Microwave-assisted synthesis of N-glycolylneuraminic acid derivatives

A rapid, efficient and scalable synthesis of biologically-relevant N-glycolylneuraminic acid derivatives from the natural N-acetyl (Neu5Ac) precursors has been developed. Microwave irradiation provides accelerated de-N-acetylation compared to more traditional methods, with optimised NaOH-promoted de-N-acetylation in only 15 min. The prepared amines were readily re-N-acylated to afford the corresponding N-glycolyl (Neu5Gc) analogues.     

Determination of ethylenediaminetetraacetic acid, ethylenediaminedisuccinic acid and iminodisuccinic acid in cosmetic products by capillary electrophoresis and high performance liquid chromatography

A capillary electrophoresis (CE) and a high performance liquid chromatography (HPLC) method are described for the simultaneous determination of ethylenediaminetetraacetic acid (EDTA), S,S′-ethylenediaminedisuccinic acid (EDDS) and R,S-iminodisuccinic acid (IDS) complexing agents as their Fe(III) complexes in cosmetics like shower cream and foam bath. The non-biodegradable EDTA is used in combination with biodegradable analogues like EDDS and IDS in many commercial products. The HPLC method involves separation by reversed-phase ion pair chromatography on a C₁₈ column using methanol-formate buffer (20 mM tetrabutylammonium hydrogen sulfate, 15 mM sodium formate adjusted to pH 4.0 with formic acid) (10:90, v/v) as mobile solvent at a flow rate of 0.8 mL min⁻¹ at 24 °C using UV detection at 240 nm. The CE separation was performed in a fused silica capillary of 50 μm i.d. with the total length of 50 cm with a 10 mM MES and MOPSO (pH 5.5) at an applied voltage of −25 kV. The samples were introduced by applying a 50 mbar pressure for 2 s. Absorbances at 215 and 225 nm were monitored for the detection of the complexes. The methodology performance of the two methods was evaluated in terms of linearity, limit of detection (LOD), limit of quantitation (LOQ) and reproducibility. The LOD values obtained from HPLC are low when compared with CE. The applicability of both the methods was demonstrated for the analysis of cosmetic products such as shower cream and foam bath. The results obtained by both CE and HPLC were found to be comparable and in good agreement.     

Synthesis of benzo-, pyrido-, thieno- and imidazo-fused N-hydroxy-4-oxopyrimidine-2-carboxylic acid derivatives

N-Hydroxy-4-oxoquinazoline-2-carboxamide derivatives (cyclic hydroxamic acids) and related pyrido- and thieno-substituted analogues, as well as a N-hydroxyhypoxanthine-2-carboxamide were synthesised for the first time, by means of a four-step sequence that involves a smooth reaction of aminohydroxamates with methyl trimethoxyacetate. Other strategies were unsuccessful.     

Synthesis of difluoromethyl substituted lysophosphatidic acid analogues

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with nuclear hormone receptor PPARγ. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogues from (S)-1,2,4-butanetriol to give two 3-difluoromethyl substituted analogues of 2-acyl-sn-glycerol 3-phosphate. These compounds are migration-blocked analogues of the liable sn-2 LPA species. Preliminary studies were conducted on a nuclear reporter assay in which monocytic cells were transfected with a luciferase construct activated by a PPARγ nuclear receptor response element and have shown that the 3-difluoromethyl substituted analogues are fully active as natural LPA.     

Synthesis of phosphatase-resistant analogues of phytic acid (InsP6)

Phytic acid is enzymatically catabolized to numerous inositol polyphosphates and subsequently to myo-inositol and inorganic phosphate. These conversions are important in energy metabolism, metabolic regulation, and signal transduction pathways. A concise synthesis of phosphatase-resistant analogues of phytic acid (InsP₆) is described in which the P-1 phosphate has been replaced by phosphorothioate, phosphoroselenate, or methylphosphonate moieties. In addition, a new synthesis of P-1 tethered aminoalkyl InsP₆ and the corresponding affinity resin are described.     

