Daniel Best

Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of N‐Alkylation on Hexosaminidase Inhibition

The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of β-GlcNAcases and β-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics.

Pharmacological chaperones for human α-N-acetylgalactosaminidase

Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal α-N-acetylgalactosaminidase (α-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human α-NAGAL both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human α-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-Å crystal structures of human α-NAGAL complexes reveal the different binding modes of iminosugars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases.

C-Branched Iminosugars: α-Glucosidase Inhibition by Enantiomers of isoDMDP, isoDGDP, and isoDAB–l-isoDMDP Compared to Miglitol and Miglustat

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 μM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.

Modular Synthesis of Arylacetic Acid Esters, Thioesters, and Amides from Aryl Ethers via Rh(II)-Catalyzed Diazo Arylation.

One-pot formation of arylacetic acid esters, thioesters, and amides via Rh(II)-catalyzed arylation of a Meldrums acid-derived diazo reagent with electron-rich arenes is described. The methodology was used to efficiently synthesize an anticancer compound.

1-De­oxy-1-fluoro-l-galactitol

The crystal structure unequivocally confirms the relative stereochemistry of the title compound, C6H13FO5 [6-deoxy-6-fluoro-d-galactitol or (2S,3R,4R,5S)-6-fluorohexane-1,2,3,4,5-pentaol]. The absolute stereochemistry was determined from the use of d-galactose as the starting material. In the crystal, the molecules are linked by O—H⋯O and O—H⋯F hydrogen bonds, forming a three-dimensional network with each molecule acting as a donor and acceptor for five hydrogen bonds.

(2S,3R,4R,5R)-3,4-Dihydr-oxy-5-(hydroxy-meth-yl)pyrrolidine-2-carboxylic acid [(2S,3R,4R,5R)-3,4-dihydr-oxy-5-(hydroxy-meth-yl)proline].

The crystal structure of the title compound, C6H11NO5, establishes the relative configuration at the four stereogenic centres; the absolute configuration is determined by the use of d-glucuronolactone as the starting material for the synthesis. Molecules are linked by intermolecular O—H⋯O and N—H⋯O hydrogen bonds into a three-dimensional network, with each molecule acting as a donor and acceptor for five hydrogen bonds.

tert-Butyl 2-de-oxy-4,5-O-isopropyl-idene-d-gluconate.

The relative configuration of tert-butyl 2-deoxy-4,5-O-isopropylidene-d-gluconate, C13H24O6, an intermediate in the synthesis of 2-deoxy sugars, was determined by X-ray crystallography, and the crystal structure consists of chains of O—H⋯O hydrogen-bonded molecules running parallel to the a axis. There are two molecules in the asymmetric unit. The absolute configuration was inferred from the use of d-erythronolactone as the starting material.

6-De­oxy-6-fluoro-d-galactose

The crystal structure unequivocally confirms the relative stereochemistry of the title compound, C6H11FO5. The absolute stereochemistry was determined by the use of d-galactose as the starting material. The compound exists as a three-dimensional O—H⋯O hydrogen-bonded network with each molecule acting as a donor and acceptor for four hydrogen bonds.

(1S)-1,2-O-Benzyl­idene-α-d-glucurono-6,3-lactone

X-ray crystallographic analysis has established that the major product from the protection of d-glucoronolactone with benzaldehyde is (1S)-1,2-O-benzylidene-α-d-glucurono-6,3-lactone, C13H12O6, rather than the R epimer. The crystal structure exists as O—H⋯O hydrogen-bonded chains of molecules lying parallel to the a axis. The absolute configuration was determined by the use of d-glucuronolactone as the starting material.

(4R)-4-(2-Allyl-2H-1,2,3-triazol-4-yl)-1,2-O-isopropyl-idene-l-threose.

X-ray crystallography unequivocally confirmed the structure of the title compound, C12H17N3O4, as (4R)-4-(2-allyl-2H-1,2,3-triazol-4-yl)-1,2-O-isopropylidene-l-threose. The absolute configuration was determined by the use of d-glucorono-3,6-lactone as the starting material. The crystal structure consists of hydrogen-bonded chains of molecules running parallel to the a axis. There are no unusual packing features.