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1.
Nat Commun ; 7: 12317, 2016 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-27502960

RESUMEN

Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [(13)C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction.


Asunto(s)
Permeabilidad de la Membrana Celular , Complejo I de Transporte de Electrón/deficiencia , Enfermedades Mitocondriales/metabolismo , Profármacos/farmacología , Ácido Succínico/farmacología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/metabolismo , Fibroblastos/patología , Humanos , Lactatos/metabolismo , Enfermedad de Leigh/patología , Metabolómica , Modelos Biológicos , Profármacos/química , Ácido Succínico/química
3.
Bioorg Med Chem Lett ; 23(23): 6248-53, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-24144851

RESUMEN

A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.


Asunto(s)
Cicloheptanos/química , Cicloheptanos/farmacología , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Animales , Broncoconstricción/efectos de los fármacos , Cicloheptanos/farmacocinética , Modelos Animales de Enfermedad , Cobayas , Humanos , Estructura Molecular , Antagonistas Muscarínicos/farmacocinética , Receptores Muscarínicos/química , Receptores Muscarínicos/metabolismo
6.
Org Biomol Chem ; 2(20): 2988-97, 2004 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-15480464

RESUMEN

Simple organocopper reagents are shown to undergo anti-stereoselective 1,4-addition to menthyloxy-substituted lactone 1 in the presence of BF3.OEt2; the Lewis acid causes partial epimerisation of the acetal centre after conjugate addition. Enolate alkylation of the adducts leads to di- and trisubstituted lactones that are converted, in favourable cases, into di- and trisubstituted cyclopentenones.


Asunto(s)
Cobre/química , Hidrocarburos Cíclicos/síntesis química , Modelos Químicos , Modelos Moleculares , Estructura Molecular
7.
Chembiochem ; 5(5): 657-65, 2004 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-15122638

RESUMEN

Chemical double mutant cycles have been used to quantify the interactions of halogens with the faces of aromatic rings in chloroform. The halogens are forced over the face of an aromatic ring by an array of hydrogen-bonding interactions that lock the complexes in a single, well-defined conformation. These interactions can also be engineered into the crystal structures of simpler model compounds, but experiments in solution show that the halogen-aromatic interactions observed in the solid state are all unfavourable, regardless of whether the aromatic rings contain electron-withdrawing or electron-donating substituents. The halogen-aromatic interactions are repulsive by 1-3 kJ mol(-1). The interactions with fluorine are slightly less favourable than with chlorine and bromine.


Asunto(s)
Halógenos/química , Hidrocarburos Aromáticos/química , Cristalografía por Rayos X , Halógenos/síntesis química , Hidrocarburos Aromáticos/síntesis química , Modelos Moleculares , Conformación Molecular , Estereoisomerismo
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