Synthesis of indole analogues of the anti-Helicobacter pylori compounds CJ-13,015, CJ-13,102, CJ-13,104 and CJ-13,108

Racemic syntheses of indole analogues of four phthalide-containing anti-Helicobacter pylori agents CJ-13,015, CJ-13,102, CJ-13,104 and CJ-13,108 are reported via manipulation of a common intermediate. This intermediate was formed by the N-alkylation of 4,6-dimethoxyindole with a long chain bromide followed by further chain extension. Oxidation, acetylation, or Barton-McCombie deoxygenation of the intermediate followed by Wacker oxidation afforded three analogues whilst further reduction of one analogue afforded the final analogue.     

Bioluminescence activity of Latia luciferin analogues: replacement of the 2,6,6-trimethylcyclohexene ring onto the methyl-substituted phenyl groups

A series of Latia luciferin analogues having methyl-substituted phenyl groups instead of the natural 2,6,6-trimethylhexene ring was synthesized and their bioluminescence activity were measured. The Latia luciferase was found to be able to moderately recognize the appropriately methyl-substituted phenyl analogues with the same light production kinetics as that of natural luciferin.     

Synthesis of substituted benzimidazo[2,1-a]isoquinolines and its condensed analogues using Pd(0)-catalyzed cyclization/C-H activation

An efficient route for the synthesis of benzimidazo[2,1-a]isoquinolines and its condensed analogues has been developed via the palladium-catalyzed cyclization/C-H activation of N-allyl and N-methallyl derivatives of benzimidazoles.     

Synthesis of Latia luciferin benzoate analogues and their bioluminescent activity

The bioluminescent system of the univalve shell Latia neritoides exhibits a luciferin-luciferase reaction. We study the enol formate structure of Latia luciferin, which is expected to be important for luminescent activity. The Latia luciferin analogues with an enol substituted benzoate moiety were synthesized and their bioluminescent activity was measured. The Latia luciferin benzoate analogues delay emission for natural luciferin in bioluminescence, indicating that the Latia bioluminescent activity can be controlled by the design of the enol ester.     

Total synthesis of lansiumamides A and B and alatamide

The total syntheses of lansiumamide A, lansiumamide B and alatamide have been completed taking advantage of the dihalo-olefination of N-formylimides. The syntheses are convergent, flexible and allow for the generation of analogues not accessible through other routes.     

One-pot synthesis of benzimidazoles from gem-dibromomethylarenes using o-diaminoarenes

A one-pot synthesis of benzimidazoles from gem-dibromomethylarenes is described. The reaction shows the method to prepare a variety of benzimidazole analogues with excellent yield.     

A novel synthesis of N(1)-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

A new synthesis of N₁-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R₁ substituents.     

Synthesis of cyclopropanoid 2-epi-muramyldipeptide analogues as potential immunostimulants

The preparation of cyclopropanoid 2-epi-muramyldipeptide analogues from suitable substituted cyclopropylamines is described.     

Efficient synthesis and antioxidant activity of coelenterazine analogues

A convenient and highly convergent method for the synthesis of new imidazo[1,2-a]pyridine-based coelenterazine analogues is reported. The imidazo[1,2-a]pyridine core was constructed through a condensation between 2-aminopyridine analogues and arylglyoxals. Additionally, a new approach to the synthesis of benzylglyoxals was introduced. The imidazo[1,2-a]pyridines display moderate antioxidant activities at a low micromolar level in 2,2-diphenyl-1-picrylhydrazyl (DPPH).     

