RESUMO
An increase in the rate of complications after prostate biopsy (PB) due to increased antibiotic-resistant bacteria is a global issue. We report the safety of aztreonam as a prophylactic antibiotic in patients undergoing PB. We investigated the complication rates according to several antibiotic regimens, including aztreonam. We hypothesized that PB complications increased following a rise in antibiotic-resistant bacteria. We examined the annual rates of complications among patients in our hospital (clinical cohort) and the Korea Health Insurance Review and Assessment Service (HIRA) cohort. Data regarding complications, hospitalization, emergency room (ER) visits, and febrile urinary tract infections occurring within 2 weeks after PB were recorded. The rate of complications was significantly lower in patients who received oral quinolone and intravenous aztreonam than in those who received oral quinolone. The complication rates did not increase throughout the study period. Additionally, 1754 patients from the HIRA cohort were included. The rates of complications, hospitalizations, and ER visits did not increase among these patients. Oral quinolone combined with intravenous aztreonam reduced the rate of febrile complications compared to quinolone alone and was safe to use after PB. Therefore, we recommend intravenous aztreonam with oral quinolone as a prophylactic antibiotic regimen before PB.
RESUMO
BACKGROUND: The effect of drugs on ATP-binding cassette transporters, especially permeabilityglycoprotein (P-gp), is an important consideration during new anti-cancer drug development. OBJECTIVE: In this context, the effects of a newly synthesized artemisinin derivative, 10-(4-phenyl-1H-1,2,3- triazol)-artemisinin (5a), were evaluated on P-gp expression and function. METHODS: Reverse transcript polymerase chain reaction and immunoblotting techniques were used to determine the effect of 5a on P-gp expression in LS174T cells. In addition, the ability of 5a to work as either a substrate or an inhibitor of P-gp was investigated through different methods. RESULTS: The results revealed that 5a acts as a novel P-gp inhibitor that dually suppresses the overexpression and function of P-glycoprotein. Co-treatment of LS174T cell line, human colon adenocarcinoma cell line, with 5a and paclitaxel recovered the anticancer effect of paclitaxel by controlling the acquired drug resistance pathway. The overexpression of P-gp induced by rifampin and paclitaxel in a colorectal cell line was suppressed by 5a which could be a novel inhibitory substrate inhibiting the transport of paclitaxel by P-gp. CONCLUSION: The results revealed that 5a can be classified as a type B P-gp inhibitor (with both substrate and inhibitor activities) with an additional function of suppressing P-gp overexpression. The results might be clinically useful in the development of anticancer drugs against cancers with multidrug resistance.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Artemisininas/química , Artemisininas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , Paclitaxel , RNA Mensageiro/metabolismoRESUMO
We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK+)-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63µM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50=9.8±0.6µM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca2+ channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension.
Assuntos
Anti-Hipertensivos/química , Benzopiranos/química , Bloqueadores dos Canais de Cálcio/química , Antagonistas do Receptor de Endotelina A/química , Antagonistas do Receptor de Endotelina B/química , Phaeophyceae/química , Administração Oral , Animais , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/farmacologia , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/fisiologia , Benzopiranos/isolamento & purificação , Benzopiranos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Antagonistas do Receptor de Endotelina A/isolamento & purificação , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/isolamento & purificação , Antagonistas do Receptor de Endotelina B/farmacologia , Masculino , Phaeophyceae/metabolismo , Coelhos , Ratos , Ratos Endogâmicos SHR , Receptor de Endotelina A/química , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/química , Receptor de Endotelina B/metabolismoRESUMO
We synthesized C-10 substituted triazolyl artemisinins by the Huisgen cycloaddition reaction between dihydroartemisinins (2) and variously substituted 1, 2, 3-triazoles (8a-8h). The antimalarial activities of 32 novel artemisinin derivatives were screened against a chloroquine-resistant parasite. Among them, triazolyl artemisinins with electron-withdrawing groups showed stronger antimalarial activities than those shown by the derivatives having electron-donating groups. In particularly, m-chlorotriazolyl artemisinin (9d-12d) showed antimalarial activity equivalent to that of artemisinin and could be a strong drug candidate.
