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1.
Molecules ; 26(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375091

RESUMO

Coffee is rich in caffeine (CF), chlorogenic acid (CGA) and phenolics. Differing types of coffee beverages and brewing procedures may result in differences in total phenolic contents (TPC) and biological activities. Inflammation and increases of platelet activation and aggregation can lead to thrombosis. We focused on determining the chemical composition, antioxidant activity and inhibitory effects on agonist-induced platelet aggregation and cyclooxygenase (COX) of coffee beverages in relation to their preparation method. We prepared instant coffee and brewed coffee beverages using drip, espresso, and boiling techniques. Coffee extracts were assayed for their CF and CGA contents using HPLC, TPC using colorimetry, platelet aggregation with an aggregometer, and COX activity using ELISA. The findings have shown all coffee extracts, except the decaffeinated types, contained nearly equal amounts of CF, CGA, and TPC. Inhibitory effects of coffee extracts on platelet aggregation differed depending on the activation pathways induced by different agonists. All espresso, drip and boiled coffee extracts caused dose dependent inhibition of platelet aggregation induced by ADP, collagen, epinephrine, and arachidonic acid (ARA). The most marked inhibition was seen at low doses of collagen or ARA. Espresso and drip extracts inhibited collagen-induced platelet aggregation more than purified caffeine or CGA. Espresso, boiled and drip coffee extracts were also a more potent inhibitors of COX-1 and COX-2 than purified caffeine or CGA. We conclude that inhibition of platelet aggregation and COX-1 and COX-2 may contribute to anti-platelet and anti-inflammatory effects of espresso and drip coffee extracts.


Assuntos
Coffea/química , Café/química , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Ácido Clorogênico/química , Ácido Clorogênico/farmacologia , Cromatografia Líquida de Alta Pressão , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Agregação Plaquetária/efeitos dos fármacos
2.
J Med Chem ; 63(24): 15752-15772, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33307675

RESUMO

ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y1 and P2Y12 on the platelet. The clinical effectiveness of inhibiting P2Y12 has been well established, and preclinical studies indicated that the inhibition of P2Y1 could provide equivalent antithrombotic efficacy as P2Y12 antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1H-imidazole scaffold of our previously reported xanthine oxidase inhibitor WSJ-557, we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y1 and P2Y12. We described the structure-activity relationships of the 2-phenyl-1H-imidazole compounds, which led to the identification of the most potent antiplatelet agents, 24w and 25w, both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that 24w demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that 24w and 25w could be promising drug candidates.


Assuntos
Inibidores Enzimáticos/química , Inibidores da Agregação de Plaquetas/química , Antagonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y12/química , Receptores Purinérgicos P2Y1/química , Xantina Oxidase/antagonistas & inibidores , Animais , Sítios de Ligação , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Estabilidade de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Meia-Vida , Humanos , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/metabolismo , Inibidores da Agregação de Plaquetas/farmacologia , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Relação Estrutura-Atividade , Ticagrelor/farmacologia , Xantina Oxidase/metabolismo
3.
Eur J Med Chem ; 192: 112187, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32155530

RESUMO

Cardiovascular diseases are the leading cause of death in the world. Platelets have a major role in cardiovascular events as they bind to the damaged endothelium activating and forming thrombi. Although some hydroquinone scaffold-containing compounds have known antiplatelet activities, currently there is a lack of evidence on the antiplatelet activity of hydroquinones carrying electron attractor groups. In this work, we evaluate the antiplatelet effect of a series of ortho-carbonyl hydroquinone derivatives on cytotoxicity and function of human platelets, using collagen and thrombin receptor activator peptide 6 (TRAP-6) as agonists. Our structure-activity relationship study shows that gem-diethyl/methyl substitutions and the addition/modifications of the third ring of ortho-carbonyl hydroquinone scaffold influence on the selective index (IC50 TRAP-6/IC50 Collagen) and the inhibitory capacity of platelet aggregation. Compounds 3 and 8 inhibit agonist-induced platelet aggregation in a non-competitive manner with IC50 values of 1.77 ± 2.09 µM (collagen) and 11.88 ± 4.59 µM (TRAP-6), respectively and show no cytotoxicity. Both compounds do not affect intracellular calcium levels and mitochondrial bioenergetics. Consistently, they reduce the expression of P-selectin, activation of glycoprotein IIb/IIIa, and release of adenosine triphosphate and CD63 from platelet. Our findings may be used for further development of new drugs in platelet-related thrombosis diseases.


