Design, Synthesis and Structural Analysis of Glucocerebrosidase Imaging Agents

Abstract

Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in β-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA-targeting activitybased probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism-based mode of action and uncover binding of the new N-functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6-fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA's preference for O6-and N-functionalised reagents, a bi-functional aziridine ABP was synthesized as a potentially more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes.

Recent advances in the accessibility, synthetic utility, and biological applications of aziridines

“…37 Later on, the same group, in collaboration with Luisi and coworkers, described the preparation of rare α-fluoroaziridines (100) by using the unknown LiCHFI as the homologating agent. In this case, it was prepared via lithium-proton exchange (deprotonation) in the presence of the lithium amide base LiN(i-Pr)Cy and ICH 2 F. After the homologation of the imine derivatives (98) with LiCHFI, a series of highly functionalized β-fluoroiodoamines (99) were isolated, which were subjected to deprotonation with NaH and after ring closure the desired α-fluoroaziridines (100) were achieved (Scheme 20path b). Only in the case of 102, the direct formation of the aziridine ring was observed (Scheme 20path c).…”

“…Among them a large variety of compounds are active against various types of oncological diseases. 97 However, several molecules displayed inhibitory activity towards other biological targets such proving to be good glucocerebrosidase (GBA), 98 cysteine proteases, 99 tuberculosis, 100 microbial, 101 and Leishmania 102 inhibitors (Fig. 1).…”

Organoselenium Compounds: Chemistry and Applications in Organic Synthesis

“…Motivated by the development of a potential treatment of Gaucher disease, the most frequent lysosomal storage disorder caused by inherited deficiencies in β‐glucocerebrosidase, [355] N ‐alkyl deoxynojirimycin derivatives possessing a selenoureido moiety of formula 439 have been synthesized [356] . In fact, 439 has been designed as a dual target molecule towards the enzyme responsible for Gaucher disease, a β‐glucosidase, and acetylcholinesterase, which is associated with the neurological complications of this disease.…”

“…In addition, the organoselenium pseudodisaccharides of general formula 432 can be straightforwardly prepared by an S N 2 reaction between a diselenide like 438, converted into selenole ion by treatment with sodium borohydride, and tosylate 437 (Scheme 92). [354] Motivated by the development of a potential treatment of Gaucher disease, the most frequent lysosomal storage disorder caused by inherited deficiencies in β-glucocerebrosidase, [355] Nalkyl deoxynojirimycin derivatives possessing a selenoureido moiety of formula 439 have been synthesized. [356] In fact, 439 has been designed as a dual target molecule towards the enzyme responsible for Gaucher disease, a β-glucosidase, and acetylcholinesterase, which is associated with the neurological complications of this disease.…”

Quantitation of a Urinary Profile of Biomarkers in Gaucher Disease Type 1 Patients Using Tandem Mass Spectrometry

“…This leads to the accumulation of several glycosphingolipid species in numerous organs and tissues, namely the spleen, the liver, and the bone marrow [ 2 ]. This ultimately impairs the natural homeostasis of the tissue and results in multisystemic clinical manifestations varying in frequency and severity [ 3 ]. While GD shows a wide continuum of phenotypes ranging from asymptomatic to early death, patients are classified into three subtypes based on the severity of the clinical manifestations and degree of neurological involvement [ 4 , 5 ].…”