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1.
J Nat Med ; 72(1): 260-266, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29151157

RESUMO

Erypoegin K is an isoflavone isolated from the stem bark of Erythrina poeppigiana. It contains a furan group at the A-ring of the core isoflavone structure and can inhibit the activity of glyoxalase I, an enzyme that catalyzes the detoxification of methylglyoxal (MG), a by-product of glycolysis. In the present study, we found that erypoegin K has a potent cytotoxic effect on human leukemia HL-60 cells. Its cytotoxic effect was much stronger than that of a known glyoxalase I inhibitor S-p-bromobenzylglutathione cyclopentyl diester. Conversely, erypoegin K demonstrated weak cytotoxicity toward normal human peripheral lymphocytes. The treatment of HL-60 cells with erypoegin K significantly induced caspase-3 activity, whereas the pretreatment of the cells with caspase-3 inhibitor suppressed erypoegin K-induced cell death. Furthermore, nuclear condensation and apoptotic genome DNA fragmentation were observed in erypoegin K-treated HL-60 cells. These results indicated that the observed cell death was mediated by apoptosis. In addition, the toxic compound MG was highly accumulated in the culture medium of erypoegin K-treated HL-60 cells, suggesting that cell apoptosis was triggered by extracellular MG. The present study showed that erypoegin K has a potent apoptosis-inducing effect on cancerous cell lines, such as HL-60.


Assuntos
Benzofuranos/química , Erythrina/química , Células HL-60/química , Isoflavonas/química , Leucemia/tratamento farmacológico , Apoptose , Humanos , Leucemia/patologia
2.
Bioorg Med Chem Lett ; 27(3): 562-566, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28003138

RESUMO

(-)-Dehydroxymethylepoxyquinomicin ((-)-DHMEQ, 1) is a specific inhibitor of NF-κB. It binds to SH group in the specific cysteine residue of NF-κB components with its epoxide moiety to inhibit DNA binding. In the present research, we have designed and synthesized an epoxide-free analog called (S)-ß-salicyloylamino-α-exo-methylene-Æ´-butyrolactone (SEMBL, 3). SEMBL inhibited DNA binding of NF-κB component p65 in vitro. It inhibited LPS-induced NF-κB activation, iNOS expression, and inflammatory cytokine secretions. It also inhibited NF-κB and cellular invasion in ovarian carcinoma ES-2 cells. Moreover, its stability in aqueous solution was greatly enhanced compared with (-)-DHMEQ. Thus, SEMBL has a potential to be a candidate for a new anti-inflammatory and anticancer agent.


Assuntos
4-Butirolactona/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Desenho de Drogas , NF-kappa B/antagonistas & inibidores , Salicilamidas/farmacologia , 4-Butirolactona/síntese química , 4-Butirolactona/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Salicilamidas/síntese química , Salicilamidas/química , Relação Estrutura-Atividade
4.
Nat Prod Commun ; 10(9): 1581-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26594764

RESUMO

It has been reported that many malignant human tissues, including breast, colon, and lung cancers, may show an elevated expression of glyoxalase I (GLO I). GLO I catalyzes the reaction to transform hemimercaptal, a compound formed from methylglyoxal (MG) and reduced glutathione, into S-D-lactoylglutathione, which is then converted to D-lactic acid by glyoxalase II. GLO I inhibitors are expected to be useful for inhibiting tumorigenesis through the accumulation of apoptosis-inducible MG in tumor cells. Here, we investigated the anti-proliferative activity of eight kinds of isoflavone isolated from Erythrina poeppigiana against the growth of HL-60 human leukemia cells from the viewpoint of GLO I inhibition. Of the compounds tested, the diprenyl isoflavone, isolupalbigenin, was shown to exhibit the highest anti-proliferative activity against HL-60 cells. Upon the treatment of HL-60 cells with isolupalbigenin, MG was significantly accumulated in the culture medium, and the caspase 3 activity of the cell lysate was elevated in a time-dependent manner. Thus, it is suggested that isolupalbigenin inhibits the enzyme GLO I, resulting in MG accumulation in the medium, and leading to cell apoptosis. Isolupalbigenin, with two prenyl groups in its A- and B-rings, might be expected to become a potent leading compound for the development of anticancer agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Erythrina/química , Isoflavonas/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/metabolismo , Antineoplásicos Fitogênicos/química , Sobrevivência Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Células HL-60 , Humanos , Isoflavonas/química , Lactoilglutationa Liase/genética , Estrutura Molecular
5.
J Nat Med ; 68(3): 636-42, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24756815

