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. 2023 Feb 13;62(8):e202217809.
doi: 10.1002/anie.202217809. Epub 2023 Jan 18.

Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors

Po-Sen Tseng  1   2   3 , Chennaiah Ande  1 , Kelley W Moremen  3   4 , David Crich  1   2   3
Affiliations

Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors

Po-Sen Tseng et al. Angew Chem Int Ed Engl. .

Abstract

Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of gluco and manno iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the gauche,gauche side chain conformations are 6- to 10-fold more potent than isosteric compounds with the gauche,trans conformation; a manno-configured iminosugar with the gauche,gauche conformation is a 27-fold better inhibitor than 1-deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization.

Keywords: Glycosidase; Iminosugar; Inhibitor; Methyl Group; Side Chain Conformation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of miglitol, zanamivir, and DADMe‐Immucillin‐G. Ac, acetyl.
Scheme 1
Scheme 1
Approximate aqueous solution populations of three staggered conformations of D‐glucopyranosides (equatorial OH at C2) and D‐mannopyranosides (axial OH at C2).
Figure 2
Figure 2
Relative rates of spontaneous hydrolysis of dinitrophenyl glycosides. DNP, 2,4‐dinitrophenyl.
Figure 3
Figure 3
Structures of castanospermine 1, 1‐deoxynojirimycin 2, glucohydroximolactam 5, 1‐deoxymannojirimycin 6, mannoimidazole 9, and the targeted inhibitors 3, 4, 7 and 8.
Figure 4
Figure 4
Partial X‐ray crystal structures of a) TmGH1 in complex with 2 (PDB ID: 2 J77), b) SsGH1 in complex with 5 (PDB ID: 1UWU), and c) BtMan2A in complex with 9 (PDB ID: 2VMF).
Scheme 2
Scheme 2
Synthesis of gluco iminosugars 2–4. Bn, benzyl; Tol, p‐tolyl; Trt, triphenylmethyl; DMAP, 4‐(dimethylamino)pyridine; PMB, p‐methoxybenzyl; TBAI, tetrabutylammonium iodide; DMF, N,N‐dimethylformamide; NIS, N‐iodosuccinimide; DMSO, dimethyl sulfoxide; MS, molecular sieves; DIPEA, N,N‐diisopropylethylamine; TFA, trifluoroacetic acid; Tf, trifluoromethanesulfonyl.
Scheme 3
Scheme 3
Synthesis of manno iminosugars 6–8. NBS, N‐bromosuccinimide.
See this image and copyright information in PMC

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