RESUMO
Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells.
Assuntos
Antineoplásicos , Ácidos Cafeicos , Álcool Feniletílico , Humanos , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/síntese química , Células HeLa , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Álcool Feniletílico/química , Álcool Feniletílico/síntese química , Água/química , Linhagem Celular Tumoral , Amidas/farmacologia , Amidas/química , Sobrevivência Celular/efeitos dos fármacosRESUMO
Plant polyphenols, such as the African potato (Hypoxis hemerocallidea)-derived bis-catechol rooperol, can display promising anticancer activity yet suffer from rapid metabolism. Embarking upon a program to systematically examine potentially more metabolically stable replacements for the catechol rings in rooperol, we report here a general, scalable synthesis of rooperol and analogues that builds on our previous synthetic approach incorporating a key Pd-catalyzed decarboxylative coupling strategy. Using this approach, we have prepared and evaluated the cancer cell cytotoxicity of rooperol and a series of analogues. While none of the analogues examined here were superior to rooperol in preventing the growth of cancer cells, analogues containing phenol or methylenedioxyphenyl replacements for one or both catechol rings were nearly as effective as rooperol.
Assuntos
Catecóis , Neoplasias , Catecóis/farmacologia , Neoplasias/tratamento farmacológico , Fenol , Fenóis , PolifenóisRESUMO
A flexible and modular peptide modeling set was designed using freely available software tools. The set consists of space-filling models of all 20 naturally occurring amino acid side chains and a modular kit for constructing peptides employing C-alpha carbons and amide bond groups. Connectors that allow free rotation about phi and psi angles on the peptide, together with explicit representation of peptide backbone hydrogen bond donor and acceptors allows for the construction of a wide range of protein secondary structure motifs. The space-filling side chain models highlight the steric, acid-base, and polarity of these groups. These models were printed using relatively affordable commercially available fused filament fabrication printers with minimal postprinting processing. Use of these models in student group activities focused on amino acids and protein secondary structural features is described. © 2019 International Union of Biochemistry and Molecular Biology, 47(4):432-437, 2019.
Assuntos
Peptídeos/química , Impressão Tridimensional , Humanos , Modelos Moleculares , Estrutura Secundária de Proteína , Software , EstudantesRESUMO
N-Methylmesoporphyrin IX (NMM) has long been known as a G-quadruplex DNA (G4) ligand. However, there has been little investigation into its G-quadruplex photocleavage activity. Herein, we demonstrate that NMM is a highly selective photocleavage agent for G4 structures but not duplex DNA. Analysis of the cleavage products by PAGE demonstrates that G4 photocleavage by NMM occurs at sites similar to those cleaved by TMPyP4, a nonselective DNA photocleavage agent. Although NMM is shown here to generate singlet oxygen in the presence of both duplex and G4, the lack of increased photocleavage in D2 O indicated that singlet oxygen is not involved in the photocleavage of G4 by NMM.
Assuntos
DNA/química , Mesoporfirinas/química , Quadruplex G , Estrutura Molecular , Processos FotoquímicosRESUMO
Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility in a wide range of reactions. One specific class of heteroatom-substituted alkynes combines this utility with the presence of an azole moiety. These N-alkynyl azoles have been known for nearly 50 years, but recently there has been a tremendous increase in the number of reports detailing the synthesis and utility of this class of compound. While much of the chemistry of N-alkynyl azoles mirrors that of the more extensively studied N-alkynyl amides (ynamides), there are notable exceptions. In addition, as azoles are extremely common in natural products and pharmaceuticals, these N-alkynyl azoles have high potential for accessing biologically important compounds. In this review, the literature reports of N-alkynyl azole synthesis, reactions, and uses have been assembled. Collectively, these reports demonstrate the growth in this area and the promise of exploiting N-alkynyl azoles in synthesis.
