An efficient regioconvergent synthesis of 3-aza-obeticholic acid.

Bile acids (BAs) are steroidal molecules that play important roles in nutrient absorption, distribution, and excretion. They also act on specific receptors implicated in various metabolic and inflammatory diseases demonstrating their importance as potential drug candidates. Accordingly, there has been a concerted effort to develop new BA derivatives to probe structure-activity relationships with the goal of discovering BA analogues with enhanced pharmacological properties.

Site-Selective Photobromination of -Acetylated Carbohydrates in Benzotrifluoride.

Ferrier photobromination enables direct synthetic access to valuable 5--bromosugars but has limitations that restrict its broader use. The reaction is typically conducted in CCl heated at reflux with irradiation by broad spectrum, energy-inefficient heat lamps. Herein, we demonstrate that the reaction proceeds rapidly and efficiently with PhCF as a safe and environmentally benign alternative to CCl at mild temperatures (≤40 °C) inside a compact photoreactor fitted with purple light-emitting diodes (LEDs).

Novel 4-O-β-d-xylopyranosyl-3,6-anhydro-l-galactopyranosyl disaccharide units in a polysaccharide from the red alga Pyrophyllon subtumens.

Thalli of the endemic epiphytic New Zealand red seaweed Pyrophyllon subtumens are known to contain a high level of xylose and a notable amount of arabinose but the extracted polysaccharide has not been characterised. The linkage/substitution of individual sugars within the water-soluble polysaccharide extract and various derivatives were determined by chemical and spectroscopic methods. No 3-linked sugars nor any d-galactose were found, which excluded agar-, carrageenan- or mixed 3-linked/4-linked β-d-xylan-type polysaccharides found in many other red macroalgae.

The discovery of 12β-methyl-17-epi-18-nor-bile acids as potent and selective TGR5 agonists.

Recent discoveries have demonstrated that the physiological function of bile acids extends to the regulation of diverse signaling processes through interactions with nuclear and G protein-coupled receptors, most notably the Farnesoid-X nuclear receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Targeting such signaling pathways pharmacologically, i.e.

3α,7-Dihydroxy-14(13→12)-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson's Disease.

Parkinson's Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson's Disease.

Synthesis of Novel C/D Ring Modified Bile Acids.

Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure-activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a -12 methyl and a -13 to -14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids.

Synthesis of 12β-methyl-18--avicholic acid analogues as potential TGR5 agonists.

In the quest for new modulators of the Farnesoid-X (FXR) and Takeda G-protein-coupled (TGR5) receptors, bile acids are a popular candidate for drug development. Recently, bile acids endowed with a C16-hydroxy group emerged as ligands of FXR and TGR5 with remarkable agonistic efficacies. Inspired by these findings, we synthesised a series of C16-hydroxylated 12β-methyl-18--bile acid analogues from a Δ-12β-methyl-18--chenodeoxycholic acid intermediate (16), the synthesis of which we reported previously.

Synthesis of 12β-Methyl-18--bile Acids.

Decoupling the roles of the farnesoid X nuclear receptor and Takeda G-protein-coupled bile acid receptor 5 is essential for the development of novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. Herein, we describe the synthesis of 12β-methyl-18--bile acids which may serve as probes in the search for new bile acid analogues with clinical applicability. A Nametkin-type rearrangement was applied to protected cholic acid derivatives, giving rise to tetra-substituted Δ- and Δ-unsaturated 12β-methyl-18--bile acid intermediates ( and ).

Chemical Synthesis of the Antiviral Nucleotide Analogue ddhCTP.

3'-Deoxy-3',4'-didehydro-cytidine triphosphate (ddhCTP) is a novel antiviral molecule produced by the enzyme viperin as part of the innate immune response. ddhCTP has been shown to act as an obligate chain terminator of flavivirus and SARS-CoV-2 RNA-dependent RNA polymerases; however, further biophysical studies have been precluded by limited access to this promising antiviral. Herein, we report a robust and scalable synthesis of ddhCTP as well as the mono- and diphosphates ddhCMP and ddhCDP, respectively.

