A Versatile Synthetic Strategy for the Preparation and Discovery of New Iminocyclitols as Inhibitors of Glycosidases

Abstract

A series of iminocyclitols was prepared using a versatile synthetic strategy, and their inhibition of glycosidases was evaluated using capillary electrophoresis. The study has demonstrated that remarkable specificities in enzyme inhibition can be achieved with small modifications on the aglycon side chain and the ring nitrogen. Among the compounds synthesized, (2R,3R,4R,5R)-N-methyl-2-(acetamidomethyl)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidine was found to be very potent against β-N-acetylhexosaminidase P with the K i value of 80 nM.

Novel Five‐Membered Iminocyclitol Derivatives as Selective and Potent Glycosidase Inhibitors: New Structures for Antivirals and Osteoarthritis

“…[19,21] The five-membered iminocyclitols that carry hydroxyl groups of a specific orientation can mimic the shape and charge of the reacting sugar moiety of the transition state. [19,22,24] Since enzyme inhibition could be significantly enhanced with slight modifications at the aglycon moiety, [25][26][27] iminocyclitols could be used as common cores for the development of selective glycosidase inhibitors through identification of an additional group to occupy the aglycon space. To quickly find such a group for attachment to the 5-membered iminocyclitol, we decided to conduct a combinatorial modification of compound 4 (Scheme 2) at the amine group in microtiter plates followed by screening in situ, a strategy successfully applied to other enzymes.…”

General Intermediates for the Synthesis of 6-C-Alkylated DMDP-Related Natural Products

“…6-C-Alkyl-DMDP iminosugars have attracted lots of attention, and several syntheses are available in the literature [7,22]. However, these syntheses are either tedious or the method was only suitable for a specific compound.…”

“…Although Wong et al had indicated the absolute configuration of homoDMDP to be (2R,3R,4R,5R,6S) based on their enantiospecific synthesis of a series of five-membered iminosugars [22], no direct experimental proof was available until our group reported the synthesis of L-homoDMDP [19]. There, we disclosed the stereochemistry of L-homoDMDP determined by analyzing the 2D-NMR of an oxazinone intermediate, a conformation-locked L-homoDMDP.…”

Stereoselective Strecker and Carbamate Annulation Methodology for the Synthesis of 1‐Amino‐1,2,5‐trideoxy‐2,5‐imino‐L‐iditol

“…This would allow us to pursue our initial goal of using an unprotected amine source and remove one step from the reaction sequence. To this end, the more soluble NH 4 OAc was used in combination with TMSCN as the nitrile source, and to our delight, this resulted in a respectable 80 % yield for the [a] As determined from analysis of the crude reaction mixture by 1 H NMR spectroscopy. [b] The configurations of syn-9a and anti-9a were determined after cyclization by 1 H NMR NOE correlations and comparison of the optical rotation values with those of known products.…”

“…[1] Of particular note is the pioneering work of Wong et al who observed that derivatization of naturally occurring 2,5-bis(hydroxymethyl)-3,4-dihydroxypyrrolidine (DMDP, 1a, Figure 1) to the 1-amino-1-deoxy-DMDP analogue (1b) resulted in the generation of a compound with pronounced inhibitory activity against N-acetylglucosaminidase. [2] The subsequent synthesis of a library of N-functionalized DMDP analogues, [3][4][5][6] many of which were readily prepared from 1-amino-1,2,5-trideoxy-2,5-imino-d-mannitol (2), [3,6] then led to the identification of potential drug therapies for the treatment of osteoarthritis, [7,8] and later, bacterial infections. [9] Similarly, the groups of Stütz and Wrodnigg developed a series of functionalized aminoiminohexitols using the Amadori rearrangement.…”