RESUMO

A novel isoflavone, erythgianin A (1), along with nine known compounds 2-10, was isolated from the stem bark of Erythrina poeppigiana (Leguminosae). The unusual isoflavone structure of 1, possessing a highly oxidized 3″,4″-dihydroxy-2″-hydroxymethyl-2″-methyl-2″,3″-dihydropyrano substituent, was determined on the basis of spectroscopic analyses. All of the isolated compounds were evaluated for their in vitro inhibitory activity toward human glyoxalase I. Among the isolates, isolupalbigenin (10) with two prenyl groups showed the highest inhibitory activity.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Erythrina/química , Lactoilglutationa Liase/antagonistas & inibidores , Fenóis/química , Fenóis/farmacologia , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Casca de Planta/química
6.
Bioorg Med Chem ; 18(3): 1143-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20071185

RESUMO

Bone deficiency causes osteoporosis and often decreases quality of life in patients with rheumatoid arthritis. Estrogens are known to protect elderly women from bone loss. Synthesis of new estradiol-bisphosphonate conjugates (E(2)-BPs) was accomplished and their in vivo activity as bone-specific estrogens were examined. Among them, MCC-565 showed selective estrogenic activity in bones; but it showed little estrogenic activity in the uterus. We also found that the linker moiety in E(2)-BPs was essential for the absorption and specificity of the conjugates.


Assuntos
Osso e Ossos/efeitos dos fármacos , Difosfonatos/química , Difosfonatos/farmacologia , Estradiol/química , Estradiol/farmacologia , Animais , Difosfonatos/síntese química , Estradiol/síntese química , Feminino , Osteoporose/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores Estrogênicos/metabolismo , Útero/efeitos dos fármacos
7.
Bioorg Med Chem Lett ; 19(18): 5380-2, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19679468

RESUMO

Previously we found that (-)-DHMEQ, a specific NF-kappaB inhibitor, covalently bound to a specific cysteine of NF-kappaB component proteins. In the course of formation of the (-)-DHMEQ and protected cysteine conjugate, we observed an unusual intramolecular N-->O acyl group migration.


Assuntos
Benzamidas/metabolismo , Cicloexanonas/metabolismo , Cisteína/metabolismo , NF-kappa B/antagonistas & inibidores , Conformação Molecular
8.
Bioorg Med Chem ; 17(17): 6188-95, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19679484

RESUMO

Conophylline, a vinca alkaloid extracted from the tropical plant Ervatamia microphylla, has been shown to induce the differentiation of insulin-producing beta-cells in cultured cells and in animals. However, its mechanism of action and the molecular target have remained unclear. Therefore, we prepared a fishing probe with conophylline to identify the target protein by using latex nano-beads, which are newly innovated tools for affinity-purification. With these conophylline-linked nano-beads, we found that conophylline directly interacted with ARL6IP. ARL6IP may thus be involved in the mechanism of cellular differentiation of beta-cells, and this probe should be useful to find other target proteins.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Hipoglicemiantes/química , Proteínas de Membrana/química , Nanopartículas/química , Plantas Medicinais/química , Alcaloides de Vinca/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/citologia , Proteínas de Membrana/metabolismo , Folhas de Planta/química , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Alcaloides de Vinca/metabolismo , Alcaloides de Vinca/farmacologia
9.
Bioorg Med Chem Lett ; 15(4): 1111-4, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15686923

RESUMO

Suppression of resistance to anticancer drugs by COTC of glyoxalase I (GloI) inhibitor targeting intracellular glutathione (GSH) and GloI was studied. Depletion of the cellular GSH content and inhibition of GloI by COTC increased chemotherapy-mediated apoptosis in apoptosis-resistant pancreatic adenocarcinoma AsPC-1 cells.


