Derivatives of (2R,3R,4S)-2-Aminomethylpyrrolidine-3,4-diol are selective α-Mannosidase inhibitors

Popowycz, Florence; Gerber‐Lemaire, Sandrine; Demange, Raynald; Rodriguez-Garcia, Eliaizar; Asenjo, Ana Teresa Carmona; Robina, Inmaculada; Vogel, Pierre

doi:10.1016/s0960-894x(01)00477-2

Cited by 56 publications

(36 citation statements)

References 37 publications

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“…It was observed that, for both compounds, many hydroxy rotamers converged to a single structure. In the case of 1 a, 30 initial structures led to 20 E, and E 5 ). The fact that 2 a can adopt a larger number of envelope conformations indicates that its ring structure is more flexible than that of 1 a.…”

Section: Computational Studiesmentioning

confidence: 95%

Inhibition of Golgi Mannosidase II with Mannostatin A Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationship Studies

Kawatkar

George

et al. 2004

ChemBioChem

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Mannostatin and aminocyclopentitetrol analogues with various substitutions at the amino function were synthesized. These compounds were tested as inhibitors of human Golgi and lysosomal alpha-mannosidases. Modification of the amine of mannostatin had only marginal effects, whereas similar modifications of aminocyclopentitetrol led to significantly improved inhibitors. Ab initio calculations and molecular docking studies were employed to rationalize the results. It was found that mannostatin and aminocyclopentitretrol could bind to Golgi alpha-mannosidase II in a similar mode to that of the known inhibitor swainsonine. However, due to the flexibility of the five-membered rings of these compounds, additional low-energy binding modes could be adopted. These binding modes may be relevant for the improved activities of the benzyl-substituted compounds. The thiomethyl moiety of mannostatin was predicted to make favorable hydrophobic interactions with Arg228 and Tyr727 that would possibly account for its greater inhibitory activity.

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Section: Computational Studiesmentioning

confidence: 95%

Inhibition of Golgi Mannosidase II with Mannostatin A Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationship Studies

Kawatkar

George

et al. 2004

ChemBioChem

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“…(1.5 ml) was added at 08 and the mixture stirred for 10 min. The solvent was evaporated and the residue conventionally acetylated with Ac 2 O/pyridine for 6 h. The resulting residue was purified by CC (SiO 2 (5)); 120.9 (C(3)); 113.8 (C(4)); 75.5 (C(2')); 71.2 (C(3')); 58.4 (C(1')); 50.9 (C(4')); 13. C(3)); 107.9 (C(4)); 71.6 (C(2')); 69.2 (C(3')); 65.5 (CH 2 of Cbz); 57.2 (C(1')); 51.0 (C (4')) ; calc.…”

Section: C R = Hmentioning

confidence: 99%

“…± Derivatives of pyrrolidine-3,4-diols ( 1,4-dideoxy-1,4-iminoalditols) constitute an important class of glycosidase inhibitors [1] although, in some cases, there is a lack of selectivity due to the higher conformational flexibility compared to 1,5-dideoxy-1,5-iminoalditols and other imino-bicyclic structures. For instance, simple meso-pyrrolidine-3,4-diol (1) is a weak and nonselective inhibitor [2] that presents activity towards several glycosidases. Approaches have been developed to increase selectivity in enzyme inhibition that consist of providing the dideoxy-iminosugar with some information about the shape and charge of the glycosyl moiety cleaved in the enzymatic hydrolysis and also that of the aglycon itself.…”

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confidence: 99%

“…We have found that pyrrolidinediols of type 2 with (benzylamino)methyl side chains [2] can be highly selective and competitive inhibitors of a-mannosidases, and we have presented a quick combinatorial approach for their preparation [4].…”

mentioning

confidence: 99%

“…13 C-NMR (100.5 MHz, CD 3 OD): 165.1 (COO i Pr); 160.1, 153.6 (C(2), C(5)); 115.5 (C(3)); 108.8 (C(4)); 77.3 (C(2')); 72.3 (C(3')); 68.9 (Me 2 CH), 60.3 (C(1')); 52.5 (C(4')); 22. 2 (3)); 108.9 (C(4)); 76.1 (C(2')); 70.1 (C(3')); 68.5 (C(1')); 62.8 (C(4'')); 59.8 (C(4')); 55.9 (C(1'')); 55.3 (PhCH 2 ); 52.8 (COOMe); 38.1 (CH of HNÀPheÀOMe); 31.6, 25.4 (C(2''), C(3'')); 13.6 (Me). EI-MS: (30, M .…”

