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1.
Angew Chem Int Ed Engl ; 60(47): 24844-24848, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34519147

RESUMO

Chiral indoline-2-carboxylic acid has been identified to enable a highly enantioselective Catellani-type annulation of (hetero)aryl, alkenyl triflate and conjugated vinyl iodides with 4-(bromomethyl)cyclohexanone, directly assembling a diverse range of chiral all-carbon bridged ring systems. Control experiments and DFT calculations suggest that the coordinating orientation of the chiral amino acid to the arylpalladium(II) center allows for high levels of stereochemical control.

2.
J Org Chem ; 84(7): 4381-4391, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30865449

RESUMO

An organocatalyzed dearomative aza-Michael/Michael addition cascade of 2-nitrobenzofurans and 2-nitrobenzothiophenes with 2-aminochalcones has been developed, opening a new channel to access a series of optically active tetrahydrobenzofuro[3,2- b]quinolines and tetrahydrobenzo[4,5]thieno[3,2- b]quinolines bearing three contiguous stereocenters with excellent diastereo- and enantioselectivities (all cases >20:1 dr, up to 99% ee). This study features the first asymmetric dearomative cascade reaction of 2-nitrobenzofurans and 2-nitrobenzothiophenes beginning with aza-Michael addition. The potential applications of the methodology were demonstrated by the preparative-scale experiment and the versatile transformations of the products.

3.
Biomed Chromatogr ; 31(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28621487

RESUMO

The aim of this study was to improve and validate a more stable and less time-consuming method based on liquid chromatography and tandem mass spectrometry (LC- MS/MS) for the quantitative measurement of imatinib and its metabolite N-demethyl-imatinib (NDI) in human plasma. Separation of analytes was performed on a Waters XTerra RP18 column (50 × 2.1 mm i.d., 3.5 µm) with a mobile phase consisting of methanol-acetonitrile-water (65:20:15, v/v/v) with 0.05% formic acid at a flow-rate of 0.2 mL/min. The Quattro MicroTM triple quadruple mass spectrometer was operated in the multiple-reaction-monitoring mode via positive electrospray ionization interface using the transitions m/z 494.0 → 394.0 for imatinib, m/z 479.6 → 394.0 for NDI and m/z 488.2 → 394.0 for IS. The method was linear over 0.01-10 µg/mL for imatinib and NDI. The intra- and inter-day precisions were all <15% in terms of relative standard deviation, and the accuracy was within ±15% in terms of relative error for both imatinib and NDI. The lower limit of quantification was identifiable and reproducible at 10 ng/mL. The method was sensitive, specific and less time-consuming and it was successfully applied in gastrointestinal stromal tumor patients treated with imatinib.


Assuntos
Antineoplásicos , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib , Adulto , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Feminino , Humanos , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/sangue , Mesilato de Imatinib/uso terapêutico , Limite de Detecção , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
4.
Acta Pharmacol Sin ; 37(11): 1442-1448, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27641736

RESUMO

AIM: Aspirin resistance has an incidence of 5%-65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A2 receptor (TXA2 receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by PLA2G7) and platelet endothelial aggregation receptor-1 (PEAR1, encoded by PEAR1) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1, TBXA2R, PLA2G7, PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. METHODS: A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB2 ELISA kit. RESULTS: Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233-0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080-6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590-42.638). CONCLUSION: A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931-rs7756935) polymorphisms.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Receptores de Superfície Celular/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética , Acidente Vascular Cerebral/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Povo Asiático , Isquemia Encefálica/sangue , Isquemia Encefálica/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Tromboxano B2/biossíntese , Tromboxano B2/sangue , Falha de Tratamento
5.
Acta Pharmacol Sin ; 37(7): 882-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27133299

