Specific inhibition of human β‐D‐glucuronidase and α‐L‐iduronidase by a trihydroxy pipecolic acid of plant origin

Bello, Isabelle Cenci di; Dorling, P. R.; Fellows, Linda E.; Winchester, Bryan

doi:10.1016/0014-5793(84)80911-4

Cited by 70 publications

(27 citation statements)

References 15 publications

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“…[98] The ASAs 43, [99] glucuronidases. Azasugars have been intensively studied as glycosidase inhibitors, and several potent azasugar-based glycosidase inhibitors have been discovered.…”

Section: Azasugar Acids (A 5 Type)mentioning

confidence: 99%

Glycosamino Acids: Building Blocks for Combinatorial Synthesis—Implications for Drug Discovery

Schweizer

2002

Angew. Chem. Int. Ed.

218

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“…[98] The ASAs 43, [99] glucuronidases. Azasugars have been intensively studied as glycosidase inhibitors, and several potent azasugar-based glycosidase inhibitors have been discovered.…”

Section: Azasugar Acids (A 5 Type)mentioning

confidence: 99%

Glycosamino Acids: Building Blocks for Combinatorial Synthesis—Implications for Drug Discovery

Schweizer

2002

Angew. Chem. Int. Ed.

218

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“…Strong and selective inhibitors of b-D-glucuronidase and a-L-iduronidase are thus of therapeutic interest. Siastatin B (1) [12] and its analogues 2 -4 [13], the pipecolic acids 5 [14] and 6 [15], and glucarolactam 8 [16] inhibit b-D-glucuronidases. The idarolactone 7 [17] is the only known inhibitor of human a-L-iduronidase.…”

mentioning

confidence: 99%

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

Pabba

Rempel

Withers

et al. 2006

Helvetica Chimica Acta

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The known glucaro-1,5-lactam 8, its diastereoisomers 9 -11, and the tetrahydrotetrazolopyridine-5-carboxylates 12 -14 were synthesised as potential inhibitors of b-D-glucuronidases and a-L-iduronidases. The known 2,3-di-O-benzyl-4,6-O-benzylidene-D-galactose (16) was transformed into the D-galactaroand L-altraro-1,5-lactams 9 and 11 via the galactono-1,5-lactam 21 in twelve steps and in an overall yield of 13 and 2%, respectively. A divergent strategy, starting from the known tartaric anhydride 41, led to the D-glucaro-1,5-lactam 8, D-galactaro-1,5-lactam 9, L-idaro-1,5-lactam 10, and L-altraro-1,5-lactam 11 in ten steps and in an overall yield of 4 -20%. The anhydride 41 was transformed into the L-thre-A C H T U N G T R E N N U N G uronate 46. Olefination of 46 to the (E)-or (Z)-alkene 47 or 48 followed by reagent-or substrate-controlled dihydroxylation, lactonisation, azidation, reduction, and deprotection led to the lactams 8 -11. The tetrazoles 12 -14 were prepared in an overall yield of 61 -81% from the lactams 54, 28, and 67, respectively, by treatment with Tf 2 A C H T U N G T R E N N U N G O and NaN 3 , followed by saponification, esterification, and hydrogen-A C H T U N G T R E N N U N G olysis. The lactams 8 -11 and 40 and the tetrazoles 12 -14 are medium-to-strong inhibitors of b-D-glucuronidase from bovine liver. Only the L-ido-configured lactam 10 (K i = 94 mM) and the tetrazole 14Introduction. -b-D-Glucuronidases (EC 3.2.1.31, family 2) 1 ) and a-L-iduronidases (EC 3.2.1.76, family 39) remove glycuronic acid residues from the non-reducing end of glycosaminoglycans such as chondroitin sulfate and hyaluronic acid.

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“…M range, because of the formation of a salt bridge between an acid catalytic group and the imino nitrogen [12]. Conduritol epoxides of the correct stereochemistry inactivate the corresponding glycosidases by alkylating the nucleophilic/counterionic carboxylate group which participates in the double displace ment mechanism of 'retaining' glycosidases, and glycosylmethyl p-nitrophenyl triazenes inactivate 'retaining' glycosidases via the cat alyzed generation of glycosylmethyl diazo nium ions [13].…”

Section: Mannopyranosylmethyl P-nitrophenyl Triazene (Iii) (Fig 1) mentioning

confidence: 99%

Goat Liver ß-Mannosidases: Molecular Properties, Inhibition and Inactivation of the Lysosomal and Nonlysosomal Forms

Kt¹,

Ra²,

Legler³

et al. 1985

Enzyme

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The two caprine hepatic ß-mannosidases have been partially purified and their properties have been compared. The lysosomal ß-mannosidase A had an apparent molecular weight of 127,000 ± 10,000 and an isoelectric point of pH 6-7. Its activity was unaffected by incubation with Triton X-100 (0.1 %) and cysteine (20 mM) and it hydrolyzed the presumed natural substrates, Man(ß1-4)GlcNAc and Man(ß1—4)GlcNaC(ß1-4)GlcNAc. The nonlysosomal ß-mannosidase B had an apparent molecular weight of 43,000 ± 2,000 and an isoelectric point of pH 5.5. ß-Mannosidase B was activated by Triton X-100 (0.1 %) and was inhibited by cysteine (20 mM). Hydrolysis of Man(ß1-4)GlcNAc, but not of Man(ß1- 4)GlcNAc(ß1-4)GlcNAc, followed incubation with ß-mannosidase B. 1,5-Dideoxy-1,5-imino- D-mannitol did not inhibit the A enzyme and only feebly (K(i) = 0.3 mM) inhibited the B enzyme; ß-D-mannopyranosylmethyl p-nitrophenyl triazene did not inactivate either enzyme but 1,2-anhydro-1,2,3,5,6/4-cyclohexane hexol inactivated the B enzyme only. The radical mechanistic differences between the two enzymes argue against their having the same genetic origin.

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Specific inhibition of human β‐D‐glucuronidase and α‐L‐iduronidase by a trihydroxy pipecolic acid of plant origin

Cited by 70 publications

References 15 publications

Glycosamino Acids: Building Blocks for Combinatorial Synthesis—Implications for Drug Discovery

Glycosamino Acids: Building Blocks for Combinatorial Synthesis—Implications for Drug Discovery

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

Goat Liver ß-Mannosidases: Molecular Properties, Inhibition and Inactivation of the Lysosomal and Nonlysosomal Forms

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