Assuntos
Antimaláricos , Artemisininas/química , Triazóis/química , Reação de Cicloadição , Plasmodium falciparum/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We synthesized a library of curcumin mimics with diverse alkylsulfonyl and substituted benzenesulfonyl modifications through a simple addition reaction of important intermediate, 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-propenone (10), with various sulfonyl chloride reactants and then tested their vasodilatation effect on depolarization (50 mM K(+))- and endothelin-1 (ET-1)-induced basilar artery contraction. Generally, curcumin mimics with aromatic sulfonyl groups showed stronger vasodilation effect than alkyl sulfonylated curcumin mimics. Among the tested compounds, six curcumin mimics (11g, 11h, 11i, 11j, 11l, and 11s) in a depolarization-induced vasoconstriction and seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) in an ET-1-induced vasoconstriction showed strong vasodilation effect. Based on their biological properties, synthetic curcumin mimics can act as dual antagonist scaffold of L-type Ca(2+) channel and endothelin A/B2 receptor in vascular smooth muscle cells. In particular, compounds 11g and 11s are promising novel drug candidates to treat hypertension related to the overexpression of L-type Ca(2+) channels and ET peptides/receptors-mediated cardiovascular diseases.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Curcumina/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo L/metabolismo , Curcumina/síntese química , Curcumina/química , Relação Dose-Resposta a Droga , Antagonistas do Receptor de Endotelina A/síntese química , Antagonistas do Receptor de Endotelina A/química , Antagonistas do Receptor de Endotelina B/síntese química , Antagonistas do Receptor de Endotelina B/química , Masculino , Estrutura Molecular , Coelhos , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Relação Estrutura-AtividadeRESUMO
Cerebral hyperperfusion syndrome (CHS) is increasingly recognized as an uncommon, but serious, complication subsequent to carotid artery stenting (CAS) and carotid endarterectomy (CEA). The onset of CHS generally occurs within two weeks of CEA and CAS, and a delay in the onset of CHS of over one week after CAS is quite rare. We describe a patient who developed CHS three weeks after CAS with status epilepticus.
RESUMO
A newly designed curcumin mimic library (11a-11k) with 2-ethylamino groups in a chalcone structure and variously substituted triazole groups as side chains was synthesized using the Huisgen 1,3-cycloaddition reaction between various alkynes (a-k) and an intermediate (10), with CuSO4 and sodium ascorbate in a solution mixture of chloroform, ethanol, and water (5:3:1) at room temperature for 5h. In the lactate dehydrogenase (LDH) release assay involving co-treatment with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and/or synthetic curcumin derivatives using TRAIL-resistant human CRT-MG astroglioma cells, the novel curcumin mimic library was found to effectively stimulate the cytotoxicity of TRAIL, causing mild cytotoxicity when administered alone. In particular, 11a and 11j are promising candidates for TRAIL-sensitizers with potential use in combination chemotherapy for brain tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Curcumina/química , Dietilaminas/química , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Triazóis/química , Protocolos de Quimioterapia Combinada Antineoplásica/síntese química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ligante Indutor de Apoptose Relacionado a TNF/síntese química , Ligante Indutor de Apoptose Relacionado a TNF/químicaRESUMO
The chlorophyll-related compound pheophorbide a (Pa) was successively purified from an edible red seaweed, Grateloupia elliptica, using silica, octadecyl silica column chromatography and reversed phase-high-performance liquid chromatography, as well as the cell cycle inhibitory and apoptotic effects of Pa being investigated in U87MG glioblastoma cells. The Pa exhibited strong anticancer effects in the absence of direct photo-irradiation against various cancer cell lines, including U87MG, SK-OV-3, and HeLa cells. Among the cancer cells, the strongest anticancer activity of Pa exhibited on U87MG cells with IC50 values of 2.8 µg/ml. In addition, Pa specifically had cytostatic activity on glioblastoma cells rather than human umbilical vein endothelial cells. Analysis of the cell cycle distribution showed that Pa induced G0/G1 arrest of U87 MG cells. In addition, arrested cells induced late apoptosis and DNA degradation under dark condition. These results suggest that Pa isolated from G. elliptica is a potential glioblastoma-specific anticancer agent without side effects on normal cells.