RESUMO

AIM: There is a high incidence of the antiplatelet drug clopidogrel resistance (CR) in Asian populations. Because clopidogrel is a prodrug, polymorphisms of genes encoding the enzymes involved in its biotransformation may be the primary influential factors. The goal of this study was to investigate the associations of polymorphisms of CYP3A4, NR1I2, CYP2C19 and P2RY12 genes with CR in Chinese patients with ischemic stroke. METHODS: A total of 191 patients with ischemic stroke were enrolled. The patients were treated with clopidogrel for at least 5 days. Platelet function was measured by light transmission aggregometry. The SNPs NR1I2 (rs13059232), CYP3A4(*)1G (rs2242480), CYP2C19(*)2 (rs4244285) and P2RY12 (rs2046934) were genotyped. RESULTS: The CR rate in this population was 36%. The CYP2C19(*)2 variant was a risk factor for CR ((*)2/(*)2+wt/(*)2 vs wt/wt, OR: 2.366, 95% CI: 1.180-4.741, P=0.014), whereas the CYP3A4(*)1G variant had a protective effect on CR ((*)1/(*)1 vs (*)1G/(*)1G+(*)1/(*)1G, OR: 2.360, 95% CI: 1.247-4.468, P=0.008). The NR1I2 (rs13059232) polymorphism was moderately associated with CR (CC vs TT+TC, OR: 0.533, 95% CI: 0.286-0.991, P=0.046). The C allele in P2RY12 (rs2046934) was predicted to be a protective factor for CR (CC+TC vs TT, OR: 0.407, 95% CI: 0.191-0.867, P=0.018). In addition, an association was found between hypertension and CR (P=0.022). CONCLUSION: The individuals with both the CYP2C19(*)2 allele and hypertension are at high risk of CR during anti-thrombosis therapy. The CYP3A4(*)1G allele, P2RY12 (rs2046934) C allele and NR1I2 (rs13059232) CC genotype may be protective factors for CR. The associated SNPs studied may be useful to predict clopidogrel resistance in Chinese patients with ischemic stroke.


Assuntos
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Resistência a Medicamentos/genética , Receptores Purinérgicos P2Y12/genética , Receptores de Esteroides/genética , Ticlopidina/análogos & derivados , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Clopidogrel , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão/genética , Masculino , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária , Polimorfismo de Nucleotídeo Único , Receptor de Pregnano X , Fatores de Proteção , Fatores de Risco , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico
6.
Phytother Res ; 30(11): 1886-1892, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27487816

RESUMO

Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the Cmax and the AUC0-∞ of clopidogrel in a dose-dependent manner. As expected, pretreatment of high dose GBE significantly increased the Cmax and AUC0-∞ of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb-drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Ginkgo biloba/química , Interações Ervas-Drogas/imunologia , Extratos Vegetais/química , Ticlopidina/análogos & derivados , Animais , Clopidogrel , Masculino , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Ticlopidina/administração & dosagem , Ticlopidina/metabolismo , Ticlopidina/farmacocinética
7.
Org Lett ; 24(3): 826-831, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35029401

RESUMO

We disclose a Ag-catalyzed asymmetric interrupted Barton-Zard reaction of α-aryl-substituted isocyanoacetates with 2- and 3-nitroindoles, which enables the dearomatization of nitroindoles and hence offers rapid access to an array of optically active tetrahydropyrrolo[3,4-b]indole derivatives bearing three contiguous stereogenic centers, including two tetrasubstituted chiral carbon atoms with pretty outcomes (up to 99% yield, 91:9 dr, and 96% ee). The synthetic potential of the protocol was showcased by the gram-scale reaction and versatile transformations of the product.

8.
Org Lett ; 21(14): 5452-5456, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31251636

RESUMO

Organocatalytic asymmetric dearomatization of 3-nitroindoles and 3-nitrobenzothiophenes by reaction with ethyl 4-mercapto-2-butenoate has been developed. A range of chiral tetrahydrothiopheneindolines and tetrahydrothiophenebenzothiophenes bearing three contiguous stereocenters are obtained in high yields with good diastereoselectivities and excellent enantioselectivities. This is the first example of thiol-triggered catalytic asymmetric dearomatization of 3-nitroindoles and 3-nitrobenzothiophenes.

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