Assuntos
Colágeno/farmacologia , Hidroquinonas/farmacologia , Fragmentos de Peptídeos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno/química , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Hidroquinonas/síntese química , Hidroquinonas/química , Estrutura Molecular , Fragmentos de Peptídeos/química , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química , Relação Estrutura-Atividade
4.
Nat Commun ; 11(1): 398, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964886

RESUMO

A prevailing dogma is that inhibition of vascular thrombosis by antagonizing platelet integrin αIIbß3 cannot be achieved without compromising hemostasis, thus causing serious bleeding and increased morbidity and mortality. It is speculated that these adverse outcomes result from drug-induced activating conformational changes in αIIbß3 but direct proof is lacking. Here, we report the structure-guided design of peptide Hr10 and a modified form of the partial agonist drug tirofiban that act as "pure" antagonists of αIIbß3, i.e., they no longer induce the conformational changes in αIIbß3. Both agents inhibit human platelet aggregation but preserve clot retraction. Hr10 and modified tirofiban are as effective as partial agonist drugs in inhibiting vascular thrombosis in humanized mice, but neither causes serious bleeding, establishing a causal link between partial agonism and impaired hemostasis. Pure orthosteric inhibitors of αIIbß3 may thus provide safer alternatives for human therapy, and valuable tools to probe structure-activity relationships in integrins.


Assuntos
Desenho de Fármacos , Hemorragia/tratamento farmacológico , Peptídeos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Trombose/prevenção & controle , Animais , Coagulação Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Voluntários Saudáveis , Humanos , Células K562 , Masculino , Camundongos , Camundongos Transgênicos , Peptídeos/química , Peptídeos/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/uso terapêutico , Testes de Função Plaquetária , Relação Estrutura-Atividade , Tirofibana/química , Tirofibana/uso terapêutico , Fator de von Willebrand/genética
5.
Arch Pharm (Weinheim) ; 353(2): e1900231, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31808975

RESUMO

A series of 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamides 6a-u were designed according to the splicing principle of structural design in the medicinal chemistry theory and were synthesized in five steps: nitration, acylation, ammoniation, reduction, and secondary ammoniation. The structures of the target compounds were characterized and verified by infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and electron spray ionization spectroscopy. Their in vitro antiplatelet aggregation activities induced by adenosine diphosphate (ADP) or arachidonic acid (AA) were assessed by Born's method. The biological evaluation revealed that all compounds exhibited certain levels of activities in both of the antiplatelet aggregation assays; compounds 6c (IC50 = 3.84 µM) and 6f (IC50 = 3.12 µM) displayed the strongest antiplatelet aggregation activities in the ADP-induced and AA-induced assay, separately. Moreover, compounds that had stronger activities were chosen for cell toxicity testing via the cell counting kit-8 assay. The results indicated that none of the compounds had obvious cell toxicity against L929 cells at the doses of 10 and 20 µM. It is worth pointing out that compound 6c showed the highest antiplatelet activity and the lowest cell toxicity. In general, 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamides have the potential to become a kind of safer and more effective antiplatelet agents.


Assuntos
Benzamidas/farmacologia , Desenho de Fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química , Relação Estrutura-Atividade
6.
Curr Top Med Chem ; 19(31): 2919-2936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31763974

RESUMO

Cilostazol is a unique platelet inhibitor that has been used clinically for more than 20 years. As a phosphodiesterase type III inhibitor, cilostazol is capable of reversible inhibition of platelet aggregation and vasodilation, has antiproliferative effects, and is widely used in the treatment of peripheral arterial disease, cerebrovascular disease, percutaneous coronary intervention, etc. This article briefly reviews the pharmacological mechanisms and clinical application of cilostazol.