Assuntos
Antineoplásicos/farmacologia , Clorofila/análogos & derivados , Citostáticos/farmacologia , Neurônios/efeitos dos fármacos , Rodófitas/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/toxicidade , Apoptose , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Clorofila/isolamento & purificação , Clorofila/farmacologia , Citostáticos/isolamento & purificação , Citostáticos/toxicidade , Fragmentação do DNA , Células Endoteliais/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Humanos , Concentração Inibidora 50RESUMO
A specific blocker of L-type Ca(2+) channels may be useful in decreasing arterial tone by reducing the open-state probability of L-type Ca(2+) channels. The aim of the present study was to evaluate the farnesylacetones, which are major active constituents of Sargassum siliquastrum, regarding their vasodilatation efficacies, selectivities toward L-type Ca(2+) channels, and in vivo antihypertensive activities. The application of 5E-(farnesylacetone 311) or 5Z-farnesylacetone (farnesylacetone 312) induced concentration-dependent vasodilatation effects on the basilar artery that was pre-contracted with depolarization and showed an ignorable potential role of endothelial-derived nitric oxide. We also tested farnesylacetone 311 or 312 to determine their pharmacological profiles for the blockade of native L-type Ca(2+) channels in basilar arterial smooth muscle cells (BASMCs) and ventricular myocytes (VMCs), cloned L- (α1C/ß2a/α2δ), N- (α1B/ß1b/α2δ), and T-type Ca(2+) channels (α1G, α1H, and α1I). Farnesylacetone 311 or 312 showed greater selectivity toward the L-type Ca(2+) channels among the tested voltage-gated Ca(2+) channels. The ranked order of the potency for farnesylacetone 311 was cloned α1CâL-type (BASMC)âL-type (VMCs)>α1B>α1H>α1I>α1G and that for farnesylacetone 312 was cloned α1CâL-type (BASMCs)âL-type (VMCs)>α1H>α1G>α1B>α1I. The oral administration of the farnesylacetone 311 (80mg/kg) conferred potent, long-lasting antihypertensive activity in spontaneous hypertensive rats, but it did not alter the heart rate.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Sargassum/química , Terpenos/farmacologia , Administração Oral , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/farmacologia , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/metabolismo , Tempo de Circulação Sanguínea , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Canais de Cálcio Tipo L/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Coelhos , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Terpenos/química , Terpenos/isolamento & purificação , Vasodilatação/efeitos dos fármacosRESUMO
An extract of the red alga, Neorhodomela aculeata, exhibited antiviral activity against human rhinoviruses. Bioassay-guided purification was performed to yield six compounds, which were subsequently identified as lanosol (1) and five polybromocatechols (2-6) by spectroscopic methods, including 1D and 2D NMR and mass spectrometric analyses. Structurally, all of these compounds, except compound 5, contain one or two 2,3-dibromo-4,5-dihydroxyphenyl moieties. In a biological activity assay, compound 1 was found to possess antiviral activity with a 50% inhibitory concentration (IC50) of 2.50 µg/mL against HRV2. Compound 3 showed anti-HRV2 activity, with an IC50 of 7.11 µg/mL, and anti-HRV3 activity, with an IC50 of 4.69 µg/mL, without demonstrable cytotoxicity at a concentration of 20 µg/mL. Collectively, the results suggest that compounds 1 and 3 are candidates for novel therapeutics against two different groups of human rhinovirus.
Assuntos
Antivirais/farmacologia , Catecóis/química , Catecóis/farmacologia , Rhinovirus/efeitos dos fármacos , Rodófitas/química , Rodófitas/metabolismo , Antivirais/química , Catecóis/metabolismo , Células HeLa , Humanos , Estrutura MolecularRESUMO
Amorphastilbol (APH-1), isolated from a Robinia pseudoacacia var. umbraculifer [corrected] seed extract, is a biologically interesting natural trans-stilbene compound with dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist activity. After total synthesis of APH-1 and its derivatives by Pd-catalyzed Suzuki-Miyaura cross-coupling of a common (E)-styryl bromide intermediate and various aromatic trifluoroborate compounds, we biologically evaluated APH-2-APH-12 for PPAR agonist activity. APH-4 and APH-11 were effective PPARα/γ transcriptional activators, compared with APH-1. Therefore, we suggest that APH-4 and APH-11 are novel dual PPARα/γ agonists and are potentially useful for treating type 2 diabetes by enhancing glucose and lipid metabolism.
