Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2

Abstract

Analogues of N‐butyl‐1‐deoxynojirimycin (NB‐DNJ) were prepared and assayed for inhibition of ceramide‐specific glucosyltransferase (CGT), non‐lysosomal β‐glucosidase 2 (GBA2) and the lysosomal β‐glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (K i values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a K i value of ≪14 nm for GBA1 inhibition and a K i of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had K i values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.

Sphingolipids and lipid rafts: Novel concepts and methods of analysis

“…Ceramide transport protein (Cert) mediates ceramide transport for sphingomyelin biosynthesis, which can be inhibited by HPA-12 (Berkes et al, 2016; Duris et al, 2011; Hanada, 2014, 2017; Hanada et al, 2003; Kumagai et al, 2005; Santos et al, 2015). Conversion of ceramide to glucosylceramide is the first step in biosynthesis of raft-associated glycosphingolipids and it is catalyzed by glucosylceramide synthase, a Golgi resident enzyme inhibited by l-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or deoxynojirimycin-type compounds (Bieberich et al, 1999; Gu et al, 2017; Mellor et al, 2004). Another Golgi-resident enzyme is sphingomyelin synthase 1 (SMS1) that catalyzes conversion of ceramide to sphingomyelin and is inhibited by D609 (Adada et al, 2016; Adibhatla et al, 2012; Chen and Cao, 2017; Holthuis and Luberto, 2010; Li et al, 2007; Luberto and Hannun, 1998; Tafesse et al, 2006; Taniguchi and Okazaki, 2014).…”

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

“…In modifying glycan acetals the endocyclic oxygen atom can also be exchanged, for example, to form iminosugars, carbasugars, or thiosugars [44,63,64,65,66,67,68,69,70]. In fact, iminosugars are found naturally and widespread among different plants and microorganisms [71,72]. Hemiaminals can be unstable and therefore the lack of a C-1 oxygen-bearing substituent has been useful for improving the structural stability of these derivatives.…”

“…On account of the endocyclic N atom which becomes positively charged at physiological pH, this class of molecules can mimic the charged oxocarbenium transition state observed in glycan-processing enzymes. Deoxynojirimycin is a well-studied naturally abundant iminosugar from which several drugs have been developed, including miglitol (for type II diabetes) and miglustat ( N -butyl-1-deoxynojirimycin; for lysosomal storage disease) [72,73].…”

Polyhydroxylated Cyclopentane β-Amino Acids Derived from d-Mannose and d-Galactose: Synthesis and Protocol for Incorporation into Peptides

“…In addition, it is feasible that these substituents on the cyclopentane rings could result in novel folding properties in β-peptides, which is a matter of evident interest in materials chemistry. Furthermore, polyhydroxylated cyclopentane β-amino acids have potential as clinical drugs , and biological tools. , Also, other molecules containing the polyhydroxylated cyclopentane ring, like some 4-amino-5-(hydroxymethyl)-1,2,3-cyclopentanetriols, have been described as potent glycosidase inhibitors. − …”