Dataset Information

Orthoester functionalized N-guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of ?-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 ?-glucocerebrosidase (GBA) at pH 7.0 with IC50 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.

SUBMITTER: Sevsek A

PROVIDER: S-EPMC6072142 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Orthoester functionalized <i>N</i>-guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of β-glucocerebrosidase.

Sevšek Alen A Sastre Toraño Javier J Quarles van Ufford Linda L Moret Ed E EE Pieters Roland J RJ Martin Nathaniel I NI

MedChemComm 20171010 11

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<sub>50</sub> 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 acti ...[more]

PMID: 30108721

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Project description:Mercaptoundecanoic acid (MUA) functionalized gold nanoparticles (AuNP-MUA) were synthesized and demonstrated to possess pH-triggered aggregation and re-dispersion, as well as the capability of phase transfer between aqueous and organic phases in response to changes in pH. The pH of aggregation for AuNP-MUA is consistent with the pKa of MUA (pH ~4) in solution, while AuNP-MUA phase transition between aqueous and organic phases occurs at pH ~9. The ion pair formation between the amine group in octadecylamine (ODA), the carboxylate group in MUA, and the hydrophobic alkyl chain of ODA facilitates the phase transfer of AuNP-MUA into an organic medium. The AuNP-MUA were investigated as a reusable catalyst in the catalytic reduction of 4-nitrophenol by borohydride-a model reaction for AuNPs. It was determined that 100% MUA surface coverage completely inhibits the catalytic activity of AuNPs. Decreasing the surface coverage was shown to increase catalytic activity, but this decrease also leads to decreased colloidal stability, recoverability, and reusability in subsequent reactions. At 60% MUA surface coverage, colloidal stability and catalytic activity were achieved, but the surface coverage was insufficient to enable redispersion following pH-induced recovery. A balance between AuNP colloidal stability, recoverability, and catalytic activity with reusability was achieved at 90% MUA surface coverage. The AuNP-MUA catalyst can also be recovered at different pH ranges depending on the recovery method employed. At pH ~4, protonation of the MUA results in reduced surface charge and aggregation. At pH ~9, ODA will form an ion-pair with the MUA and induce phase transfer into an immiscible organic phase. Both the pH-triggered aggregation/re-dispersion and aqueous/organic phase transfer methods were employed for catalyst recovery and reuse in subsequent reactions. The ability to recover and reuse the AuNP-MUA catalyst by two different methods and different pH regimes is significant, based on the fact that nanoparticle-catalyzed reactions may occur under different pH conditions.

Dataset Information

Orthoester functionalized N-guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of ?-glucocerebrosidase.

Publications

Orthoester functionalized <i>N</i>-guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of β-glucocerebrosidase.

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