Assuntos
Cicloexanonas/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glutationa/antagonistas & inibidores , Lactoilglutationa Liase/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cicloexanonas/farmacologia , Humanos , Neoplasias Pancreáticas/patologia , Relação Estrutura-Atividade
10.
Int J Antimicrob Agents ; 24(3): 241-6, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15325427

RESUMO

The phytochemical 2',4'-dihydroxy-8-gamma,gamma-dimethylallyl-2",2"-dimethylpyrano[5",6":6,7]isoflavanone (bidwillon B) was isolated from Erythrina variegata and its antibacterial properties against methicillin-resistant Staphylococcus aureus (MRSA) were investigated. Bidwillon B inhibited the growth of 12 MRSA strains at minimum inhibitory concentrations (MICs) of 3.13-6.25mg/l, while MICs of mupirocin were 0.20-3.13 mg/l. The minimum bactericidal concentration (MBC) for bidwillon B and mupirocin against MRSA were 6.25-25mg/l (MBC(90): 12.5mg/l) and 3.13-25mg/l (MBC(90): 25mg/l), respectively. When bidwillon B and mupirocin were combined, synergistic effects were observed for 11 strains of MRSA (fractional inhibitory concentration indices, 0.5-0.75). The MBCs of mupirocin in the presence of bidwillon B (3.13 mg/l) were reduced to 0.05-1.56 mg/l. Bidwillon B at MIC values strongly inhibited incorporation of radio-labelled thymidine, uridine, glucose and isoleucine into MRSA cells. Mupirocin showed lower inhibitory effects than bidwillon B on thymidine, uridine and glucose incorporation, but incorporation of isoleucine was completely blocked with this antibiotic. These results indicate that bidwillon B possesses sufficient anti-MRSA activity for inhibiting growth and recovery, and that the compound acts synergistically with mupirocin. The results also suggest that both compounds act on MRSA via different mechanisms. Bidwillon B may prove to be a potent phytotherapeutic and/or combination agent with mupirocin in the elimination of nasal and skin carriage of MRSA.


Assuntos
Antibacterianos/farmacologia , Erythrina/química , Isoflavonas/farmacologia , Mupirocina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/isolamento & purificação , Sinergismo Farmacológico , Glucose/metabolismo , Isoflavonas/química , Isoflavonas/isolamento & purificação , Isoleucina/metabolismo , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/metabolismo , Timidina/metabolismo , Uridina/metabolismo
11.
Leuk Res ; 26(12): 1097-103, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12443882

RESUMO

All-trans retinoic acid (ATRA) induces the differentiation of acute promyelocytic leukemia (APL) cells into neutrophils. We found that bestatin, an inhibitor of CD13/aminopeptidase N, enhanced the sensitivity of APL NB4 cells to ATRA at concentrations of 0.1-1000ng/ml. A structurally different aminopeptidase N inhibitor, actinonin, also increased the effect of ATRA on differentiation, but an inactive stereoisomer of bestatin, (2R,3S)-AHPA-(R)-Leu, did not. Bestatin synergistically enhanced the cytostatic effect of ATRA on NB4 cells. Masking of the cell-surface CD13 by anti-CD13 antibody WM15 blocked the synergistic effect of bestatin and ATRA on differentiation. Thus bestatin, an immunomodulator clinically used for nonlymphocytic leukemia, synergistically increased the ATRA-induced differentiation of NB4 cells by inhibiting CD13/aminopeptidase N on the cell-surface.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucina/análogos & derivados , Leucina/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/farmacologia , Aminopeptidases/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígenos CD13/antagonistas & inibidores , Antígenos CD13/fisiologia , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Leucemia Promielocítica Aguda/patologia , Inibidores de Proteases/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Bioorg Med Chem ; 10(12): 3933-9, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12413845

RESUMO

We previously found dehydroxymethylepoxyquinomicin (DHMEQ) inhibited NF-kappaB activation and showed anti-inflammatory activity in vivo. Here we designed and synthesized analogues of DHMEQ and tested their biological activity as NF-kappaB inhibitors in human T cell leukemia Jurkat cells. The hydroxyl group at the 2-position of the benzamide moiety was found to be essential for the inhibitory activity. But etherification of this group did not diminish the activity completely. Thus, for further mechanistic studies the hydroxyl group at the 2-position may be useful for extension with a linker and biotin moiety.


Assuntos
Antineoplásicos/síntese química , Benzamidas/farmacologia , Cicloexanonas/farmacologia , NF-kappa B/antagonistas & inibidores , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Benzamidas/síntese química , Cicloexanonas/síntese química , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/farmacologia
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