The structural basis of the inhibition of human α-mannosidases by azafuranose analogues of mannose

Abstract

Eight pyrrolidine, five pyrrolizidine and one indolizidine analogue(s) of the known alpha-mannosidase inhibitor, the azafuranose, 1,4-dideoxy-1,4-imino-D-mannitol (DIM), have been tested for inhibition of the multiple forms of alpha-mannosidase in human liver in vitro. Substitution of the ring nitrogen markedly decreased or abolished inhibition, but loss of the C-6 hydroxy group, as in 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM, enhanced inhibition, particularly of the lysosomal alpha-mannosidase. Addition of the anomeric substituent-CH2OH decreased inhibition. To be a potent inhibitor of the lysosomal, Golgi II and neutral alpha-mannosidases, a polyhydroxylated pyrrolidine must have the same substituents and chirality as mannofuranose at C-2, C-3, C-4 and C-5. These four chiral centres can also be part of a polyhydroxylated indolizidine, e.g. swainsonine, but not of a pyrrolizidine, e.g. cyclized DIM, ring-contracted swainsonine or 1,7-diepi-australine. DIM did not inhibit lysosomal alpha-mannosidase intracellularly, but both 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM caused accumulation of partially catabolized glycans in normal human fibroblasts. Analysis of these induced storage products by h.p.l.c. showed that both compounds also inhibited Golgi alpha-mannosidase II and that 6-deoxy-6-fluoro-DIM was also a good inhibitor of the endoplasmic reticulum alpha-mannosidase and specific lysosomal alpha (1-6)-mannosidase. None of the mannofuranose analogues appeared to inhibit Golgi alpha-mannosidase I.

Highly Diastereoselective Additions to Polyhydroxylated Pyrrolidine Cyclic Imines: Ready Elaboration of Aza‐Sugar Scaffolds To Create Diverse Carbohydrate‐Processing Enzyme Probes

“…For example, the five-membered ring isomer of DMJ is a potent class II a-d-mannosidase inhibitor. [8] Therefore, it is not generally straightforward to predict by an entirely logical design based upon configurational analogy the structure of the best inhibitor for a given carbohydrate-processing enzyme.…”

“…[7b] In addition, in certain cases, five-membered ring aza-sugars have been shown to give rise to higher inhibition than their six-membered ring counterparts [8] and subtle selectivities may be observed for five-versus sixmembered ring systems. For example, the five-membered ring isomer of DMJ is a potent class II a-d-mannosidase inhibitor.…”

Chemoenzymatic Synthesis and Inhibitory Activities of Hyacinthacines A1 and A2 Stereoisomers

“…In this context, it has been reported that australine analogues, that have the same configuration at C-7a, also inhibited human a-mannosidases. [23] Next, K i and type of inhibition were determined for the active compounds (Table 2, and the LineweaverBurke plots in Figure 1, see the Dixon plots in the Supporting information). Compound 6, K i = 4.7 mM, is a rather potent competitive inhibitor of a-d-glucosidase from rice, indicating that it would mimic the substrate and interact with the enzyme active site.…”

Synthesis of modified D-mannose core derivatives and their impact on GH38 α-mannosidases

“…[17][18][19] On the other hand, to the best of our knowledge the potency and selectivity of five-and six-member ring compounds containing endocyclic oxygen, such as derivatives of D-lyxose and D-mannose, have not been investigated in detail. These carbohydrate cores possess cis-configured OH groups at positions 2 and 3, which are necessary for binding to Zn 2+ co-factor at the active site of dGMII.…”