Assuntos
Alcinos/síntese química , Azóis/síntese química , Amidas/química , Produtos Biológicos , Catálise , Ciclização , Estrutura Molecular , Oxirredução , PolímerosRESUMO
Mutation 'hotspot' regions in the genome are susceptible to genetic instability, implicating them in diseases. These hotspots are not random and often co-localize with DNA sequences potentially capable of adopting alternative DNA structures (non-B DNA, e.g. H-DNA and G4-DNA), which have been identified as endogenous sources of genomic instability. There are regions that contain overlapping sequences that may form more than one non-B DNA structure. The extent to which one structure impacts the formation/stability of another, within the sequence, is not fully understood. To address this issue, we investigated the folding preferences of oligonucleotides from a chromosomal breakpoint hotspot in the human c-MYC oncogene containing both potential G4-forming and H-DNA-forming elements. We characterized the structures formed in the presence of G4-DNA-stabilizing K+ ions or H-DNA-stabilizing Mg2+ ions using multiple techniques. We found that under conditions favorable for H-DNA formation, a stable intramolecular triplex DNA structure predominated; whereas, under K+-rich, G4-DNA-forming conditions, a plurality of unfolded and folded species were present. Thus, within a limited region containing sequences with the potential to adopt multiple structures, only one structure predominates under a given condition. The predominance of H-DNA implicates this structure in the instability associated with the human c-MYC oncogene.
Assuntos
DNA/química , Conformação de Ácido Nucleico/efeitos dos fármacos , Oligonucleotídeos/química , Proteínas Proto-Oncogênicas c-myc/química , Quebra Cromossômica/efeitos dos fármacos , DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Instabilidade Genômica/efeitos dos fármacos , Humanos , Mutagênicos/toxicidade , Mutação/efeitos dos fármacos , Oligonucleotídeos/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Transcrição Gênica/efeitos dos fármacosRESUMO
DNA containing repeating G-rich sequences can adopt higher-order structures known as G-quadruplexes (G4). These structures are believed to form within telomeres and the promoter regions of some genes, particularly in a number of proto-oncogenes, where they may play a role in regulating transcription. Alternatively, G4 DNA may act as a barrier to replication. To investigate these potential biological roles, probes that combine highly selective G4 DNA targeting with photocleavage activity can allow temporal detection of G4 DNA, providing opportunities to obtain novel insights about the biological roles of G4 DNA. We have designed, synthesized, and screened a small library of potential selective G-quadruplex DNA photocleavage agents incorporating the G-quadruplex targeting moiety of 360A with known photocleavage groups linked via "click" chemistry.
Assuntos
Química Click/métodos , DNA/química , Quadruplex G , Fotoquímica/métodosRESUMO
A validated LCMS method was developed for the quantitative determination of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) from rat plasma. Separation was achieved using a reverse-phase C12 HPLC column (150 × 2.00 mm, 4 µm) with gradient elution running water (A) and acetonitrile (B). Mass spectrometry was performed with electrospray ionization in negative mode. This method was used to determine the pharmacokinetic profiles of CAPA and CAPE in male Sprague-Dawley rats following intravenous bolus administration of 5, 10 and 20 mg/kg of CAPA and 20 mg/kg of CAPE. The pharmacokinetic analysis suggests the lack of dose proportionality in the dose range of 5-20 mg/kg of CAPA. Total clearance values for CAPA ranged from 45 to 156 mL/min and decreased with increasing dose of CAPA. The volume of distribution for CAPA ranged from 17,750 to 52,420 mL, decreasing with increasing dose. The elimination half-life for CAPA ranged from 243.1 to 295.8 min and no statistically significant differences were observed between dose groups in the range of 5-20 mg/kg (p > 0.05). The elimination half-life for CAPE was found to be 92.26 min.
Assuntos
Ácidos Cafeicos/sangue , Ácidos Cafeicos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Álcool Feniletílico/análogos & derivados , Animais , Ácidos Cafeicos/química , Cromatografia de Fase Reversa/métodos , Limite de Detecção , Modelos Lineares , Masculino , Álcool Feniletílico/sangue , Álcool Feniletílico/química , Álcool Feniletílico/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A new p38α inhibitor: Using a D-recruitment site (DRS) probe for p38α which exploits covalent interaction with Cys119 and alkyne-azide "click" chemistry to identify small molecules that recognize the p38α DRS, the anti-inflammatory natural product rooperol was identified as a novel p38α inhibitor.
