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1.
J Med Chem ; 52(23): 7446-57, 2009 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-19775168

RESUMEN

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.


Asunto(s)
Azetidinas/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Cetólidos/química , Cetólidos/farmacología , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Animales , Bacterias/efectos de los fármacos , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Susceptibilidad a Enfermedades , Descubrimiento de Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Cetólidos/efectos adversos , Cetólidos/síntesis química , Cetólidos/uso terapéutico , Ratones , Pruebas de Sensibilidad Microbiana
2.
J Org Chem ; 74(3): 1388-90, 2009 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-19099410

RESUMEN

Herein described is an operationally simple procedure for generating benzyl indium species from readily available benzyl bromides and indium metal followed by in situ palladium-catalyzed coupling with aryl halides. The procedure provides diarylmethanes in modest to excellent yield and tolerates a variety of functional groups in both coupling partners.


Asunto(s)
Compuestos de Bencidrilo/síntesis química , Compuestos de Bencilo/química , Indio/química , Yodobencenos/química , Compuestos Organometálicos/química , Compuestos de Bencilo/síntesis química , Catálisis , Hidrocarburos Bromados/química , Compuestos Organometálicos/síntesis química , Paladio/química
3.
Chem Res Toxicol ; 20(10): 1488-97, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17892269

RESUMEN

The hypothesis that the psychological side effects associated with the anesthetic phencyclidine (PCP) may be caused by irreversible binding of PCP or its reactive metabolite(s) to critical macromolecules in the brain has resulted in numerous in vitro studies aimed at characterizing pathways of PCP bioactivation. The studies described herein extend the current knowledge of PCP metabolism and provide details on a previously unknown metabolic activation pathway of PCP. Following incubations with NADPH- and GSH-supplemented human and rat liver microsomes and recombinant P450 2B enzymes, two sulfhydryl conjugates with MH+ ions at 547 and 482 Da, respectively, were detected by LC/MS/MS. Shebley et al. [(2006) Drug Metab. Dispos. 34, 375-383] have also observed the GSH conjugate 1 with MH+ at 547 Da in PCP incubations with rat P450 2B1 and rabbit P450 2B4 isoforms fortified with NADPH and GSH. The molecular weight of 1 is consistent with a bioactivation pathway involving Michael addition of the sulfhydryl nucleophile to the putative 2,3-dihydropyridinium metabolite of PCP obtained via a four-electron oxidation of the piperidine ring in the parent compound. The mass spectrum of the novel GSH adduct 2 with an MH+ ion at 482 Da was suggestive of a unique PCP bioactivation pathway involving initial ortho- or para-hydroxylation of the phenyl ring in PCP followed by spontaneous decomposition to piperidine and an electrophilic quinone methide intermediate, which upon reaction with GSH yielded adduct 2. The LC retention times and mass spectral properties of enzymatically generated 2 were identical to those of a reference standard obtained via reaction of GSH with synthetic p-hydroxyPCP in phosphate buffer (pH 7.4, 37 degrees C). 1H NMR and 13C-distortionless enhancement by polarization transfer (DEPT) NMR spectral studies on synthetically generated 2 suggested that the structural integrity of the p-hydroxyphenyl and cyclohexyl rings likely was preserved and that the site of GSH addition was the benzylic carbon joining the two scaffolds. The formation of 2 in human microsomes was reduced upon addition of the dual P450 2C19/P450 2B6 inhibitor (+)- N-3-benzylnirvanol. Consistent with this finding, both recombinant P450 2B6 and P450 2C19 catalyzed PCP bioactivation to 2. In the absence of GSH, synthetic p-hydroxyPCP underwent rapid decomposition (t1/2 approximately 5.2 min) to afford p-hydroxyphenylcyclohexanol and p-hydroxyphenylcyclohexene, presumably via the quinone methide intermediate. Overall, our findings on the facile degradation of synthetic p-hydroxyPCP to yield an electrophilic quinone methide intermediate capable of reacting with nucleophiles, including GSH and water, suggest an inherent instability of the putative phenolic PCP metabolite. Thus, if formed enzymatically in vivo, p-hydroxyPCP may not require further metabolism to liberate the quinone methide, which can then react with macromolecules. To our knowledge, this is the first report of a quinone methide reactive intermediate obtained in human-liver microsomal metabolism of PCP.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2B1/metabolismo , Alucinógenos/metabolismo , Indolquinonas/metabolismo , Microsomas Hepáticos/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Fenciclidina/metabolismo , Animales , Biotransformación , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP2B6 , Glutatión/metabolismo , Humanos , Ratas , Proteínas Recombinantes/metabolismo , Espectrometría de Masa por Ionización de Electrospray
5.
J Am Chem Soc ; 124(42): 12557-65, 2002 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-12381200

RESUMEN

A catalytic amount of Pd(dba)(2) ligated by either carbene precursor N,N'-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium (1) or P(t-Bu)(3) mediated the coupling of aryl halides and ester enolates to produce alpha-aryl esters in high yields at room temperature. The reaction was highly tolerant of functionalities and substitution patterns on the aryl halide. Improved protocols for the selective monoarylation of tert-butyl acetate and the efficient arylation of alpha,alpha-disubstituted esters were developed with LiNCy(2) as base and P(t-Bu)(3) as ligand. In addition, tert-butyl esters, such as those of Naproxen and Flurbiprofen, were prepared from tert-butyl propionate and aryl bromides in high yields in the presence of Pd(dba)(2) and the hindered, saturated heterocyclic carbene ligand precursor.


Asunto(s)
Ésteres/síntesis química , Hidrocarburos Halogenados/química , Paladio/química , Acetatos/química , Aminas/química , Catálisis , Hidrocarburos Aromáticos/síntesis química , Hidrocarburos Aromáticos/química , Cinética , Ligandos , Compuestos Organometálicos/química , Temperatura
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