Assuntos
Canabinoides/síntese química , Hipoglicemiantes/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Robinia/química , Estilbenos/síntese química , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Boratos/química , Canabinoides/isolamento & purificação , Canabinoides/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Extratos Vegetais/química , Sementes/química , Estilbenos/isolamento & purificação , Estilbenos/farmacologiaRESUMO
In this study, we investigate an anti-mitotic potential of the novel synthetic coumarin-based compound, 7-diethylamino-3(2'-benzoxazolyl)-coumarin, in 5-fluorouracil-resistant human gastric cancer cell line SNU-620-5FU and its parental cell SNU-620. It exerts the anti-proliferative effects with similar potencies against both cancer cells, which is mediated by destabilization of microtubules and subsequent mitotic arrest. Furthermore, this compound enhances caspase-dependent apoptotic cell death via decreased expression of anti-apoptotic genes. Taken together, our data strongly support anti-mitotic potential of 7-diethylamino-3(2'-benzoxazolyl)-coumarin against drug-resistant cancer cells which will prompt us to further develop as a novel microtubule inhibitor for drug-resistant cancer chemotherapy.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Antimitóticos/farmacologia , Benzoxazóis/farmacologia , Cumarínicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Moduladores de Tubulina/farmacologiaRESUMO
A novel curcumin mimic library (14a-14h and 15a-15h) possessing variously substituted benzimidazole groups was synthesized through the aldol reaction of (E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one (7) or (E)-4-(3-hydroxy-4-methoxyphenyl)but-3-en-2-one (13) with diversely substituted benzimidazolyl-2-carbaldehyde (12a-12h). The MTT assay of the cancer cells MCF-7, SH-SY5Y, HEP-G2, and H460 showed that compound 14c with IC(50) of 1.0 and 1.9µM has a strong inhibitory effect on the growth of SH-SY5Y and Hep-G2 cells, respectively, and that compound 15h with IC(50) of 1.9µM has a strong inhibitory effect on the growth of MCF-7 cancer cells.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Curcumina/química , Curcumina/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos/química , Benzimidazóis/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Curcumina/síntese química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mimetismo Molecular , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Some promising new antiresorptive agents of potential utility for treating osteoporosis were uncovered in a curcumin mimics library possessing a substituted triazole moiety, which is synthesized by the Cu(I)-catalyzed Huisgen 1,3-cycloaddition reaction between two azido intermediates (9 and 10) and various alkynes (a-k). A tartarate-resistant acid phosphatase (TRAP) activity assay was carried out with RANKL-induced osteoclastogenesis of mouse monocyte/macrophage RAW264.7 cells; the results indicated that the curcumin mimics derived from intermediate 10 exhibited stronger inhibitory activity than 9. In particular, curcumin mimics 12h, 13c, and 13e strongly inhibited osteoclast differentiation.
Assuntos
Conservadores da Densidade Óssea , Diferenciação Celular/efeitos dos fármacos , Curcumina , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Ligante RANK/antagonistas & inibidores , Triazóis , Animais , Conservadores da Densidade Óssea/síntese química , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Linhagem Celular , Curcumina/síntese química , Curcumina/química , Curcumina/farmacologia , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Macrófagos/citologia , Camundongos , Estrutura Molecular , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologiaRESUMO
We have synthesized novel vasodilatation farnesylacetones 1 and 2, which are major active constituents of Sargassum siliquastrum collected from the coast of the East Sea in Korea, in 9 steps. A test of the vasodilatation effect of synthetic intermediates and their deprotected compounds on the basilar arteries of rabbits revealed that 14 and 14-1 have a similar dilation effect as their target marine natural products 1 and 2.
Assuntos
Acetona/análogos & derivados , Biologia Marinha , Vasodilatadores/síntese química , Acetona/química , Acetona/farmacologia , Animais , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/fisiologia , Coelhos , Vasodilatadores/farmacologiaRESUMO
A diastereomeric and regioisomeric library of 10-substituted triazolyl artemisinin compounds (6a-6h, 7a-7h, and 8a-8h) with a potent growth inhibitory activities against various cancer cell lines was established. These compounds were synthesized by a reaction with dihydroartemisinin (2) and various substituted triazoles (5a-5h) in methylene chloride using a BF(3)Et(2)O catalyst. Most of the compounds exhibited a strong potency in the submicromolar range, and, in particular, 6f, 7f, and 8f, which have a pentylphenyltriazole moiety, proved to be promising candidates for preclinical trials.