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confidence: 99%

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Synthesis and Glycosidase Inhibitory Activities of 5‐(1′,4′‐Dideoxy‐1′,4′‐imino‐D‐erythrosyl)‐2‐methyl‐3‐furoic Acid (=5‐[(3S,4R)‐3,4‐Dihydroxypyrrolidin‐2‐yl]‐2‐methylfuran‐3‐carboxylic Acid) Derivatives: New Leads as Selective α‐L‐Fucosidase and β‐Galactosidase Inhibitors

Vargas

Robina

Demange

et al. 2003

Helvetica Chimica Acta

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The GarcÌa-Gonza¬lez reaction of d-glucose and ethyl acetoacetate generated ethyl 5-[(1'S)-d-erythrosyl]-2-methyl-3-furoate (5), which was converted to ethyl 5-[(1'R)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (3c) and to ethyl 5-[(1'S)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (4c). Similar methods were developed to generate other carboxylic acid derivatives such as methyl (see 3e and 4e), isopropyl (see 3f), and butyl esters (see 3g), S-phenyl (see 3a) and S-ethyl thioesters (see 3m), N-benzylcarboxamides 3b and 4b, glycine-derived amide 3h, and N-phenyl (see 3i), N-isopropyl (see 3j and 4j), N,N-diethyl-(see 3k and 4k), and N-ethyl-carboxamides (see 3l). All the new 5-(1',4'-dideoxy-1',4'-imino-d-erythrosyl)-3-furoic acid ( 5-[(3S,4R)-3,4-dihydroxypyrrolidin-2-yl)furan-3-carboxylic acid) derivatives 3 and 4 were assayed for inhibitory activity towards 25 commercially available glycosidases. Derivative 3a with a S-phenyl thioester group is a good and selective a-l-fucosidase inhibitor (K i 2 ± 4 mm), whereas 4b (with a N-benzylcarboxamide group) is a good b-galactosidase inhibitor.Introduction. ± Derivatives of pyrrolidine-3,4-diols ( 1,4-dideoxy-1,4-iminoalditols) constitute an important class of glycosidase inhibitors [1] although, in some cases, there is a lack of selectivity due to the higher conformational flexibility compared to 1,5-dideoxy-1,5-iminoalditols and other imino-bicyclic structures. For instance, simple meso-pyrrolidine-3,4-diol (1) is a weak and nonselective inhibitor [2] that presents activity towards several glycosidases.

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An Efficient Combinatorial Method for the Discovery of Glycosidase Inhibitors The concept and part of the text of this work were presented at the XIth Eurocarb Conference in Lisbon on September 7, 2001, under the title “An Efficient Combinatorial Method for the Discovery of Glycosidase Inhibitors. Imines Equilibrating with (2R,3R,4S)-2-Aminomethyl pyrrolidine-3,4-diol and Aldehydes are Inhibitors of α-Mannosidases and Models for the Inhibitory Activity of Corresponding Amines”.

et al. 2002

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A dynamic imine library formed in solution provides a fast route to drug discovery. Imine formation from diamine 4 and a sublibrary of aldehydes can be used for the efficient discovery of glycosidase inhibitors through a new combinatorial approach. When the equilibrium shown is reached rapidly under dilute conditions, a mixture of imines is produced and can be screened by the glycosidase, which binds preferentially to the best inhibitor.

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Derivatives of (2R,3R,4S)-2-Aminomethylpyrrolidine-3,4-diol are selective α-Mannosidase inhibitors

Cited by 56 publications

References 37 publications

Inhibition of Golgi Mannosidase II with Mannostatin A Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationship Studies

Inhibition of Golgi Mannosidase II with Mannostatin A Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationship Studies

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