Patrick Weber

Building upon a previously established (2+3)‐cycloaddition strategy, a series of N,N‐dialkylated aminocyclopentanes was synthesized using a partially protected eno‐furanose as the starting point. The resulting N‐methylisoxazolidine was subsequently transformed into the corresponding aminocyclopentane, which was further N‐alkylated, yielding a collection of compounds with potential as inhibitors and pharmacological chaperones of β‐d‐glucocerebrosidase. A comprehensive screening involving a range of biologically relevant glycosidases unveiled that these compounds exhibit remarkable potency and selectivity as inhibitors of human lysosomal β‐d‐glucocerebrosidase. However, none of these compounds exhibit significant activity enhancement of Morbus Gaucher related p.N409S/p.L483P mutant β‐d‐glucocerebrosidase.

We report the synthesis and testing of a novel type (new lead structure) of powerful and highly selective human O-N-acetyl-β-d-glucosaminidase (enzyme associated with Alzheimer's disease) inhibitors that are not based on transition state mimetics.

A set of cyclopentanoid α-galactosidase ligands was prepared from a partially protected ω-eno-aldose via a reliable (2 + 3)-cycloaddition protocol with slightly modified conditions. The obtained N-benzylisoxazolidine ring was selectively opened and the configuration of the hydroxymethylgroup was inverted. Consecutive deprotection provided an aminocyclopentane, which was N-alkylated to furnish a set of potential α-galactosidase inhibitors. Their glycosidase inhibitory activities were screened with a panel of standard glycosidases of biological significance.

Highly functionalized cyclopentanes have frequently been found as core scaffolds or partial structures of biologically active natural products, not only in well-known prostaglandins ¹ but also in carbohydrate conjugates such as trehazolins ^2,3 and allosamidin ⁴ as well as in carba nucleosides neplanocin ⁵ and aristeromycin. ⁶ Moreover, there are many examples of cyclopentane derivatives designed for medicinal purposes. ⁷ Based on early work by Padwa ⁸ and Oppolzer, ⁹ Vasella and Bernet ¹⁰ have thoroughly 66explored an efficient route to C-branched aminocyclopentane-polyols relying on a (2 + 3)-cycloaddition reaction. Jäger's laboratory ¹¹ as well as Reymond and his group ¹² provided early examples of hydroxymethyl aminocyclopentane triols as efficient glycosidase inhibitors. In the same context, we have exploited ¹³ these guiding references for our modified approach to related compounds, including deoxyfluoro derivatives featuring β-d-gluco configuration.

The scope of a series of N-alkylated iminosugar based inhibitors in the d-gluco as well as d-xylo configuration towards their interaction with human lysosomal β-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis of N-alkylated iminosugar scaffolds conjugated to a variety of terminal groups via a benzoic acid ester linker. The terminal groups such as nitrile, azide, alkyne, nonafluoro-tert-butyl and amino substituents enable follow-up chemistry as well as visualisation experiments. All compounds showed promising inhibitory properties as well as selectivities for β-glucosidases, some exhibiting activities in the low nanomolar range for β-glucocerebrosidase.

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for G_M1-gangliosidosis and Morquio B disease.

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexosaminidase activities in vivo.