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

Abstract

Development of effective inhibitors of Golgi α-mannosidase II (GMII, E.C.3.2.1.114) with minimal off-target effects towards the phylogenetically-related lysosomal α-mannosidase (LMan, E.C.3.2.1.24) is a complex task due to complicated structural and...

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

“…The enzymes screened included two Golgi types (GMIIb and AMAN-2) and two lysosomal types (LManII and JBMan) (Table 1). As for the Golgi-type mannosidases, AMAN-2 is a more relevant enzyme because its amino acid sequence and the 3D structure of its active site are almost identical to those of human GMII [22].…”

“…The resulting biochemical evaluation revealed that imino-ᴅ-lyxitols with N-substituents possessing a polar basic functional group (amidine or guanidine) were 6-7 times less active toward AMAN-2 than GMIIb and had poorer selectivities (SI below 35). In contrast, imino-ᴅ-lyxitols bearing a nonpolar N-arylalkyl chain (benzyl, p-iodobenzyl, 2-naphthylmethyl) showed slightly higher inhibitory activities toward AMAN-2 and good to excellent selectivities [22], indicating that they are more suitable candidates for the next-generation design of potent and selective GMII inhibitors.…”

“…This class II mannosidase is inhibited by swainsonine very effectively (IC 50 = 1-5 × 10 −7 M) [18] and is frequently used as an acidic α-mannosidase model for structural and mechanistic inhibition studies [19][20][21]. On the other hand, Caenorhabditis elegans α-mannosidase II (AMAN-2) represents a Golgi-type α-mannosidase (GH38 family, E.C.3.2.1.114) and has the amino acid sequence and predicted 3D structure (based on a built homology model) of the active site almost identical to those of human GMII [22]. In addition, analysis of the available X-ray structures of GH38 enzymes such as dGMII [23], bovine lysosomal α-mannosidase II (bLMan) [17] and JBMan [24] showed that the active sites of Golgi and acidic α-mannosidases are structurally very similar.…”

“…Next, we turned our attention to modifications of 1,4-imino-ᴅlyxitol which configurationally better resembles swainsonine or DIM. The most promising N-substituents from the previous study were selected and a small library of N-substituted 1,4imino-ᴅ-lyxitols was prepared [22] (Figure 1). In addition, more relevant Caenorhabditis elegans α-mannosidase II (AMAN-2) (GH38 family, E.C.3.2.1.114) was included in the biochemical assay as its active site is more similar to human GMII than that of GMIIb.…”

“…Therefore, the current study is dedicated to designing further modifications of these analogs. This contribution deals with the synthesis of 1,4-imino-ᴅ-lyxitols altered at C-5 and substituted at the endocyclic nitrogen by the most successful arylalkyl chains (benzyl, p-iodobenzyl, 2-naphthylmethyl) found in our previous studies [22,30,33]. The biological activity of the novel synthesized compounds was evaluated toward the GH38 family enzymes (AMAN-2, GMIIb, fruit fly lysosomal α-mannosidase II (LManII) and JBMan).…”