Selective Golgi α-mannosidase II inhibitors: N-alkyl substituted pyrrolidines with a basic functional group

Abstract

N-Alkylated 1,4-dideoxy-1,4-imino-L-lyxitols (N-alkylated polyhydroxypyrrolidines) differing in the alkyl chain length (from C7 to C14) and its capping functional group (methyl, amine, amidine and guanidine) have been synthesized. Based on a...

1,4-Dideoxy-1,4-imino-d- andl-lyxitol-based inhibitors bind to Golgi α-mannosidase II in different protonation forms

“…The synthetic approach to the target derivatives has been previously based on combining computer-assisted design with our previous findings on potent and selective GMII inhibitors. [12][13][14] Utilization of D-ribose as a starting material led to the derivatives having a 1,4-imino-1,4-dideoxy-L-lyxitol core. These derivatives were further substituted at the endocyclic nitrogen with an arylalkyl or alkyl group, and were optionally terminated with functional groups, such as halogen, amidine or guanidine.…”

“…The endocyclic nitrogen of core 6 was substituted similarly as reported previously 12,14 e.g. with (substituted) benzyl, dodecyl, alkyl amidine and alkyl guanidine functions.…”

“…Thus, AMAN-2 is a better enzyme model for searching of selective inhibitors of human GMII than Co(II)-dependent GMIIb used in our previous studies. [12][13][14] In addition, the enzyme assays were performed for the non-substituted derivative 6, DIM and swainsonine to compare the effect of N-substitution.…”

“…Recently, selective inhibitors of GMII were prepared and tested in biological assays (Fig. 1) [10][11][12][13][14] and the relevant literature has been reviewed in detail. [15][16][17][18] Other types of promising α-glycosidase inhibitors are multivalent compounds 19,20 and allosteric-site inhibitors.…”

Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

“…The intrinsic instability of aminoacetal functionalities makes impractical the synthesis of iminosugar O -glycosides or of analogues having other heteroatom substituents at the pseudoanomeric position. Instead, aglycon-like appendages have been incorporated through N -substitution − and C -branching approaches, − which accounts for the two major subclasses of iminosugar derivatives on record.…”