RESUMEN
Methods for the preparation of 1,3-amino alcohols and their derivatives containing two stereogenic centers usually involve a two-step installation of the chiral centers. An aldol-Tishchenko reaction of chiral sulfinimines which involves the first reported reduction of a CâN in this type of reaction is described. Two and even three chiral centers can be installed in one synthetic step, affording anti-1,3-amino alcohols in good diastereo- and enantioselectivity.
RESUMEN
The asymmetric alkylation of ketones represents a fundamental transformation in organic chemistry. Chiral auxiliaries have been used almost exclusively for this transformation. Herein we describe a strategy for the generation of enantiomerically enriched α-alkylated ketones up to an er of 83 : 17, using a chiral ligand protocol.
Asunto(s)
Hidrazonas/química , Esparteína/química , Alquilación , Ligandos , EstereoisomerismoRESUMEN
2-Heptyl-3-hydroxy-4-quinolone (PQS) and its precursor 2-heptyl-4-quinolone (HHQ) are key signalling molecules of the important nosocomial pathogen Pseudomonas aeruginosa. We have recently reported an interkingdom dimension to these molecules, influencing key virulence traits in a broad spectrum of microbial species and in the human pathogenic yeast Candida albicans. For the first time, targeted chemical derivatisation of the C-3 position was undertaken to investigate the structural and molecular properties underpinning the biological activity of these compounds in P. aeruginosa, and using Bacillus subtilis as a suitable model system for investigating modulation of interspecies behaviour.
Asunto(s)
4-Quinolonas/química , 4-Quinolonas/metabolismo , Bacillus subtilis/fisiología , Pseudomonas aeruginosa/fisiología , Quinolonas/química , Quinolonas/metabolismo , 4-Quinolonas/síntesis química , Biopelículas , Línea Celular , Humanos , Modelos Moleculares , Quinolonas/síntesis química , Percepción de QuorumRESUMEN
Coated capillary electrophoresis equipped with a boron doped diamond (BDD) electrode was developed for analysis of chemically synthesised 2-heptyl-3-hydroxy-4-quinolone (HHQ), 2-heptyl-3-hydroxy-4-quinolone (PQS), and 2-methyl analogues. Detection was then extended to biological samples. PQS and its biological precursor, HHQ, are two key regulators of bacterial cooperative behaviour known as quorum sensing in the nosocomial pathogen Pseudomonas aeruginosa. The fused silica capillary was coated with a thin layer of poly (diallyldimethylammonium) chloride to reverse the electroosmosis, allowing fast migration of PQS and HHQ with improved selectivity. The four model compounds were baseline resolved using a 50 mM H(3)PO(4)-Tris, pH 2.0 buffer with 20% (v/v) acetonitrile as buffer additive. With an injection time of 3 s, the detection limits of four analytes ranging from 60 to 100 nM (S/N=3) were observed when the BDD electrode was poised at +1.5 V vs. 3 M Ag/AgCl. As expected, no PQS or HHQ was detected from the supernatant of the P. aeruginosa (pqsA) mutant. A concentration of HHQ of 247 µM was detected from the supernatant of the pqsH mutant, which catalyses the conversion of HHQ to PQS in the presence of molecular oxygen by monooxygenase. The separation and detection scheme was applicable to follow the conversion of HHQ to PQS in P. aeruginosa when entering the stationary phase of growth. The results obtained by coated capillary electrophoresis with BDD detection were validated and compared well with LC-MS data.
Asunto(s)
Diamante/química , Electroforesis Capilar/instrumentación , Pseudomonas aeruginosa/química , Quinolonas/análisis , Biomarcadores/análisis , Boro/química , Quemaduras/microbiología , Electrodos , Electroforesis Capilar/métodos , Humanos , Límite de Detección , Polietilenos/química , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/aislamiento & purificación , Compuestos de Amonio Cuaternario/química , Percepción de Quorum , Reproducibilidad de los Resultados , Compuestos de PlataRESUMEN
The Pseudomonas quinolone signal (PQS), and its precursor 2-heptyl-4-quinolone (HHQ), play a key role in coordinating virulence in the important cystic fibrosis pathogen Pseudomonas aeruginosa. The discovery of HHQ analogues in Burkholderia and other microorganisms led us to investigate the possibility that these compounds can influence interspecies behaviour. We found that surface-associated phenotypes were repressed in Gram-positive and Gram-negative bacteria as well as in pathogenic yeast in response to PQS and HHQ. Motility was repressed in a broad range of bacteria, while biofilm formation in Bacillus subtilis and Candida albicans was repressed in the presence of HHQ, though initial adhesion was unaffected. Furthermore, HHQ exhibited potent bacteriostatic activity against several Gram-negative bacteria, including pathogenic Vibrio vulnificus. Structure-function analysis using synthetic analogues provided an insight into the molecular properties that underpin the ability of these compounds to influence microbial behaviour, revealing the alkyl chain to be fundamental. Defining the influence of these molecules on microbial-eukaryotic-host interactions will facilitate future therapeutic strategies which seek to combat microorganisms that are recalcitrant to conventional antimicrobial agents.