Assuntos
Ácidos/química , Artemisininas/síntese química , Artemisininas/farmacologia , Divisão Celular/efeitos dos fármacos , Artemisininas/química , Catálise , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância MagnéticaRESUMO
PURPOSE: Impending central retinal vein occlusion is associated with mild or no loss of vision; however, its progress and vision prognosis have not been clearly defined until now. Therefore, we studied the progress and prognoses in patients with impending central retinal vein occlusion. METHODS: For this study, we selected ten subjects who had been diagnosed with impending central retinal vein occlusion, and we retrospectively reviewed their progress and prognoses. RESULTS: The average age of the subjects was 31.0 years (18 to 48 years). Eight patients were male and two were female. The average observational period was 5.5 months. Six out of ten subjects were found to have no underlying systemic disease, four subjects had underlying disease. All ten patients were affected unilaterally. When initially tested, the affected eyes showed an average vision of LogMar 0.30. The final vision test revealed an average of LogMar 0.04, which indicates good progress and prognosis. In one patient, retinal hemorrhage and macular edema progressively worsened after the diagnosis, and the patient was treated with radial optic neurotomy. CONCLUSIONS: The cases of impending central retinal vein occlusion that we observed seemed to primarily affect young patients with generally good prognoses. However, in some cases, the degrees of obstruction and hemorrhage increased as time progressed. This suggests that impending central retinal vein occlusion could develop into the prodromal phase of an acute attack.
Assuntos
Oclusão da Veia Retiniana/fisiopatologia , Adolescente , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Microtubules are a proven target for anticancer drug development because they are critical for mitotic spindle formation and the separation of chromosomes at mitosis. We here report a novel synthetic microtubule inhibitor 7-diethylamino-3(2'-benzoxazolyl)-coumarin (DBC). DBC causes destabilization of microtubules, leading to a cell cycle arrest at G(2)/M stage. In addition, human cancer cells are more sensitive to DBC (IC(50) 44.8-475.2nM) than human normal fibroblast (IC(50) 7.9microM), and DBC induces apoptotic cell death of cancer cells. Furthermore, our data show that DBC is a poor substrate of drug efflux pumps and effective against multidrug resistant (MDR) cancer cells. Taken together, these results describe a novel pharmacological property of DBC as a microtubule inhibitor, which may make it an attractive new agent for treatment of MDR cancer.
Assuntos
Aminocumarinas/farmacologia , Benzoxazóis/farmacologia , Cumarínicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Moduladores de Tubulina/farmacologia , Aminocumarinas/uso terapêutico , Antimitóticos/farmacologia , Antimitóticos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzoxazóis/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cumarínicos/uso terapêutico , Fase G2/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Microtúbulos/efeitos dos fármacos , Moduladores de Tubulina/uso terapêuticoRESUMO
In order to discover novel small vasodilatory molecules for potential use in the treatment of vascular disease, we tested the vasodilatation effect of two types of synthetic curcumin mimics, amide type (3) and sulfonyl amide type (4), upon the basilar artery of rabbits. In general, the sulfonyl amide type mimic (4) is more potent than the amide type (3). Curcumin (1) and compounds 12 and 20 effectively dilated the basilar artery of white rabbits.
Assuntos
Artéria Basilar/fisiologia , Curcumina/síntese química , Mimetismo Molecular , Ácidos Sulfínicos/síntese química , Vasodilatação/fisiologia , Animais , Artéria Basilar/efeitos dos fármacos , Curcumina/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Mimetismo Molecular/fisiologia , Coelhos , Ácidos Sulfínicos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/farmacologiaRESUMO
Most of the 10-substituted triazolylartemisinin synthesized via the Huisgen 1,3-dipolar cylcoaddition of diastereomeric 10-azidoartemisinin (5, 6, and 7) with various alkynes (a-h) exhibit strong growth inhibition activity, even at sub-micromolar concentrations, against various cancer cell lines such as DLD-1, U-87, Hela, SiHa, A172, and B16. In particular, 10b and 10f showed a highly strong cytotoxicity.