Rhodri C. Griffiths

Inhibition of UDP-Gal Mutase and Mycobacterial Galactan Biosynthesis by Pyrrolidine Analogues of Galactofuranose

Abstract Some pyrrolidine analogues of galactofuranose - synthesised from carbohydrate lactones - are the first known inhibitors of E. coli K12 UDP-Gal mutase and mycobacterial galactan biosynthesis. This inhibition may form a new chemotherapeutic strategy for the treatment of human pathogens which contain integral galactofuranosyl structures such as tuberculosis and leprosy.

Glycosidase-inhibiting pyrrolidine alkaloids from Hyacinthoides non-scripta

Abstract The glycosidase-inhibiting pyrrolidine alkaloids (2 R ,3 R ,4 R ,5 R )-2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP), 2,5-dideoxy-2,5-imino- dl - glycero - d - manno -heptitol (homoDMDP), homoDMDP-7- O -apioside and 1,4-dideoxy-1,4-imino- d -arabinitol have been identified in the leaves of bluebells ( Hyacinthoides non-scripta ). HomoDMDP and homoDMDP-7- O -apioside are new natural products. Glycosidase inhibition by the aglycones is compared and could explain the symptoms of poisoning of livestock by bluebells.

Triazole carboxylic acids as anionic sugar mimics? Inhibition of glycogen phosphorylase by a d-glucotriazole carboxylate

Abstract Triazole-carboxylic acids related to d -glucose and d -galactose may be prepared by intramolecular [1,3]-dipolar cycloadditions of azides to unsaturated esters, followed by bromine oxidation of the resulting triazoline. Such materials may provide a series of anionic mimics of carbohydrates.

L-(+)-swainsonine and other pyrrolidine inhibitors of naringinase: Through an enzymic looking glass from D-mannosidase to L-rhamnosidase?

Abstract The synthesis and inhibitory properties towards naringinase (L-rhamnosidase) of L-(+)-swainsonine and of a number of more highly oxygenated analogues, and of some monocyclic equivalents, are reported. L-(+)-swainsonine and 1,4,6-trideoxy-1,4-imino-L-mannitol are powerful and specific inhibitors of naringinase.

Tetrazoles of manno- and rhamno-pyranoses: Contrasting inhibition of mannosidases by [4.3.0] but of rhamnosidase by [3.3.0] bicyclic tetrazoles

Abstract The synthesis of tetrazoles derived from D-manno and D-rhamnopyranose from L-gulonolactone and of L-rhamnopyranose from D-gulonolactone is described. These and other materials are assessed as inhibitors of glycosidases. The [4.3.0] tetrazoles of D-manno- and D-rhamnopyranose are inhibitors of human liver α-mannosidase. In contrast the D-furanose analogues show no inhibitory activity whilst the [3.3.0] L-rhamno furanotetrazole is a potent rhamnosidase inhibitor, a potential inhibitor of mycobacterial cell wall biosynthesis and as such may provide a strategy for the treatment of tuberculosis.

5-epi-Deoxyrhamnojirimycin is a potent inhibitor of an α-l-rhamnosidase: 5-epi-deoxymannojirimycin is not a potent inhibitor of an α-d-mannosidase

Abstract Whereas deoxyrhamnojirimycin (LRJ) 1 shows no significant inhibition of naringinase (an α- l -rhamnosidase), its C-5 epimer 2 is a potent and specific inhibitor of the enzyme and demonstrates the value of unambiguous chemical synthesis of such materials in the evaluation of their biological properties. In contrast, moderately weak inhibition towards an α- d -mannosidase is shown by both deoxymannojirimycin (DMJ) 5 and its C-5 epimer 6 . Mimics of l -rhamnose which are recognised by enzymes that synthesise or process l -rhamnose may inhibit either the biosynthesis of the sugar or its incorporation into mycobacterial cell walls, providing new strategies for the treatment of diseases such as tuberculosis and leprosy. Molecular modelling studies provide a rationale for the surprisingly potent activity of the C-5 epimer 2 compared with LRJ 1 and support a general hypothesis that potent piperidine glycosidase inhibitors mimic the 4 H 3 conformation of the relevant glycopyranosyl cation intermediate.

INHIBITION OF NARINGINASE (L-RHAMNOSIDASE) BY PIPERIDINE ANALOGUES OF L-RHAMNOSE: SCAFFOLDS FOR LIBRARIES INCORPORATING TRIHYDROXYPIPECOLIC ACIDS

Abstract L-Deoxyrhamnojirimycin 1 does not inhibit naringinase significantly but 5-epi-L-deoxyrhamnojirimycin 2 is a potent inhibitor. Conversely, α-C-glycosides of 1 are good inhibitors of L-rhamnosidase whereas those of 2 are not. Intermediate azabicyclic lactones are likely to be of use for the incorporation of a number of trihydroxypipecolic acids into peptide libraries.

Specific inhibition of glycogen phosphorylase by a spirodiketopiperazine at the anomeric position of glucopyranose

Abstract A key intermediate bicyclic lactone 6 allows control of the anomeric configuration of a spirodiketopiperazine of glucopyranose 5 which is a specific inhibitor of glycogen phosphorylase, showing no inhibition of α- and β-glucosidases, α- and β-galactosidases, β-N-acetylglucosaminidase, pectinase, xylanase or cellulase.

The isolation from Nicandra physalodes and identification of the 3-O-β-D-glucopyranoside of 1α,2β,3α,6α-tetrahydroxy-nor-tropane (Calystegine B1)

Abstract The isolation and identification of 3-O-β-D-glucopyranosyl-1α,2β,3α,6α-tetrahydroxy- nor -tropane from Nicandra physalodes Boehm. fruits (Solanaceae) is reported.

2-Hydroxycastanospermines (dihydroxy-L-swainsonines) from octonolactones: Inhibition of naringinase (L-rhamnosidase)

Short syntheses of 2S-2-hydroxycastanospermine, and 2R- and 2S-2-hydroxy-6-epicastanospermine — in which there are 6 adjacent chiral centres and 8 contiguous carbon atoms containing functional groups from eight carbon sugar lactones — depend on efficient cyclisations to give piperidines with trans-acetonides as protecting groups. Inhibition of naringinase (L-rhamnosidase) by 2S-2-hydroxy-6-epicastanospermine and 2S-2-hydroxycastanospermine may be due to a structural resemblance to the unnatural L-(+)-swainsonine.