Assuntos
Catecóis/metabolismo , Catecóis/farmacologia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Sítios de Ligação/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacologia , Modelos Moleculares , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Ligação Proteica , Conformação Proteica , Espectrometria de Fluorescência , Temperatura , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
In this work, the benzimidazole-pyrrole conjugates 6a-h and benzimidazole-tetracycles conjugates 12-14 were prepared. The cytotoxicity of the compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 was tested against lung cancer cell line A549. Compound 6b exhibited higher activity than the bis-benzoxazole natural product (UK-1), the standard. The tested 4g,h, 6a-h, 10 and 12-14 exhibited remarkable cytotoxicity activity against breast cancer cell line MCF-7 with higher activity than tamoxifen. Furthermore, compound 4h was found to be also more potent than doxurubicin. The antitumor promotion activity of synthesized compounds 4g,h, 6a-h, 10 and 12-14 has been estimated by studying their possible inhibitory effects on EBV-EA activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds, the inhibitory activities of compounds 8, 13 and 14 demonstrated strong inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation without showing any cytotoxicity on the Raji cells and their effects being stronger than that of a representative control, oleanolic acid. Moreover, the molecular docking of the new compounds into plasminogen activator (uPA) receptor has been in correlation with the antitumor activity. All synthesized compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 were docked into same groove of the binding site of the native co-crystalized (4-iodobenzo[b]thiophene-2-carboxamidine) ligand (PDB code:1c5x) for activity explaination. Compounds 4h, 6b and 13, giving the best docking results, were further studied to estimate their effect on the level of uPA using AssayMax human urokinase (uPA) ELISA kit. In case of A549 cell line, compound 6 exhibited similar activity to MMC, and for MCF-7 cell line, compound 4h exhibited similar activity to doxorubicin, in inhibiting the expression of uPA.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Antineoplásicos/síntese química , Benzimidazóis/síntese química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/fisiologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Células MCF-7 , Modelos Moleculares , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-Atividade , Tetraciclinas/síntese química , Tetraciclinas/química , Tetraciclinas/farmacologia , Ativação Viral/efeitos dos fármacosRESUMO
A rapid fluorescence assay for G-quadruplex DNA cleavage was used to investigate the preference of TMPyP4 photochemical and Mn·TMPyP4 oxidative cleavage. Both agents most efficiently cleave the c-Myc promoter G-quadruplex. Direct PAGE analysis of selected assay samples showed that for a given cleavage agent, different cleavage products are formed from different G-quadruplex structures. Cleavage assays carried out in the presence of excess competitor nucleic acid structures revealed the binding selectivity of cleavage agents, while comparisons with duplex cleavage efficiency employing a dual-labeled hairpin oligonucleotide revealed neither agent prefers G-quadruplex over duplex substrates. Finally, this assay was used to identify the perylene diimide Tel11 as a photocleavage agent for the c-Myc G-quadruplex.
Assuntos
Clivagem do DNA , Quadruplex G , Imidas/química , Perileno/análogos & derivados , Sequência de Bases , Transferência Ressonante de Energia de Fluorescência , Genes myc , Humanos , Estrutura Molecular , Conformação de Ácido Nucleico , Perileno/química , Processos Fotoquímicos , Regiões Promotoras Genéticas , Espectrometria de FluorescênciaRESUMO
A validated C18 reverse-phase HPLC method with UV detection at 320 nm was developed and used for the stability evaluation of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) in rat plasma. CAPA is the amide derivative of CAPE, a naturally occurring polyphenolic compound that has been found to be active in a variety of biological pathways. CAPA has been shown to protect endothelial cells against hydrogen peroxide-induced oxidative stress to a similar degree to CAPE. CAPE has been reported to be rapidly hydrolyzed in rat plasma via esterase enzymes. CAPA is expected to display a longer half-life than CAPE by avoiding hydrolysis via plasma esterases. The stability of CAPA and CAPE in rat plasma was investigated at three temperatures. The half-lives for CAPA were found to be 41.5, 10 and 0.82 h at 25, 37 and 60 °C, respectively. The half-lives for CAPE were found to be 1.95, 0.35 and 0.13 h at 4, 25 and 37 °C, respectively. The energy of activation was found to be 22.1 kcal/mol for CAPA and 14.1 kcal/mol for CAPE. A more stable compound could potentially extend the beneficial effects of CAPE.
