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New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.
Asunto(s)
Hipoglucemiantes , PPAR alfa , PPAR gamma , Animales , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Ratones , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/síntesis química , Humanos , Relación Estructura-Actividad , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Estructura Molecular , Relación Dosis-Respuesta a Droga , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Simulación del Acoplamiento Molecular , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismoRESUMEN
Enzymes and peptide catalysts consist of the same building blocks but require vastly different environments to operate best. Herein, we show that an enzyme and a peptide catalyst can work together in a single reaction vessel to catalyze a two-step cascade reaction with high chemo- and stereoselectivity. Abundant linear alcohols, nitroolefins, an alcohol oxidase, and a tripeptide catalyst provided chiral γ-nitroaldehydes in aqueous buffer. High yields (up to 92 %) and stereoselectivities (up to 98 % ee) were achieved for the cascade through the rational design of the peptide catalyst and the identification of common reaction conditions.
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Alcoholes , Péptidos , Estereoisomerismo , CatálisisRESUMEN
[This corrects the article DOI: 10.1021/acscatal.2c04444.].
RESUMEN
The challenges of light-dependent biocatalytic transformations of lipophilic substrates in aqueous media are manifold. For instance, photolability of the catalyst as well as insufficient light penetration into the reaction vessel may be further exacerbated by a heterogeneously dispersed substrate. Light penetration may be addressed by performing the reaction in continuous flow, which allows two modes of applying the catalyst: (i) heterogeneously, immobilized on a carrier, which requires light-permeable supports, or (ii) homogeneously, dissolved in the reaction mixture. Taking the light-dependent photodecarboxylation of palmitic acid catalyzed by fatty-acid photodecarboxylase from Chlorella variabilis (CvFAP) as a showcase, strategies for the transfer of a photoenzyme-catalyzed reaction into continuous flow were identified. A range of different supports were evaluated for the immobilization of CvFAP, whereby Eupergit C250 L was the carrier of choice. As the photostability of the catalyst was a limiting factor, a homogeneous system was preferred instead of employing the heterogenized enzyme. This implied that photolabile enzymes may preferably be applied in solution if repair mechanisms cannot be provided. Furthermore, when comparing different wavelengths and light intensities, extinction coefficients may be considered to ensure comparable absorption at each wavelength. Employing homogeneous conditions in the CvFAP-catalyzed photodecarboxylation of palmitic acid afforded a space-time yield unsurpassed by any reported batch process (5.7 g·L-1·h-1, 26.9 mmol·L-1·h-1) for this reaction, demonstrating the advantage of continuous flow in attaining higher productivity of photobiocatalytic processes.
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Biocatalysis, using enzymes for organic synthesis, has emerged as powerful tool for the synthesis of active pharmaceutical ingredients (APIs). The first industrial biocatalytic processes launched in the first half of the last century exploited whole-cell microorganisms where the specific enzyme at work was not known. In the meantime, novel molecular biology methods, such as efficient gene sequencing and synthesis, triggered breakthroughs in directed evolution for the rapid development of process-stable enzymes with broad substrate scope and good selectivities tailored for specific substrates. To date, enzymes are employed to enable shorter, more efficient, and more sustainable alternative routes toward (established) small molecule APIs, and are additionally used to perform standard reactions in API synthesis more efficiently. Herein, large-scale synthetic routes containing biocatalytic key steps toward >130 APIs of approved drugs and drug candidates are compared with the corresponding chemical protocols (if available) regarding the steps, reaction conditions, and scale. The review is structured according to the functional group formed in the reaction.
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Biocatálisis , Preparaciones FarmacéuticasRESUMEN
Chemical and biocatalytic synthesis of seven previously undescribed marchantin A ester derivatives has been presented. Chemical synthesis afforded three peresterified bisbibenzyl products (TE1-TE3), while enzymatic method, using lipase, produced regioselective monoester derivatives (ME1-ME4). The antiproliferative activities of all prepared derivatives of marchantin A were tested on MRC-5 healthy human lung fibroblast, A549 human lung cancer, and MDA-MB-231 human breast cancer cell lines. All tested esters were less cytotoxic in comparison to marchantin A, but they also exhibited lower cytotoxicity against healthy cells. Monoesters displayed higher cytotoxic activities than the corresponding peresterified products, presumably due to the presence of free catechol group. Monohexanoyl ester ME3 displayed the same IC50 like marchantin A against MDA-MB-231 cells, but the selectivity was higher. In this way, regioselective enzymatic monoesterification enhanced selectivity of marchantin A. ME3 was also the most active among all derivatives against lung cancer cells A549 with the slightly lower activity and selectivity in comparison to marchantin A.
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Antineoplásicos Fitogénicos/química , Bibencilos/química , Éteres Cíclicos/química , Células A549 , Antineoplásicos Fitogénicos/toxicidad , Bibencilos/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Esterificación , Éteres Cíclicos/toxicidad , HumanosRESUMEN
Biocatalytic oxidations mediated by laccases are gaining importance due to their versatility and beneficial environmental effects. In this study, the oxidation of 1,4-dihydropyridines has been performed using three different types of bacterial laccase-based catalysts: purified laccase from Bacillus licheniformis ATCC 9945a (BliLacc), Escherichia coli whole cells expressing this laccase, and bacterial nanocellulose (BNC) supported BliLacc catalysts. The catalysts based on bacterial laccase were compared to the commercially available Trametes versicolor laccase (TvLacc). The oxidation product of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained within 7-24â¯h with good yields (70-99%) with all three biocatalysts. The substrate scope was examined with five additional 1,4-dihydropyridines, one of which was oxidized in high yield. Whole-cell biocatalyst was stable when stored for up to 1-month at 4⯰C. In addition, evidence has been provided that multicopper oxidase CueO from the E. coli expression host contributed to the oxidation efficiency of the whole-cell biocatalyst. The immobilized whole-cell biocatalyst showed satisfactory activity and retained 37% of its original activity after three biotransformation cycles.