Reassessing the putative molecular Target(s) of potent antitubercular 2-(Alkylsulfonyl)acetamides.

Simple alkyl-sulfonylacetamides have potent antitubercular activity and significantly decrease mycolic acid levels in mycobacteria. Although these compounds were originally designed to inhibit the ketoacyl synthase domain of fatty acid synthase, structure-activity relationships and biochemical evidence do not fully support fatty acid synthase as the target. In 2004, an enzyme family involved in the activation and transfer of fatty acids as acyl-adenylates was identified in mycobacteria, separate from the universal acetyl-CoA carrier mechanism. These fatty acyl-AMP ligases (FAAL), encoded by the FadD family play important roles in the biosynthesis of mycolic acids along with fatty acid metabolism and are hypothesised here to be the molecular target of the sulfonylacetamides. Due to structural similarities with the ligase's natural substrate, it is believed these compounds are exerting action via competitive inhibition of these highly potent molecular targets. The primary aim of this investigation was to synthesize an extended library of sulfonylacetamide derivatives, building upon existing structural activity relations to validate the molecular mechanism with the aid of molecular modelling, while also attempting to explore novel structural isosteres for further drug design and development. Sulfonylacetamide derivatives were modified based on the putative molecular target resulting in derivatives with improved activities towards Mycobacteriumtuberculosis (H37Rv). The most active novel derivatives reported were 19, 22b, 22c and 46 displaying MIC90 levels of 1.4, 16.0, 13.0 and 5.9 µg/mL, respectively.

Synthesis of 1-Deoxymannojirimycin from d-Fructose using the Mitsunobu Reaction.

Three different Mitsunobu reactions have been investigated for the synthesis of 1-deoxymannojirimycin (1-DMJ) from d-fructose. The highest yielding and most practical synthesis can be undertaken on a 10 g scale with minimal chromatography. In the key step, N,O-di-Boc-hydroxylamine reacts with methyl 1,3-isopropylidene-α-d-fructofuranose under Mitsunobu conditions to give 14. Acidic hydrolysis affords nitrone 15, which reduces quantitatively via catalytic hydrogenolysis to afford 1-DMJ (4) in 55% overall yield from d-fructose (cf. 37% for azide route and 29% for nosyl route).

Recent results from non-basic glycosidase inhibitors: How structural diversity can inform general strategies for improving inhibition potency.

This review covers the literature in the past 15 years on glycosidase inhibitors lacking a basic nitrogen (for example iminosugars/azasugars) with a focus on natural terpenoids, and mono- and polycyclic aromatic hydrocarbons. From quite diverse structures, insight into inhibitor structural features that may be applicable to optimisation of all glycosidase inhibitors including iminosugars are identified.

Rational Design and Synthesis of Methyl-ß-d-galactomalonyl Phenyl Esters as Potent Galectin-8N Antagonists.

Galectin-8 is a ß-galactoside-recognizing protein having an important role in the regulation of bone remodeling and cancer progression and metastasis. Methyl ß-d-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8N extended carbohydrate-binding site. The chemically synthesized compounds had in vitro binding affinity toward galectin-8N in the range of 5-33 µM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds' ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in the SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8N by engaging its unique arginine (Arg59) and simultaneously cross-linking to another arginine (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to the discovery of novel monosaccharide galactose-based antagonists, with the strongest-binding compound (Kd 5.72 µM) holding 7-fold tighter than the disaccharide lactose.

Carbohydrate-based nanocarriers and their application to target macrophages and deliver antimicrobial agents.

Many deadly infections are produced by microorganisms capable of sustained survival in macrophages. This reduces exposure to chemadrotherapy, prevents immune detection, and is akin to criminals hiding in police stations. Therefore, the use of glyco-nanoparticles (GNPs) as carriers of therapeutic agents is a burgeoning field. Such an approach can enhance the penetration of drugs into macrophages with specific carbohydrate targeting molecules on the nanocarrier to interact with macrophage lectins. Carbohydrates are natural biological molecules and the key constituents in a large variety of biological events such as cellular communication, infection, inflammation, enzyme trafficking, cellular migration, cancer metastasis and immune functions. The prominent characteristics of carbohydrates including biodegradability, biocompatibility, hydrophilicity and the highly specific interaction of targeting cell-surface receptors support their potential application to drug delivery systems (DDS). This review presents the 21st century development of carbohydrate-based nanocarriers for drug targeting of therapeutic agents for diseases localized in macrophages. The significance of natural carbohydrate-derived nanoparticles (GNPs) as anti-microbial drug carriers is highlighted in several areas of treatment including tuberculosis, salmonellosis, leishmaniasis, candidiasis, and HIV/AIDS.

Facile amidinations of 2-aminophenylboronic acid promoted by boronate ester formation.

Amidine synthesis by amine addition to nitriles normally requires high temperatures or harsh catalysts. Here, we report that boronate esters can facilitate amidination of proximal amines with moderate heating. With amidines present in a number of drugs and the synthetic handle provided by the boron, this chemistry should find useful applications.

