Orthoester functionalizedN-guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of β-glucocerebrosidase

Abstract

Alkylated guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol bearing an orthoester moiety were prepared using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that one of the compounds prepared displays potent inhibition against human β-glucocerebrosidase (GBA) at pH 7.0 with IC values in the low nanomolar range. Notably, a significant drop in inhibitory activity is observed when the same compound is tested at pH 5.2. This pH sensitive activity is due to degradation of the orthoester functionality at lower pH accompanied by loss of the alkyl group. This approach provides a degree of control in tuning enzyme inhibition based on the local pH. Compounds like those here described may serve as tools for studying various lysosomal storage disorders such as Gaucher disease. In this regard, the most active compound was also evaluated as a potential pharmacological chaperone by assessing its effect on GBA activity in an assay employing fibroblasts from Gaucher patients.

Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

“…Two important prerequisites for a glycomimetic becoming a pharmacological chaperone candidate for a given LSD are high selectivity towards the lysosomal enzyme target and high endoplasmic reticulum (pH 7) versus lysosome (pH 4.5) binding affinity ratio [ 19 , 20 ]. The conversion of the amine-type endocyclic nitrogen of iminosugars into a pseudoamide-type functionality, with high sp 2 -hybridation character (sp 2 -iminosugars) [ 21 , 22 ], has demonstrated to be a very promising strategy to improve both parameters, with several sp 2 -iminosugar representatives under investigational or preclinical development for the LSDs Gaucher [ 23 , 24 , 25 , 26 , 27 ], Fabry [ 28 ], G M1 -gangliosidosis [ 29 , 30 ], and Tay-Sachs diseases [ 31 ].…”

Concise asymmetric synthesis of new enantiomericC-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease

“…26 N-Nonyldeoxynojirimycin (NN-DNJ), a potent ASSC, 22 was also evaluated as a reference compound and an IC50 value of 2.97 µM was found in accordance with previous studies. 29 Remarkably, removal of the hydroxymethyl moiety in 2 led to a marked increase in β-GCase inhibition. Indeed, the latter displayed an IC50 of 0.78 µM, a value about 10 times lower than the one reported for α-1-C-Octyl-DAB 1.…”

pH‐Responsive Trihydroxylated Piperidines Rescue The Glucocerebrosidase Activity in Human Fibroblasts Bearing The Neuronopathic Gaucher‐Related L444P/L444P Mutations in GBA1 Gene

“…Inspired by the pioneering results reported by C. Ortiz Mellet et al [16] and N. I. Martin et al [17] on a set of 1deoxynojirimycin and 1,5-dideoxy-1,5-imino-d-xylitol derivatives connected via an exocyclic N-thioureidic or N-guanidinium moiety to an orthoester containing a lipophilic chain, we report here our results on the use of the orthoester functionality linked to a trihydroxypiperidine iminosugar that has shown promising results as PC for GCase in our studies. [18,19,20] Both Ortiz Mellet's and Martin's groups employed a racemic aminodiol to build the orthoester moiety, thus forming mixtures of four diastereoisomers.…”