Synthesis of C-labelled sulfated N-acetyl-d-lactosamines to aid in the diagnosis of mucopolysaccharidosis diseases.

Morquio A syndrome is an autosomal mucopolysaccharide storage disorder that leads to accumulation of keratan sulfate. Diagnosis of this disease can be aided by measuring the levels of keratan sulfate in the urine. This requires the liquid chromatography tandem mass spectrometry (LCMS/MS) measurement of sulfated N-acetyl-d-lactosamines in the urine after cleavage of the keratan sulfate with keratanase II.

A fluorescent probe for GM1 gangliosidosis related β-galactosidase: N-(dansylamino)hexylaminocarbonylpentyl-1,5-dideoxy-1,5-imino-D-galactitol.

N-(Dansylamino)hexylaminocarbonylpentyl-1,5-dideoxy-1,5-imino-D-galactitol, a strong competitive inhibitor of β-galactosidase, enhances residual β-galactosidase activities in fibroblasts and serves as lead en route to diagnostic compounds for tracking the fate of mutant β-gal as well as aberrant GM1 gangliosides by live cell imaging.

1-Deoxy-D-galactonojirimycins with dansyl capped N-substituents as β-galactosidase inhibitors and potential probes for GM1 gangliosidosis affected cell lines.

Two simple and reliably accessible intermediates, N-carboxypentyl- and N-aminohexyl-1-deoxy-D-galactonojirimycin were employed for the synthesis of a set of terminally N-dansyl substituted derivatives. Reaction of the terminal carboxylic acid of N-carboxypentyl-1-deoxy-D-galactonojirimycin with N-dansyl-1,6-diaminohexane provided the chain-extended fluorescent derivative. Employing bis(6-dansylaminohexyl)amine, the corresponding branched di-N-dansyl compound was obtained.

Alkyl 4-chlorobenzoyloxycarbamates as highly effective nitrogen source reagents for the base-free, intermolecular aminohydroxylation reaction.

Ethyl- (7), benzyl- (8), tert-butyl- (9), and fluorenylmethyl-4-chlorobenzoyloxycarbamates (10) have been prepared as storable and easy-to-prepare nitrogen sources for use in the intermolecular Sharpless aminohydroxylation reaction and its asymmetric variant. These reagents were found to be effective under base-free reaction conditions. The scope and limitations of these methods have been explored using a variety of alkenes, among which, trans-cinnamates, in particular, proved to be good substrates.

1-Deoxynojirimycins with dansyl capped N-substituents as probes for Morbus Gaucher affected cell lines.

Cyclization by double reductive amination of d-xylo-hexos-5-ulose with methyl 6-aminohexanoate gave (methoxycarbonyl)pentyl-1-deoxynojirimycin. Reaction of the terminal carboxylic acid with N-dansyl-1,6-diaminohexane provided the corresponding chain-extended fluorescent derivative. By reaction with bis(6-dansylaminohexyl)amine, the corresponding branched di-N-dansyl compound was obtained.

A synchrotron radiation study of the one-dimensional complex of sodium with (1S)-N-carboxylato-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, a member of the 'immucillin' family.

The sodium salt of [immucillin-A-CO(2)H](-) (Imm-A), namely catena-poly[[[triaquadisodium(I)](mu-aqua)[mu-(1S)-N-carboxylato-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol][triaquadisodium(I)][mu-(1S)-N-carboxylato-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol]] tetrahydrate], {[Na(2)(C(12)H(13)N(4)O(6))(2)(H(2)O)(7)] x 4 H(2)O}(n), (I), forms a polymeric chain via Na(+)-O interactions involving the carboxylate and keto O atoms of two independent Imm-A molecules. Extensive N,O-H..

Third-generation immucillins: syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase.

ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe-ImmG (9) displayed the lowest inhibition constants of 2.

Chemotaxonomy of New Zealand red algae in the family Gigartinaceae (Rhodophyta) based on galactan structures from the tetrasporophyte life-stage.

