found to be potent inhibitors of rice α-glucosidase with K i and IC 50 values in the nanomolar concentration range. Iminosugars 2b and 1b were found to be more potent inhibitors than their parent iminosugar. These results were substantiated by in silico molecular docking studies. A dx.doi.org/10.1021/jo3009534 | J. Org. Chem. XXXX, XXX, XXX−XXX H 1a 2.92 (dd) 2.63 (dd) 2.90 (dd) J 1a,1e = 14.8 Hz J 1a,1e = 12.0 Hz J 1a,1e = 13.5 Hz J 1a,2e = 3.0 Hz J 1a,2a =12.0 Hz J 1a,2e = 4.1 Hz H 1e 3.01 (dd) 2.95 (dd) 2.98 (dd) J 1e,1a = 14.8 Hz J 1e,1a = 12.0 Hz J 1e,1a = 13.5 Hz J 1e,2e = 1.7 Hz J 1e,2a = 4.0 Hz J 1e,2e = 7.1 Hz . Conformations of 2a, 2b and 2c.
Amino Acid-Based Synthesis and Glycosidase Inhibition of Cyclopropane-Containing Iminosugars
Synthesis of four iminosugars fused to a cyclopropane ring is described using L-serine as the chiral pool. The key steps are large-scale preparation of an α,β-unsaturated piperidinone followed by completely stereoselective sulfur ylide cyclopropanation. Stereochemistry of compounds has been studied by nuclear Overhauser effect spectroscopy (NOESY) experiments and 1 H homonuclear decoupling to measure constant couplings. The activity of these compounds against different glycosidases has been evaluated. Although inhibition activity was low (compound 8a presents a (K i) of 1.18 mM against βgalactosidase from Escherichia coli), interestingly, we found that compounds 8a and 8b increase the activity of neuraminidase from Vibrio cholerae up to 100%.
Helvetica Chimica Acta, 1995
The title compounds 6 and 7 have been prepared from the known 2,3-di-U-benzyl-4,6-0-benzylidene-o-galactose (18) and N'-acetyl-triO -benzyl-D-glucosamine oxime (29) in eight and six steps, respectively. The azidonitrile leading to the benzylated galacto-tetrazole 16 was prepared from 14 and cyclized under the conditions of its formation (Scheme I). The alcohol 13 was obtained by oxidation of 10 followed by reduction. Better yields and diastereoselectivities were realized, when the benzylidene-protected D-gafacto-alcohol 20 was subjected to oxidoreduction, yielding the L-altro-alcohol 22 via the ketone 21 (Scheme 2). Treatment of the corresponding tosylate 24 with NaN, yielded the tetrazole 25, which was deprotected to 6. The tetrabenzyl ether 16 (from 14, or from 25 via 27) was reduced to 28 and deprotected to give the known deoxygalactostatin 8 (Scheme 2). Oxidation of the hydroxynitrile 30, derived from 29, followed by reduction of 32 yielded mostly the Lido -hydroxynitrile (Scheme 3), which was tosylated and treated with NaN3 to give the tetrazole 3Sa and its manno-isomer 36a, while AI(N,), yielded (E)and (2)-38 (Scheme 4). The intermediate azide 39 was isolated besides 40 when NH,N,/DMF was used; thermolysis of 39 gave mostly 3Sa, which was deprotected to 7, besides some elimination product 41. Both 6 and 7 are stable in the pH range 1-10; at pH 12, 6 is unaffected but, 7 shows some epimerization to the manno-configurated isomer 43. The tetrazole 6 is a competitive inhibitor of the P-galactosidases from E. coli (4 = 1 p~, pH 6.8) and bovine liver (4 = 0.8 VM, pH 7.0); the N-acetyl-P-D-glucosaminidase from bovine kidney is competitively inhibited by 7 (4 % 0.2 p~, pH 4.1). Introduction.-We have designed the gluco-tetrazole 1 [I] [2] and its manno-epimer 2 [2] as neutral transition-state analogues for the inhibition of a-glucosidases and p-mannosidases, respectively. These tetrazoles possess a half-chair conformation in the solid state; in solution, 1 is a half-chair t6H7) and 2 a sofa (S7). A detailed kinetic study demonstrated that the inhibition is competitive and configurationally selective, and established these tetrahydrotetrazolopyridines (tetrahydropyridotetrazoles)') as transition-state analogues [2]. The inhibitory properties of the gluco-tetrazole 1 parallel those of D-glucono-l,5-lactone, but, unlike the corresponding lactones, 1 and 2 are stable towards hydrolysis over a wide range of pH values, an advantage for co-crystallization [9] and for their potential use as templates in the generation of catalytic antibodies [lo] [ll]. Additionally, reduction of the tetra-0-benzyl-protected tetrazole 3 is a key step in a new route to deoxynojirimycin [I]. Galactose and N-acetylglucosamine derivatives possessing an sp2-hybridized anomeric center, such as galactono-1,5-1actam 4 [I21 and derivatives [ 131, the N-acetylglucosaminolactone 5 [14], the related lactone oximes [14] [15] and the lactam [14], are ') For the preparation of carbohydrate-derived tetrazoloazepines, see [3] [4]. Aside from tetrazolo derivatives, some monosaccharide-derived imidazolopyridines were isolated IS] [6] or prepared [7] [8] and investigated for glycosidase inhibition.
Tetrahedron Letters, 2011
The syntheses of 4-C-Me-DAB [1,4-dideoxy-1,4-imino-4-C-methyl-D-arabinitol] from Lerythronolactone and of 4-C-Me-LAB [from D-erythronolactone] require only a single acetonide protecting group. The effect of pH on the NMR spectra of 4-C-Me-DAB [pK a of the salt around 8.4] is discussed and illustrates the need for care in analysis of both coupling constants and chemical shift. 4-C-Me-DAB (for rat intestinal sucrase K i 0.89 μM, IC 50 0.41 μM) is a competitive-whereas 4-C-Me-LAB (for rat intestinal sucrase K i 0.95 μM, IC 50 0.66 μM) is a noncompetitive-specific and potent α-glucosidase inhibitor. A rationale for the α-glucosidase inhibition by DAB, LAB, 4-C-Me-DAB, 4-C-Me-LAB, and isoDAB-but not isoLAB-is provided. Both are inhibitors of endoplasmic reticulum (ER) resident α-glucosidase I and II. This paper describes the synthesis of the enantiomers 4-C-Me-DAB 1D [1,4-dideoxy-1,4imino-4-C-methyl-D-arabinitol] and 4-C-Me-LAB 1L with only a single acetonide needed as a protecting group, both of which are micromolar inhibitors of some α-glucosidases; in accord with Asano's hypothesis, i the D-iminosugar 1D is a competitive inhibitor, whereas the enantiomer 1L is a non-competitive inhibitor.