Assuntos
Amidas/sangue , Ácidos Cafeicos/sangue , Álcool Feniletílico/análogos & derivados , Amidas/química , Animais , Ácidos Cafeicos/química , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Estabilidade de Medicamentos , Cinética , Masculino , Álcool Feniletílico/sangue , Álcool Feniletílico/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , TemperaturaRESUMO
A new class of potential antitumor agents inspired by the enediyne antitumor antibiotics has been synthesized: the 1,2-dialkynylimidazoles. The aza-Bergman rearrangement of these 1,2-dialkynylimidazoles has been investigated theoretically at the B3LYP/6-31G(d,p) level and experimentally by measuring the kinetics of rearrangement in 1,4-cyclohexadiene. There is a good correlation between the theoretical and experimental results; subtle substituent effects on the initial aza-Bergman cyclization barrier predicted by theory are confirmed by experiment. Yet, despite the ability of these 1,2-dialkynylimidazoles to undergo Bergman rearrangement to diradical/carbene intermediates under relatively mild conditions, there is no correlation between the rate of Bergman cyclization and cytotoxicity to A459 cells. In addition, cytotoxic 1,2-dialkynylimidazoles do not cause nicking of supercoiled plasmid DNA or cleavage of bovine serum albumin. An alternative mechanism for cytotoxicity involving the unexpected selective thiol addition to the N-ethynyl group of certain 1,2-dialkynylimidazoles is proposed.
Assuntos
Alcinos/síntese química , Antineoplásicos/síntese química , Imidazóis/síntese química , Alcinos/química , Alcinos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Ciclização , Clivagem do DNA , DNA Super-Helicoidal/química , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Temperatura Alta , Humanos , Imidazóis/química , Imidazóis/farmacologia , Cinética , Soroalbumina Bovina/química , Estereoisomerismo , Relação Estrutura-Atividade , TermodinâmicaRESUMO
A series of catechol ring-fluorinated derivatives of caffeic acid phenethyl amide (CAPA) were synthesized and screened for cytoprotective activity against H2O2 induced oxidative stress in human umbilical vein endothelial cells (HUVEC). CAPA and three fluorinated analogs were found to be significantly cytoprotective when compared to control, with no significant difference in cytoprotection between caffeic acid phenethyl ester (CAPE) and CAPA.
Assuntos
Ácidos Cafeicos/farmacologia , Citoproteção/efeitos dos fármacos , Fenetilaminas/farmacologia , Álcool Feniletílico/análogos & derivados , Ácidos Cafeicos/síntese química , Linhagem Celular , Halogenação , Humanos , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenetilaminas/síntese química , Álcool Feniletílico/farmacologia , Veias Umbilicais/citologiaRESUMO
1,2-Dialkynylimidazoles have been reported to undergo thermal cyclization/rearrangement to diradical and carbene intermediates. Optimization of the synthesis of the 1,2-dialkynylimidazole has provided sufficient material for kinetic and biological studies. The 1,2-dialkynylimidazole is cytotoxic against a wide range of cancer cells and induces apoptosis in A549 cells. Experimentally-determined kinetics of the thermolysis of (E(a) = 30.0 kcal mol(-1)) are in excellent agreement with DFT calculations of the cyclization/rearrangement to diradical and cyclopentapyrazine carbene intermediates (E(a) = 29.7 kcal mol(-1)). Commensurate with the relatively high barrier for cyclization of , no evidence for cleavage of supercoiled DNA under physiological conditions was found; however, under aqueous conditions at 70 degrees C formed a covalent adduct with a model peptide. These studies indicate that if cyclization of is involved in its anticancer activity, the cyclization must be facilitated, perhaps through initial protein binding, which could lead to covalent protein modification.