The identification of the polysaccharides from tetrasporophytic plants of nine endemic New Zealand species belonging to the Gigartinaceae, 'Gigartina' ancistroclada, 'G.' grandifida, Gigartina dilatata, G. divaricata, G.

Transition state analogues in quorum sensing and SAM recycling.

Transition state structures can be derived from kinetic isotope effects and computational chemistry. Molecular electrostatic potential maps of transition states serve as blueprints to guide synthesis of transition state analogue inhibitors of target enzymes. 5'- Methylthioadenosine phosphorylase (MTAP) functions in the polyamine pathway by recycling methylthioadenosine (MTA) and maintaining cellular S-adenosylmethionine (SAM).

Azetidine based transition state analogue inhibitors of N-ribosyl hydrolases and phosphorylases.

N-ribosyl phosphorylases and hydrolases catalyze nucleophilic displacement reactions by migration of the cationic ribooxacarbenium carbon from the fixed purine to phosphate and water nucleophiles, respectively. As the lysis reaction progresses along the reaction coordinate, the distance between the purine and carbocation increases and the distance between carbocation and nucleophile decreases. Immucillin-H and DADMe-immucillin-H have been shown previously to be potent inhibitors of purine nucleoside phosphorylases and lie more toward the reactant and products side of this reaction coordinate, respectively.

L-Enantiomers of transition state analogue inhibitors bound to human purine nucleoside phosphorylase.

Human purine nucleoside phosphorylase (PNP) was crystallized with transition-state analogue inhibitors Immucillin-H and DADMe-Immucillin-H synthesized with ribosyl mimics of l-stereochemistry. The inhibitors demonstrate that major driving forces for tight binding of these analogues are the leaving group interaction and the cationic mimicry of the transition state, even though large geometric changes occur with d-Immucillins and l-Immucillins bound to human PNP.

Picomolar inhibitors as transition-state probes of 5'-methylthioadenosine nucleosidases.

Transition states can be predicted from an enzyme's affinity to related transition-state analogues. 5'-Methylthioadenosine nucleosidases (MTANs) are involved in bacterial quorum sensing pathways and thus are targets for antibacterial drug design. The transition-state characteristics of six MTANs are compared by analyzing dissociation constants (K(d)) with a small array of representative transition-state analogues.

Transition state analogue inhibitors of N-ribosyltransferases: new drugs by targeting nucleoside processing enzymes.

The characterization of the transition state structure of a number of N-ribosyltransferases has enabled the design and synthesis of some extremely powerful inhibitors of these enzymes. We have three generations of inhibitors for some nucleoside processing enzymes which are therapeutic targets, and the potency of these compounds confers special advantages in their development as new drugs against cancer, autoimmune diseases, microbial infections and malaria.

A practical synthesis of (3R,4R)-N-tert-butoxycarbonyl-4-hydroxymethylpyrrolidin-3-ol.

The title compound (+)-, required for production of transition state analogue inhibitors of enzymes involved in T-cell-dependent disorders, was synthesized in five steps. A 1,3-dipolar cycloaddition of the nitrone formed from formaldehyde and N-benzylhydroxylamine to diethyl maleate gave the racemic cis-isoxazolidine (+/-)-. Reduction of the N-O bond of this compound gave pyrrolidone (+/-)- in excellent yield.

Inhibition and structure of Trichomonas vaginalis purine nucleoside phosphorylase with picomolar transition state analogues.

Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms.

Structure and inhibition of a quorum sensing target from Streptococcus pneumoniae.

Streptococcus pneumoniae 5'-methylthioadenosine/S-adenosylhomocysteine hydrolase (MTAN) catalyzes the hydrolytic deadenylation of its substrates to form adenine and 5-methylthioribose or S-ribosylhomocysteine (SRH). MTAN is not found in mammals but is involved in bacterial quorum sensing. MTAN gene disruption affects the growth and pathogenicity of bacteria, making it a target for antibiotic design.