New tricyclic geldanamycin analogues from an engineered strain of Streptomyces hygroscopicus JCM4427

Two tricyclic geldanamycin analogues, DHQ5 (1) and DHQ6 (2), were produced by a combinatorial mutant (AC15) contained a site-directed mutagenesis on the geldanamycin polyketide synthase (PKS) gene with inactivation of the post-PKS tailoring genes (gel7) of Streptomyces hygroscopicus JCM4427. The structural diversity of tricyclic geldanamycin analogues is due to the formation of unusual additional rings, which are formed by alkylation of the C-21 position by C-12 in DHQ5 (1) and by electrophilic addition of the C-15 hydroxyl group to the double bond (C-8-C-9), which leads to the migration of the double bond (to C-7-C-8) and the elimination of a carbamoyloxy group in DHQ6 (2).     

Single- and double-chained truncated jaspine B analogues: asymmetric synthesis, biological evaluation and theoretical study of an unexpected 5-endo-dig process

An optimized synthesis of jaspine B analogues bearing an n-octyl or a p-fluorophenethyl lipophilic appendage was developed. Key to the approach was the use of acetylenic nucleophiles for the stereocontrolled introduction of the side chain and the implementation of a novel cyclization procedure to build the tetrahydrofuran ring. Three N-substituted amine or amide derivatives were also accessed. The biological activity of these four jaspine B analogues was shown to strongly depend on the nature of both the N-substituent and the aliphatic moiety connected to the tetrahydrofuran ring. Gratifyingly, the truncated jaspine B derivative proved to be a pro-apoptotic inhibitor of the conversion of ceramide into sphingomyelin. Finally, the efficient formation of a fused bis-furan derivative according to a 5-endo-dig process was observed under saponification conditions. On the basis of a theoretical study, a mechanistic pathway was delineated highlighting the Lewis acidity of the K⁺ ion as the driving force for this transformation in a strongly alkaline medium.     

Synthesis of granulatimide bis-imide analogues

The synthesis of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, structurally related to granulatimide is reported. These compounds can be considered as granulatimide analogues in which a maleimide heterocycle replaces the imidazole moiety. The synthesis of pyridino[2,3-b]dipyrrolo[3,4-e:3,4-g]indole-1,3,4,6-tetraones is also reported. In these compounds, a 7-azaindole unit replaces the indole moiety present in the granulatimide and isogranulatimide structures.     

Synthesis of a cell-permeable analogue of a glycosylphosphatidylinositol (GPI) intermediate that is toxic to the living bloodstream form of Trypanosoma brucei

The synthesis of two cell-permeable analogues related to a GPI intermediate is described for studies with living trypanosomes and human (HeLa) cells. One of the analogues is metabolised by the former GPI pathway and is toxic to the parasite Trypanosoma brucei but not to human cells.     

5-Trihydroxypropyl-dihydrouracil derivatives as precursors of 1-azasugars: application to the stereoselective synthesis of d-galacto-isofagomine

A new route for the synthesis of isofagomine analogues has been carried out by using as precursors enantiopure 5-trihydroxypropyl-dihydrouracil derivatives obtained from aldol-type addition of 1,3-dibenzyl-dihydrouracil to isopropylidene-protected glyceraldehyde. The synthesis of d-galacto-isofagomine is reported.     

(2S,5R/2R,5S)-Aminoethylpipecolyl aepip-aegPNA chimera: synthesis and duplex/triplex stability

This article reports the design and facile synthesis of novel chiral six-membered PNA analogues (2S,5R/2R,5S)-1-(N-Boc-aminoethyl)-5-(thymin-1-yl)pipecolic acid, aepipPNA IV that upon incorporation into standard aegPNA sequences effected stabilization of complexes with complementary target DNA. Substitution of aegPNA unit by the designed monomer at the C-terminus was more effective than substitution at N-terminus. The stabilizing behaviour improved with degree of substitution and was found to be dependent on their relative positions in the sequence. The six-membered piperidine ring in the design may freeze the rigid chair conformations and the relative stereochemistry of the substituents may in effect direct the complex formation with DNA/RNA by sequence-specific nucleobase recognition. In the present aepipPNA analogues, the l-trans stereochemical disposition of the substituents seems to lead to the favorable pre-organization of the PNA oligomers for complex formation with DNA. The results reported here further expand the repertoire of cyclic PNA analogues.