Assuntos
Alcinos/síntese química , Alcinos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imidazóis/síntese química , Imidazóis/farmacologia , Alcinos/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclização , Humanos , Imidazóis/química , Cinética , Modelos Moleculares , Estrutura Molecular , TermodinâmicaRESUMO
To determine the relationship between catechol ring modifications and the activity of caffeic acid phenethyl ester (CAPE) as a cytoprotective agent, six catechol ring-fluorinated CAPE derivatives were evaluated for their cytoprotective abilities, as well as for their antioxidant and heme oxygenase-1 (HO-1) inducing capacity in a human umbilical vein endothelial cell (HUVEC) model of oxidant stress. To ascertain the involvement of HO-1 induction in the cytoprotective effects of CAPE analogues, their ability to induce HO-1 at 20microM was determined by reverse transcriptase polymerase chain reaction, western blotting and the use of HO-1 inhibitor tin protoporphyrin IX. There was significant induction of HO-1 by CAPE derivatives. Inhibition of HO-1 enzymatic activity resulted in reduced cytoprotection. Modification of the catechol ring of CAPE by introduction of fluorine at various positions resulted in dramatic changes in cytoprotective activity. The maintenance of at least one hydroxyl group on the CAPE catechol ring and the phenethyl ester portion was required for HO-1 induction. CAPE and its derivatives were screened for their ability to scavenge intracellular reactive oxygen species generated in HUVECs by measuring 5-(and-6)-chlormethyl-2', 7'-dichlorodihydrofluorescein diacetate oxidation. The maintenance of 3, 4-dihydroxyl groups on the catechol ring was required for antioxidant activity, but antioxidant activity did not guarantee cytoprotection. Methylation or replacement of one hydroxyl group on the catechol ring of CAPE, however, provided both pro-oxidant and cytoprotective activities. These results indicate that the induction of HO-1 plays a more important role in the cytoprotective activity of CAPE derivatives than their direct antioxidant activity.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Citoproteção/efeitos dos fármacos , Halogenação , Heme Oxigenase-1/biossíntese , Álcool Feniletílico/análogos & derivados , Linhagem Celular , Indução Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Vitamina K 3/farmacologiaRESUMO
Reactions of 1-alkynylimidazoles involving the formation of their 2-lithio derivatives followed by addition of aldehydes or ketones are presented. The method gives access to 1-alkynyl-2-(hydroxymethyl)imidazoles which undergo 6-endo-dig or 5-exo-dig cyclization under AuCl(3)- or base-catalyzed conditions to yield imidazo[1,2-c]oxazoles and imidazo[2,1-c][1,4]oxazine heterocycles. Under transition metal catalysis, the reaction occurs in a regiospecific manner, leading exclusively to the product of 6-endo-dig attack, whereas under basic conditions, the reaction takes place in a regioselective manner giving preferentially the product from 5-exo-dig attack.
Assuntos
Compostos Heterocíclicos/síntese química , Imidazóis/síntese química , Aldeídos , Ciclização , Ouro , Imidazóis/química , Cetonas , Lítio , MétodosRESUMO
Based on the mild, thermal rearrangement of 1,2-dialkynylimidazoles to reactive carbene or diradical intermediates, a series of 1,2-dialkynylimidazoles were designed as potential irreversible p38 MAP kinase alpha-isoform (p38alpha) inhibitors. The synthesis of these dialkynylimidazoles and their kinase inhibition activity is reported. The 1-ethynyl-substituted dialkynylimidazole 14 is a potent (IC(50)=200 nM) and selective inhibitor of p38alpha. Moreover, compound 14 covalently modifies p38alpha as determined by ESI-MS after 12h incubation at 37 degrees C. The unique kinase inhibition, covalent kinase adduct formation, and minimal CYP450 2D6 inhibition by compound 14 demonstrate that dialkynylimidazoles are a new, promising class of p38alpha inhibitors.
Assuntos
Imidazóis/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/síntese química , Regulação Alostérica , Cristalografia por Raios X , Desenho de Fármacos , Imidazóis/química , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Químicos , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Especificidade por Substrato , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologiaRESUMO
The pharmacokinetic profiles of caffeic acid phenethyl ester (CAPE) and its catechol-ring fluorinated derivative (FCAPE) were determined in rats after intravenous administration of 5, 10 or 20 mg/kg for CAPE and 20 mg/kg for FCAPE, respectively. The plasma concentrations of CAPE and FCAPE were measured using a validated liquid chromatography tandem mass spectrometric method. The pharmacokinetic parameters were estimated using non compartmental analysis (NCA) and biexponential fit. The results showed that the area under the plasma concentration-time curve for CAPE treatment increased in a proportion greater than the increase in dose from 5 to 20 mg/kg of CAPE. Total body clearance values for CAPE ranged from 42.1 to 172 ml/min/kg (NCA) and decreased with the increasing dose of CAPE. Similarly, the volume of distribution values for CAPE ranged from 1555 to 5209 ml/kg, decreasing with increasing dose. The elimination half-life for CAPE ranged from 21.2 to 26.7 min and was independent of dose. That FCAPE was distributed extensively into rat tissues and eliminated rapidly was indicated by a high value of volume of distribution and similar short elimination half-life as that of CAPE.