The crystal structures of 3-O-benzyl-1,2-O-iso-propyl-idene-5-O-methane-sulfonyl-6-O-tri-phenyl-methyl-α-d-gluco-furan-ose and its azide displacement product.

The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated. The stereochemical configurations of 3-O-benzyl-1,2-O-iso-propyl-idene-5-O-methane-sulfonyl-6-O-tri-phenyl-methyl-α-d-gluco-furan-ose, C36H38O8S (3) [systematic name: 1-[(3aR,5R,6S,6aR)-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl)-2-(trit-yloxy)ethyl methane-sulfonate], a stable inter-mediate, and 5-azido-3-O-benzyl-5-de-oxy-1,2-O-iso-propyl-idene-6-O-tri-phenyl-methyl-ß-l-ido-furan-ose, C35H35N3O5 (4) [systematic name: (3aR,5S,6S,6aR)-5-[1-azido-2-(trit-yloxy)eth-yl]-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the mol-ecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3, neighbouring mol-ecules are linked by C-H⋯O hydrogen bonds, forming chains along the b-axis direction. The chains are linked by C-H⋯π inter-actions, forming layers parallel to the ab plane. In the crystal of 4, mol-ecules are also linked by C-H⋯O hydrogen bonds, forming this time helices along the a-axis direction. The helices are linked by a number of C-H⋯π inter-actions, forming a supra-molecular framework.

A Simple Glycolipid Mimic of the Phosphatidylinositol Mannoside Core from Mycobacterium tuberculosis Inhibits Macrophage Cytokine Production.

Glycolipids from Mycobacterium tuberculosis have a profound impact on the innate immune response of the host. Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor that has been shown to bind trehalose dimycolate (TDM) from the mycobacterium and instigate intracellular signalling in the immune cell. There are structural similarities between the structures of TDM and phosphatidyl inositol mannoside (PIM). We thus hypothesized that these latter structures might also modulate an immune response in a similar manner. To test this, we synthesized a series of new mannose derivatives modified with fatty esters at the 6-position and assessed the release of inflammatory cytokines in human U937 macrophages under the induction of lipopolysaccharides (LPS) after glycolipid treatment. The results showed that the amount of two major cytokines-tumour necrosis factor (TNF)-α and interleukin (IL)-6-released from LPS-stimulated U937 cells decreased significantly when compared to a control upon treatment with the prepared glycolipids, thus indicating a reduction in cytokine production by the macrophages.

Back to (non-)Basics: An Update on Neutral and Charge-Balanced Glycosidase Inhibitors.

Glycosidases have important anti-cancer, anti-viral and anti-diabetic properties. This review covers the literature in the past 15 years since our initial review in this journal on "neutral" glycosidase inhibitors lacking a basic nitrogen found in iminosugars and azasugars or inhibitors that are neutral by virtue of being "charge-balanced" (zwitterionic). These structurally diverse inhibitors include lactones, lactams, epoxides such as cyclophellitol, and sulfonium ion derivatives of the natural product salacinol. Synthetic efforts toward cyclophillitol, salicinol and derivatives are also highlighted. Importantly, certain metals can inhibit glycosidases and care must be taken to remove residual catalysts from synthetic material to be tested against these enzymes.

Redox state influence on human galectin-1 function.

Intracellular and extracellular functions of human galectin-1 are influenced by its redox surroundings due to the presence of six cysteines within its amino acid sequence. Galectin-1 recognises intracellular-membrane-anchored Ras proteins that act as molecular switches regulating multiple signal transduction pathways. Human tumours frequently express Ras proteins that have become continuously activated due to point mutations, and this typically leads to deregulation of tumour cell growth, angiogenesis and invasion of metastatic cancer cells. Of significance is that galectin-1 preferably recognises H-Ras, one of the human Ras isoforms, and in particular galectin-1 recognition of the H-Ras farnesyl moiety is paramount to H-Ras membrane anchorage, a prerequisite step for H-Ras-mediated signal transduction regulating normal cell growth and malignant transformation. Herein the impact of the redox state on galectin-1's ability to interact with farnesyl analogues is explored. We demonstrate for the first time that reduced galectin-1 directly binds farnesyl and does so in a carbohydrate-independent manner. A K28T mutation abolishes farnesyl recognition by reduced dimeric galectin-1 whilst its carbohydrate-binding activity is retained, thus demonstrating the presence of an independent region on galectin-1 pertaining to growth inhibitory activity. Intriguingly, oxidised galectin-1 also recognises farnesyl, the biological implication of this novel finding is yet to be elucidated. Further, the redox effect on galectin-1 extracellular function was investigated and we discover that oxidised galectin-1 demonstrates a protective effect upon acute lymphoblastic leukaemia cells challenged by oxidative stress.

Direct Mitsunobu monoesterification of N-protected tobramycin competes with intramolecular pyrrolidine formation in ester prodrug synthesis.

