Amidine, amidrazone, and amidoxime derivatives of monosaccharide aldonolactams: synthesis and evaluation as glycosidase inhibitors

Papandreou, George; Tong, Michael K.; Ganem, Bruce

doi:10.1021/ja00078a004

Cited by 117 publications

(73 citation statements)

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“…Family 19 inhibitors could be designed to mimic the more planar oxocarbenium ion geometry with the delocalized positive charge. Some such inhibitors have been synthesized including amidines, amidrazones (28), and nojiritetrazoles (11). We expect that selective inhibition of family 19 chitinases can be achieved by condensation of one of these transition state analogs with the NAG-NAG-NAG glycone specificity of chitinase.…”

Section: Discussionmentioning

confidence: 99%

The role of enzyme distortion in the single displacement mechanism of family 19 chitinases

Brameld

Goddard

1998

Proc. Natl. Acad. Sci. U.S.A.

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By using molecular dynamics simulations, we have examined the binding of a hexaNAG substrate and two potential hydrolysis intermediates (an oxazoline ion and an oxocarbenium ion) to a family 19 barley chitinase. We find the hexaNAG substrate binds with all sugars in a chair conformation, unlike the family 18 chitinase which causes substrate distortion. Glu 67 is in a position to protonate the anomeric oxygen linking sugar residues D and E whereas Asn 199 serves to hydrogen bond with the C2 N-acetyl group of sugar D, thus preventing the formation of an oxazoline ion intermediate. In addition, Glu 89 is part of a f lexible loop region allowing a conformational change to occur within the active site to bring the oxocarbenium ion intermediate and Glu 89 closer by 4-5 Å. A hydrolysis product with inversion of the anomeric configuration occurs because of nucleophilic attack by a water molecule that is coordinated by Glu 89 and Ser 120. Issues important for the design of inhibitors specific to family 19 chitinases over family 18 chitinases also are discussed.

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Section: Discussionmentioning

confidence: 99%

The role of enzyme distortion in the single displacement mechanism of family 19 chitinases

Brameld

Goddard

1998

Proc. Natl. Acad. Sci. U.S.A.

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“…24, that inhibits brewers yeast a-glucosidase (K i 59 mm) [53]. The inhibitory power of compounds with an sp 2 -hybridized anomeric center against a-glycosidases has been related to their basicity; while neutral lactone-type inhibitors are selective for b-glycosidases, their basic analogues are less selective [56] [57]. This rule appears to be valid also for a-l-fucosidases.…”

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confidence: 99%

Synthesis of anL-Fucose-Derived Cyclic Nitrone and its Conversion toα-L-Fucosidase Inhibitors

Peer

Vasella

1999

HCA

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The L‐fuco‐nitrone 1 has been synthesized from allyl 4,6‐O‐benzylidene‐α‐D‐glucopyranoside (4) in 11 steps and an overall yield of 18%. The key step is the intramolecular alkylation of an intermediary 1,1‐bis(hydroxylamine) derived from the tosyloxy oximes (E/Z)‐2. The nitrone 1 has been transformed into the diamine 30, the indolizidines 39 and 40, the indolizidinones 34 and 35, and the imidazole 44, all inhibiting bovine epididymis α‐L‐fucosidase with IC50 values between 105 nM and 240 μM.

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“…They possess some glycosidase inhibitory properties [I] [2], but, except in the D-mannose and D-rhamnose series [3-51, they are in general weaker inhibitors when compared to the corresponding 5-amino-5-deoxy-~-hexoses Ib or to their I-deoxy derivatives lc in the D-glucose [6], D-gUlOSe [7], D-galactose [8], L-rhamnose [4], or L-fucose [9] series (Scheme I ) . h-lactams are important intermediates for the synthesis of more potent inhibitors like 1-deoxy-amino-sugars [4] [7] [9-1 I], amidines [12-151, amidrazones [14-161, amidoximes [15] [17], pyrrolo-and imidazolosugars [I 81, or polyhydroxyindolizines [I 91. In the pyrrolidinone series, amidrazones, which are obtained from D-ribono-y-lactam, are potent nucleotide hydrolase inhibitors We describe herein a straightforward synthesis of 5-amino-5-deoxypentono-and 5-amino-5,6-dideoxyhexono-6-lactams 13a, 14, 15a, 16, 13b, and 15b in the D-ribose, L-arabinose, D-xylose, L-lyxose, D-allose, and D-glucose series, respectively, starting from the readily available (E)-pentadienoic acid 2a [21] and from the commercial (E,E)-hexadienoic acid (= sorbic acid) 2b.…”

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confidence: 99%

Asymmetric synthesis of pentono‐ and 6‐deoxyhexono‐δ‐lactams via hetero‐Diels‐Alder reactions with nitroso dienophile

Defoin¹,

Sarazin²,

Sifferlen³

et al. 1998

Helvetica Chimica Acta

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Asymmetric Didvilldrr reaction of the pentadienoic and hexadienoic acids 2a, b with the chiral chloronitroso derivative 3 gave the primary adducts 4a, b with good-to-excellent enantioselectivity. Subsequent ci.v-or rrcmv-dihydroxylation and hydrogenolytic cleavage of the N -0 bond led to the 5-amino-5-deoxypcutono-h-lactams 13a. 14, lSa, and 16 in the D-ribose, L-arabinose, 1,-xylose, and L-lyxose series, respectively, and to the 5-amino-5.6-dideoxyhexono-6-lactams 13b and 1Sh in the r,-allose and u-glucose series, respectively.Introduction. -5-Amino-5-deoxyhexono-6-lactams la are stable amino-sugars which were easily synthesized.

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Amidine, amidrazone, and amidoxime derivatives of monosaccharide aldonolactams: synthesis and evaluation as glycosidase inhibitors

Cited by 117 publications

References 0 publications

The role of enzyme distortion in the single displacement mechanism of family 19 chitinases

The role of enzyme distortion in the single displacement mechanism of family 19 chitinases

Synthesis of anL-Fucose-Derived Cyclic Nitrone and its Conversion toα-L-Fucosidase Inhibitors

Asymmetric synthesis of pentono‐ and 6‐deoxyhexono‐δ‐lactams via hetero‐Diels‐Alder reactions with nitroso dienophile

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