α-d-Mannose derivatives as models designed for selective inhibition of Golgi α-mannosidase II

N‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II

“…In the following subsections, the results from syntheses, biological assays, and molecular modeling are described and discussed in connection with the selected Golgi and lysosomal enzymes from GH family 38, which are abbreviated as follows: GMII (human Golgi α‐mannosidase II),, dGMII (fruit fly Golgi α‐mannosidase II, the homologue of mammalian Golgi α‐mannosidase II), GMIIb (fruit fly Golgi α‐mannosidase II with some distinct differences in comparison with other invertebrates and vertebrates), LMan (human lysosomal α‐mannosidase),, dLMan (fruit fly lysosomal α‐mannosidase, CG6206 gene product), LManII (fruit fly lysosomal α‐mannosidase, one of the acidic class II mannosidases), JBMan (Jack bean α‐mannosidase, the plant homologue of the acidic class II mannosidases) and bLMan (bovine lysosomal α‐mannosidase) . The fruit fly GMIIb, LManII, and JBMan were used for enzymatic assays in this study and our previous studies;– GMII, dGMII, LMan, dGMII, and JBMan were used in other studies;– and dGMII and bLMan are the enzymes with available crystal structures ,…”

“…[f] Calculated IC 50 values by Bobovská et al., based on measured in vitro assays with human α‐mannosidases . [g] IC 50 values measured for GMIIb and LManII by Poláková et al . [h] K i value measured for hERManI by Vallée et al .…”

“…It is known that certain polyhydroxypyrrolidines derived from natural 1,4‐dideoxy‐1,4‐imino‐ d ‐mannitol ( 24 ), an azafuranose analogue of mannose, are inhibitors of both GMII and LMan at the micromolar or millimolar level with a weak selectivity index to GMII observed for some N‐substituted derivatives, (for more details of the design of the structure of the inhibitors, see the Molecular Modeling section). Our research group has recently published a series of articles with mannose derivatives to find a structural feature of the inhibitor with impact on selectivity –. These studies revealed that a selective GMII inhibitor should have a linker of the benzyl type and a modified 6‐OH functional group.…”

Pharmacological Chaperones for the Treatment of α-Mannosidosis

“…36,37 The same holds true for the fivemembered carbocyclic inhibitor mannostatin A ( Figure 1) and polyhydroxylated pyrrolidine alkaloids. 38,39 Third, whereas polyhydroxylated piperidine-type iminosugar derivatives are generally good chaperone candidates for lysosomal enzymes with a matching configurational specificity, 18 the related manno-configured representative 1-deoxymannonojirimycin (DMJ) does not bind LAMAN; it is instead an inhibitor of the ER -mannosidase I and Golgi mannosidase I. 40 The neutral bicyclic analogue 5N,6O-oxomethylidenemannonojirimycin (OMJ), 41 a member of the sp 2 -iminosugar glycomimetic family (i.e., sugar look-alikes possessing a pseudoamide-type nitrogen atom, with a high sp 2 -hybridation character, at the position of the endocyclic oxygen in monosaccharides), 42 likewise failed to inhibit class II GH38 mannosidases.…”

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

“…Evaluation of these derivatives revealed that benzyl is a suitable hydrophobic linker. Some of them showed a weak inhibitory activity and selectivity against GMIIb [28–29]. Therefore, the structural design was further developed and a modification of the saccharide core, i.e., a replacement of the D-mannose unit to five-membered imino-L-lyxitol core has been suggested.…”