Unlike the related aminoglycoside neomycin B, N-protected tobramycin can be selectively esterified at its sole, primary hydroxyl group under Mitsunobu conditions. However, depending on the reaction conditions, the reaction can take a different course with intramolecular cyclization of an N-Boc amine leading to formation of an unusual tobramycin pyrrolidine derivative as the major reaction product.

1-O-Benzyl-2,3-O-iso-propyl-idene-6-O-tosyl-α-l-sorbo-furan-ose.

IN THE TITLE COMPOUND (SYSTEMATIC NAME: {(3aS,5S,6R,6aS)-3a-[(benz-yloxy)meth-yl]-6-hy-droxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl}methyl 4-methyl-benzene-sulfonate), C23H28O8S, the absolute structure and relative stereochemistry of the four chiral centres have been established by X-ray crystallography, with the absolute configuration inferred from the use of l-sorbose as the starting material. The central furan-ose ring adopts a slightly twisted envelope conformation (with the C atom bearing the methyl-benzene-sulfonate substituent as the flap) from which three substituents depart pseudo-axially (-CH2-O-benzyl, -OH and one acetonide O atom) and two substituents pseudo-equatorially (-CH2-O-tosyl and second acetonide O atom). The dioxalane ring is in a flattened envelope conformation with the fused CH C atom as the flap. In the crystal, mol-ecules pack in columns along [010] linked by O-H⋯O hydrogen bonds involving the furan-ose hy-droxy group and furan-ose ether O atom.

Iodine-promoted ribosylation leads to a facile acetonide-forming reaction.

Iodine not only promotes smooth beta-selective glycosylation of ribose tetra-acetate under exceptionally mild conditions, it also catalyzes an expedient acetonide-forming reaction in this system when dry acetone is used as a solvent.

Boronolectin with divergent fluorescent response specific for free sialic acid.

A fluorescent boronate receptor with a unique response to free sialic acid has been developed; this divergent response system may find use in design of other fluorophores to discriminate between structurally similar analytes.

2-Propynyl 2-hydroxy-benzoate.

The title compound, C(10)H(8)O(3), has been synthesized as part of our investigations into the generation of new anti-bacterial agents and serves as a building block for the synthesis of compound libraries. The compound crystallizes with two independent mol-ecules in the asymmetric unit. The transoid propynyl ester groups are coplanar with the 2-hydroxy-benzoate group with maximum deviations of -0.3507 (3) and 0.1591 (3) Šfor the terminal carbons, with intra-molecular O-H⋯O hydrogen bonding providing rigidity to the structure and ensuring that the reactivity of the alkyne is not compromised by steric factors. The propynyl group forms inter-molecular C-H⋯O inter-actions with the phenolic O atom. Supra-molecular chains along the b axis are found for both mol-ecules with links by weak O-H⋯O inter-molecular inter-actions in the first independent mol-ecule and C-H⋯O inter-actions in the second.

3α-Azido-5-cholestene.

The crystal structure of the title compound, C(27)H(45)N(3), has been determined as part of our investigation into the hydro-phobic modification of amino-glycoside anti-biotics. The isopropyl group showed disorder for the tertiary carbon (equal occupancies), with high thermal motion for the peripheral atoms of the isopropyl and azide groups also apparent in the structure. The axial disposition of the azide group is consistent with the clean inversion of stereochemistry at C-3 under Mitsunobu conditions.

Painting the target around the arrow: two-step prodrug therapies from a carbohydrate chemist's perspective.

Selective accumulation of an exogenous enzyme or activating agent at a target cell allows use of prodrugs that will be unmasked only at this site. This can reduce the side effects of chemotherapy and allow more potent drugs to be used in various treatments. Examples of this two-step prodrug therapy include antibody- (ADEPT, ADAPT), genetic- (GDEPT, VDEPT) and macromolecule-based approaches (PDEPT, LEAPT). Carbohydrate chemistry and glycobiology feature in each of these areas and is the focus of this review.

Carbonic anhydrase inhibitors: inhibition of isozymes I, II, and IX with triazole-linked O-glycosides of benzene sulfonamides.

We report the synthesis of a series of benzene sulfonamides containing triazole-O-glycoside tails for evaluation as carbonic anhydrase (CA) inhibitors. These glycoconjugates were synthesized by the 1,3-dipolar cycloaddition reaction of 4-azidobenzenesulfonamide with O-propynyl glycosides. Compounds were assessed for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX (h = human). Against hCA I these compounds were either micromolar or low-nanomolar inhibitors, while against hCA II and IX inhibition in the range of 6.8-53 and 9.7-107 nM, respectively, was observed. The most potent inhibitor against hCA IX was the galactose derivative 8 (Ki = 9.7 nM); this is so far the most potent glycoconjugate inhibitor reported for the tumor-associated hCA IX. These carbohydrate-tethered sulfonamides may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly.