RESUMO
We report chemoselective hydrogenation of α,ß-unsaturated anilides catalyzed by the palladium-polymethylhydrosiloxane (hydrosilane) system. Under this condition, C-C double bonds are selectively reduced while other reducible groups such as acetyl groups, nitro groups, nitriles, benzyl ethers, and halogens are largely tolerated. This chemoselective hydrogenation is promising for the development of efficient synthetic routes for multi-functional compounds.
Assuntos
Paládio , Hidrogenação , Paládio/química , Catálise , Estrutura Molecular , Silanos/químicaRESUMO
The reductive Heck hydroarylation of unactivated alkenes has emerged as an essential reaction for regioselective hydroarylation. Herein, we report a palladium-catalyzed reductive Heck hydroarylation of unactivated alkenes under mild conditions with enhanced functional group tolerance using hydrosilane as the reducing reagent. Under the optimal conditions, the alkylarene yields increased, resulting in minimal undesired products. Mechanistic studies using deuterated reagents indicated the involvement of two competing catalytic cycles.
RESUMO
Background and purpose: In this study, we aimed to elucidate the action mechanisms of propofol, particularly those underlying propofol-induced protein kinase C (PKC) translocation. Experimental approach: Various PKCs fused with green fluorescent protein (PKC-GFP) or other GFP-fused proteins were expressed in HeLa cells, and their propofol-induced dynamics were observed using confocal laser scanning microscopy. Propofol-induced PKC activation in cells was estimated using the C kinase activity receptor (CKAR), an indicator of intracellular PKC activation. We also examined PKC translocation using isomers and derivatives of propofol to identify the crucial structural motifs involved in this process. Key results: Propofol persistently translocated PKCα conventional PKCs and PKCδ from novel PKCs (nPKCs) to the plasma membrane (PM). Propofol translocated PKCδ and PKCη of nPKCs to the Golgi apparatus and endoplasmic reticulum, respectively. Propofol also induced the nuclear translocation of PKCζ of atypical PKCs or proteins other than PKCs, such that the protein concentration inside and outside the nucleus became uniform. CKAR analysis revealed that propofol activated PKC in the PM and Golgi apparatus. Moreover, tests using isomers and derivatives of propofol predicted that the structural motifs important for the induction of PKC and nuclear translocation are different. Conclusion and implications: Propofol induced the subtype-specific intracellular translocation of PKCs and activated PKCs. Additionally, propofol induced the nuclear translocation of PKCs and other proteins, probably by altering the permeability of the nuclear envelope. Interestingly, propofol-induced PKC and nuclear translocation may occur via different mechanisms. Our findings provide insights into the action mechanisms of propofol.
RESUMO
A plethora of dimeric natural products exist with diverse chemical structures and biological activities. A major strategy for dimerization is aryl coupling catalyzed by cytochrome P450 or laccase. Actinorhodin (ACT) from Streptomyces coelicolor A3(2) has a dimeric pyranonaphthoquinone structure connected by a C-C bond. In this study, we identified an NmrA-family dimerizing enzyme, ActVA-ORF4, and a cofactor-independent oxidase, ActVA-ORF3, both involved in the last step of ACT biosynthesis. ActVA-ORF4 is a unique NAD(P)H-dependent enzyme that catalyzes the intermolecular C-C bond formation using 8-hydroxydihydrokalafungin (DHK-OH) as the sole substrate. On the other hand, ActVA-ORF3 was found to be a quinone-forming enzyme that produces the coupling substrate, DHK-OH and the final product, ACT. Consequently, the functional assignment of all essential enzymes in the biosynthesis of ACT, one of the best-known model natural products, has been completed.
Assuntos
Antraquinonas , Quinonas , Quinonas/química , Antraquinonas/química , Oxigenases de Função MistaRESUMO
The asymmetric total synthesis of angucycline antibiotics (S)-brasiliquinones B and C was accomplished. The benz[a]anthraquinone core was constructed via oxidative cyclization of a hydroquinone-silyl enol ether hybrid. The resultant pentacyclic acetal was converted to the silyl enol ether, which was treated with Pd(II)/O2 to afford brasiliquinone C, after multistep conversion including dehydrogenation, desilylation and deacetalization, and hydroquinone oxidation. The (S)-configuration of natural brasiliquinones was confirmed based on the stereochemical correlation with the synthetic products.
Assuntos
Acetais , Éter , Álcoois , Antraquinonas , Antibacterianos , Ciclização , Éteres , Etil-Éteres , Hidroquinonas , Estrutura Molecular , Estresse Oxidativo , EstereoisomerismoRESUMO
In this article, we report the total synthesis of 6-deoxydihydrokalafungin (DDHK), a key biosynthetic intermediate of a dimeric benzoisochromanequinone antibiotic, actinorhodin (ACT), and its epimer, epi-DDHK. Tricyclic hemiacetal with 3-siloxyethyl group was subjected to Et3SiH reduction to establish the 1,3-cis stereochemistry in the benzoisochromane, and a subsequent oxidation/deprotection sequence then afforded epi-DDHK. A bicyclic acetal was subjected to AlH3 reduction to deliver the desired 1,3-trans isomer in an approximately 3:1 ratio, which was subjected to a similar sequence to that used for the 1,3-cis isomer that successfully afforded DDHK. A semisynthetic approach from (S)-DNPA, an isolable biosynthetic precursor of ACT, was also examined to afford DDHK and its epimer, which are identical to the synthetic products.
Assuntos
Técnicas de Química Sintética , Antraquinonas/síntese química , Antraquinonas/química , Antraquinonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Oxirredução , EstereoisomerismoRESUMO
Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N3 can be more easily alkylated than N1 under basic conditions. In this study, we explored methods for direct N1-selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide (tBuOK) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N1-monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.
Assuntos
Anticonvulsivantes/química , Hidantoínas/química , Fenitoína/química , Potássio/química , Anticonvulsivantes/síntese química , Azidas/química , Butanóis/química , Hidantoínas/síntese química , Metilação , Fenitoína/síntese químicaRESUMO
Stable-isotope-labeled probes suitable for magnetic resonance imaging (MRI) would have various potential medical applications, such as tumor imaging. Here, with the aim of developing MRI probes targeting peptide transporters, we synthesized a series of [19F]dipeptides by introducing one or two fluorine atoms or a trifluoromethyl group into the benzene ring of l-phenylalanyl-ψ[CS-N]-l-alanine (Phe-ψ-Ala), which is resistant to cleavage by peptidases. The mono- and difluoro dipeptides were efficiently transported by PEPT1 and PEPT2. Moreover, (3,5)-difluoro Phe-ψ-Ala was metabolically stable in human hepatocyte culture, and had a low distribution volume in mice. An acute toxicity study in mice revealed no apparent effect on body weight or behavior. The biodistribution and biodynamics of this compound could be clearly visualized by 19F-MRI in vivo, although specific signal enhancement was observed only in the bladder, but not in the tumor of tumor-xenografted mice. Although there was no specific signal enhancement of the tested compound at the tumor, the present study provides some challenging points regarding 19F-MRI probes for future investigation.
Assuntos
Dipeptídeos/farmacocinética , Neoplasias/diagnóstico por imagem , Transportador 1 de Peptídeos/metabolismo , Simportadores/metabolismo , Animais , Transporte Biológico , Dipeptídeos/química , Dipeptídeos/toxicidade , Imagem por Ressonância Magnética de Flúor-19 , Células HEK293 , Células HeLa , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Tecidual , Testes de Toxicidade AgudaRESUMO
Flavin-dependent monooxygenases are ubiquitous in living systems and are classified into single- or two-component systems. Actinorhodin, produced by Streptomyces coelicolor, is a representative polycyclic polyketide that is hydroxylated through the action of the two-component ActVA-5/ActVB hydroxylase system. These homologous systems are widely distributed in bacteria, but their reaction mechanisms remain unclear. This in vitro investigation has provided chemical proof of two consecutive hydroxylations via hydroxynaphthalene intermediates involved in actinorhodin biosynthesis. The ActVA-5 oxygenase component catalyzed a stepwise dihydroxylation of the substrate, whereas the ActVB flavin reductase not only supplied a reduced cofactor, but also regulated the quinone-hydroquinone interconversion of an intermediate. Our study provides clues for understanding the general biosynthetic mechanisms of highly functionalized aromatic natural products with structural diversity.
Assuntos
Antibacterianos/biossíntese , Oxigenases de Função Mista/metabolismo , Streptomyces coelicolor/metabolismo , Antraquinonas/metabolismo , Proteínas de Bactérias/metabolismo , Hidroxilação , CinéticaRESUMO
N-Methyl-d-aspartate (NMDA) receptors have been implicated in learning and memory, and may also play a central role in various conditions leading to neuronal degradation. NMDA receptor antagonists could therefore be of therapeutic benefit for a number of neurological disorders. We have designed hybrid compounds of polyamines and memantine, both of which function as NMDA channel blockers. The triamine derivative with a guanidine moiety showed more potent antagonistic activity than memantine.
Assuntos
Desenho de Fármacos , Memantina/química , Fármacos Neuroprotetores/síntese química , Poliaminas/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Animais , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Ligação Proteica , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Xenopus laevis/crescimento & desenvolvimentoRESUMO
The chairs of each of the 8 Special Interest Groups of the Board of Pharmaceutical Sciences of the International Pharmaceutical Federation have compiled opinions with regard to major challenges for the pharmaceutical sciences over the next 5-10 years. Areas covered are drug design and discovery, natural products, formulation design and pharmaceutical technology, pharmacokinetics/pharmacodynamics and systems pharmacology, translational and personalized medicine, biotechnology, analytical sciences and quality control, and regulatory science.
Assuntos
Biotecnologia/tendências , Descoberta de Drogas/tendências , Sociedades Farmacêuticas , Tecnologia Farmacêutica/tendências , Sistemas de Liberação de Medicamentos , Internacionalidade , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Preparações Farmacêuticas/normas , FarmacocinéticaRESUMO
In this study, we examined the stabilization mechanism of drug supersaturation by hypromellose (HPMC) and polyvinylpirrolidone (PVP). The poorly water-soluble drugs, phenytoin (diphenylhydantoin, DPH), and its synthesized derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) were used. DPH supersaturation was efficiently maintained by both HPMC and PVP. HPMC maintained the supersaturation of MDPH and DMDPH in a similar manner to that of DPH, whereas the ability of PVP to maintain drug supersaturation increased as follows: DPH > MDPH > DMDPH. Caco-2 permeation studies and nuclear magnetic resonance measurements revealed that the permeability and molecular state of the drug in a HPMC solution barely changed. In fact, the solubilization of the drug into PVP changed its apparent permeability and molecular state. The drug solubilization efficiency by PVP was higher and followed the order: DPH > MDPH > DMDPH. The different drug solubilization efficiencies most likely result from the different strengths in the intermolecular interaction between the DPH derivatives and PVP. The difference in the stabilization mechanism of drug supersaturation by HPMC and PVP could determine whether the efficient maintenance of the drug supersaturation was dependent on the drug species.
Assuntos
Anticonvulsivantes/química , Excipientes/química , Derivados da Hipromelose/química , Modelos Químicos , Fenitoína/química , Povidona/química , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Composição de Medicamentos , Estabilidade de Medicamentos , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Absorção Intestinal/efeitos dos fármacos , Cinética , Espectroscopia de Ressonância Magnética , Metilação , Estrutura Molecular , Fenitoína/análogos & derivados , Fenitoína/metabolismo , Fenitoína/farmacologia , Solubilidade , SoluçõesRESUMO
We describe the total synthesis of angular chromenoquinone 1 isolated from Conospermum plants. Iodophenol, a precursor of pyranobenzyne, was prepared by Claisen rearrangement of an iodoresorcinol derivative. Diels-Alder reaction of the pyranobenzyne and a substituted furan proceeded in low regioselectivity to afford desired 1 and its regioisomer.
Assuntos
Benzopiranos/síntese química , Produtos Biológicos/síntese química , Proteaceae/química , Quinonas/síntese química , Benzopiranos/química , Produtos Biológicos/química , Reação de Cicloadição , Furanos , Quinonas/química , EstereoisomerismoRESUMO
Quantitative analysis of miroestrol (1) and kwakhurin (3) by HPLC, leading to standardisation of commercially available Thai miracle herb 'Kwao Keur' which has been identified with Pueraria mirifica, was established using independent solvent systems. The simple isolation procedure of highly estrogenic miroestrol (1) and deoxymiroestrol (2) from P. mirifica was also proposed.
Assuntos
Isoflavonas/química , Pueraria/química , Esteroides/química , Esteroides/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Cumarínicos/química , Cumarínicos/isolamento & purificaçãoRESUMO
We report an enantioselective synthesis of the polyhydroxylated pyrrolidine alkaloid (+)-DMDP. The key steps in the synthesis were guanidinium ylide mediated asymmetric aziridination, stereospecific ring opening of trans-3-vinylaziridine-2-carboxylate with an oxygen nucleophile, iodine-mediated 5-endo-trig amino cyclization, and Prévost displacement. In addition, a potential common intermediate for the polyhydroxylated pyrrolizidine alkaloids (+)-hyacinthacine A(1) and (+)-1-epi-australine was synthesized from a diastereoisomeric cis-aziridine coformed in the asymmetric aziridination using the same strategy. A rationale for the diastereoselectivity observed for the iodine-mediated amino cyclization reactions is proposed on the basis of the heats of formation of the products.
Assuntos
Alcaloides/síntese química , Ácidos Carboxílicos/síntese química , Pirrolidinas/síntese química , Alcaloides de Pirrolizidina/síntese química , Compostos de Vinila/síntese química , Alcaloides/química , Ácidos Carboxílicos/química , Ciclização , Estrutura Molecular , Pirrolidinas/química , Alcaloides de Pirrolizidina/química , Estereoisomerismo , Compostos de Vinila/químicaRESUMO
The mechanism of drug nanoparticle formation of phenytoin (DPH) and its derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) was investigated. The drug, polyvinylpyrrolidone K17 (PVP), and sodium dodecyl sulfate were coground to obtain the ground mixture (GM). The DPH GM was amorphous; however, MDPH and DMDPH GMs contained drug crystals. Spectral changes in infrared and (13)C solid-state nuclear magnetic resonance were observed in the DPH GM, partially observed in the MDPH GM, and hardly observed in the DMDPH GM. Mean particle sizes of the DPH, MDPH, and DMDPH GM nanosuspension were almost the same; however, stability after storage differed in the order of DPH > MDPH > DMDPH. The intermolecular interaction between the drug and PVP reflected not only the crystallinity of the drug in the GM but also the stability of the GM suspension. The size and stiffness of drug nanoparticles were evaluated using atomic force microscopy. Crystallization of the amorphous GM and agglomeration of the primary nanocrystals were observed in the DPH GM suspension. In contrast, primary nanocrystals were observed in the DMDPH GM suspension. The size of the drug nanocrystals formed from the different molecular states of the drug in the GM reflects the agglomerated states in water and stability.
Assuntos
Nanopartículas , Fenitoína/química , Química Farmacêutica , Cristalização , Estabilidade de Medicamentos , Espectroscopia de Ressonância Magnética , Metilação , Microscopia de Força Atômica , Nanotecnologia , Tamanho da Partícula , Fenitoína/análogos & derivados , Povidona/química , Dodecilsulfato de Sódio/química , Espectroscopia de Infravermelho com Transformada de Fourier , Tecnologia Farmacêutica/métodos , Água/químicaRESUMO
In this study, we describe the antitumor activity of QO-1, one of the new 2-aryl-1,4-naphthoquinone-1-oxime methyl ether derivatives. QO-1 is a derivative of macarpine, a natural occurring product from Rutaceae plant. It could potently inhibit cell growth when tested on 19 cancer cell lines. To investigate its mechanism, two cell lines (HeLa and MCF-7) sensitive to QO-1 were selected. Based on flow cytometry, it was found to induce G(2)/M-phase arrest. Moreover, it could cause microtubule depolymerization both in vitro and in vivo. On the other hand, QO-1 activated spindle assembly checkpoint (SAC) proteins. Expression of Bub1, one of the SAC, was gradually increased, reaching a peak after 16 - 20 h, and then gradually decreased. Instead, QO-1 increased the sub-G(1) population, which suggested a cell death population. Actually, expression of Bcl-2 family proteins and activation of caspase-3/7 were evidences of apoptosis. Consistent with these results, cells with DNA fragmentation and multinucleated cells were increased time-dependently after QO-1 exposure. In conclusion, QO-1 has promising antitumor effects via microtubule depolymerization.
Assuntos
Apoptose/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Naftoquinonas/química , Naftoquinonas/farmacologia , Moduladores de Tubulina/farmacologia , Apoptose/fisiologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Células HeLa , Humanos , Éteres Metílicos/química , Éteres Metílicos/farmacologia , Microtúbulos/metabolismo , Moduladores de Tubulina/químicaRESUMO
From the fruits and leaves of Aglaia erythrosperma (Meliaceae), 10 chemical constituents were isolated and identified, i.e. the dammarane triterpenoids cabraleadiol (1), cabraleahydroxylactone (2), ethyl eichlerianoate (3), eichlerialactone (4), aglinin A (5), cabralealactone (6), the aglaialactone 5,6-desmethylenedioxy-5-methoxy-aglalactone (7), the flavagline 4'-demethoxy-3',4'-methylenedioxy-methyl rocaglate (8) and two coumarins: scoparone and scopoletin. Flavagline 8 exhibited antimalarial activity with an IC(50) value of 7.30 µg mL(-1) and was strongly cytotoxic against small cell lung cancer (NCI-H187), epidermoid carcinoma (KB) and breast cancer (BC) cell lines, with IC(50) values of 2.17, 2.10 and 0.11 µg mL(-1), respectively. Aglinin A (5) displayed moderate cytotoxicity against all the three cancer cell lines, whereas ethyl eichlerianoate (3), cabralealactone (6) and the aglaialactone 7 were exclusively cytotoxic to NCI-H187 cell line. Cabraleahydroxylactone (2) showed antiviral activity against herpes simplex virus type-1 with an IC(50) value of 3.20 µg mL(-1), in comparison with the standard acyclovir (IC(50) = 1.90 µg mL(-1)). When tested for antimycobacterial activity against Mycobacterium tuberculosis H(37)Ra, compounds 1-4 and 6-8 displayed minimum inhibitory concentration in the range of 25-50 µg mL(-1).
Assuntos
Aglaia/química , Antibacterianos/isolamento & purificação , Antimaláricos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Antivirais/isolamento & purificação , Benzofuranos/isolamento & purificação , Frutas/química , Folhas de Planta/química , Antibacterianos/análise , Antibacterianos/farmacologia , Antimaláricos/análise , Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/farmacologia , Antivirais/análise , Antivirais/farmacologia , Benzofuranos/análise , Benzofuranos/farmacologia , Linhagem Celular Tumoral , Cumarínicos/análise , Cumarínicos/isolamento & purificação , Citotoxinas/análise , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Fitosteróis/análise , Fitosteróis/isolamento & purificação , Pregnanos/análise , Pregnanos/isolamento & purificação , Espectrofotometria Ultravioleta , TailândiaRESUMO
There are a number of reports indicating that CYP2B6*6 (c.516G>T and c.785A>G) is responsible for decreased clearance of efavirenz (EFV), although increased disposition of cyclophosphamide (CPA) in individuals with this polymorphism was observed. Thus, we hypothesized that the effects of the two single nucleotide polymorphisms (SNPs) of CYP2B6*6 on the metabolism of drugs might be considerably different between these two agents. To clarify this possibility, we expressed two major variants of this enzyme, CYP2B6.6 (Q172H and K262R) and CYP2B6.4 (K262R), and investigated metabolic activities of these variants toward EFV and CPA. Kinetic analyses clearly indicated that CYP2B6.4 possessed enhanced metabolic activity toward EFV compared with that of the wild-type enzyme (CYP2B6.1), whereas CPA was metabolized less efficiently by CYP2B6.4 than by CYP2B6.1. On the other hand, CYP2B6.6 showed a completely opposite character, suggesting that Q172H gives inverse effects on metabolic activities of CYP2B6 affected by K262R. Although it is recognized that effects of amino acid change in cytochrome P450 on the metabolic activity depend on substrates, this study revealed SNPs giving an opposite effect on the metabolism of two clinically important drugs currently used. Furthermore, this study provides the first evidence that Q172H can reverse the direction of the effect caused by K262R in CYP2B6 on the metabolism of certain drugs.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Benzoxazinas/farmacocinética , Ciclofosfamida/farmacocinética , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Alcinos , Animais , Ciclopropanos , Citocromo P-450 CYP2B6 , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Inativação Metabólica , Fígado/enzimologia , Fígado/metabolismo , Oxigenases de Função Mista/metabolismo , Farmacocinética , Polimorfismo de Nucleotídeo Único , Processamento de Proteína Pós-TraducionalRESUMO
Kinamycin antibiotics, strongly active against gram-positive bacteria, were isolated from the culture broth of Streptomyces murayamaensis. The structures of kinamycins and prekinamycin, isolated from the same bacteria, were at first determined to be benzo[b]carbazole with cyanamide [N-C ≡ N]. Later re-examination of spectroscopic analysis concluded that those compounds should be benzo[b]fluorene with diazoalkane [Câ» - N(+)≡ N]. However, the structure of the latter was re-revised to benzo[a]fluorene and renamed as isoprekinamycin. We have continued our effort for the synthesis of kinamycin antibiotics from the point of view of total synthesis and structural determination. In this review, our approach toward total synthesis of kinamycins was described.