Assuntos
Cilostazol/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cilostazol/química , Humanos , Estrutura Molecular , Inibidores da Agregação de Plaquetas/química
7.
Cardiovasc Hematol Agents Med Chem ; 17(2): 115-124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622211

RESUMO

AIM: This study aims to find out the components responsible for the antithrombotic activity of Nelumbo nucifera. MATERIAL AND METHODS: Petroleum ether, chloroform and hydroalcoholic extracts of whole plant of Nelumbo nucifera (Lotus) were prepared and assessed for its thrombolytic, anti-platelet aggregation activity and bleeding time. The extracts were further analyzed through HPTLC and GC-MS. Statistical analysis was conducted through ANOVA trailed by Tukey's multiple comparison test test. RESULTS: Hydroalcoholic extract showed the highest activity at the concentration of 400µg/ml in thrombolytic assay (42.03 ± 5.76), anti-platelet aggregation assay (57.93 ± 1.68) and bleeding time (70.17 ± 2.16) in comparison to clopodigrel (33.76 ± 3.43), aspirin (66.55 ± 1.86) and aspirin (93.85 ± 2.75) at the concentration of 100 µg/ml respectively. 25 peaks were identified through GC-MS, out of which, ferulic acid (14.2µ/g) and quercetin (5.4 µ/g) are active chemical compounds. HPTLC showed different chromatograms in hydroalcoholic extracts like (1) chlorogenic, (2) quercetin, (3) benzoic acid, (4) caffeic acid, (5) ferulic acid, (6) kaempferol, and (7) gallic acid. CONCLUSION: Based on these findings, flavonoids present in hydroalcoholic extract may be developed into a drug for clinical application for the treatment of thrombosis in patients.


Assuntos
Fibrinolíticos/uso terapêutico , Flavonoides/uso terapêutico , Nelumbo/química , Extratos Vegetais/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Trombose/tratamento farmacológico , Animais , Tempo de Lise do Coágulo de Fibrina , Fibrinolíticos/química , Flavonoides/química , Masculino , Extratos Vegetais/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Ratos Wistar , Terapia Trombolítica
8.
Molecules ; 24(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597284

RESUMO

Sea buckthorn (Elaeagnus rhamnoides (L.) A. Nelson) is a small tree or bush. It belongs to the Elaeagnaceae family, and has been used for many years in traditional medicine in both Europe and Asia. However, there is no data on the effect of sea buckthorn leaves and twigs on the properties of blood platelets. The aim of the study was to analyze the biological activity of phenolic extracts from leaves and twigs of sea buckthorn in blood platelets in vitro. Two sets of extracts were used: (1) phenolic compounds from twigs and (2) phenolic compounds from leaves. Their biological effects on human blood platelets were studied by blood platelet adhesion, platelet aggregation, arachidonic acid metabolism and the generation of superoxide anion. Cytotoxicity was also evaluated against platelets. The action of extracts from sea buckthorn twigs and leaves was compared to activities of the phenolic extract (a commercial product from the berries of Aronia melanocarpa (Aronox®) with antioxidative and antiplatelet properties. This study is the first to demonstrate that extracts from sea buckthorn leaves and twigs are a source of bioactive compounds which may be used for the prophylaxis and treatment of cardiovascular pathologies associated with blood platelet hyperactivity. Both leaf and twig extracts were found to display anti-platelet activity in vitro. Moreover, the twig extract (rich in proanthocyanidins) displayed better anti-platelet potential than the leaf extract or aronia extract.


Assuntos
Elaeagnaceae/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Inibidores da Agregação de Plaquetas/farmacologia , Humanos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação
9.
Chin J Nat Med ; 17(8): 591-599, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472896

RESUMO

Whitmania pigra has been used as a traditional Chinese medicine (TCM) for promoting blood circulation, alleviating blood coagulation, activating meridians and relieving stasis for several hundred years. However, the therapeutic components of this species, especially proteins and peptides were poorly exploited. Until now only a few of them were obtained by using chromatographic isolation and purification. In recent decade, transcriptome techniques were rapidly developed, and have been used to fully reveal the functional components of many animal venoms. In the present study, the cDNA of the salivary gland of Whitmania pigra was sequenced by illumina and the transcriptome was assembled by using Trinity. The proteome were analysed by LC-MS/MS. Based on the data of the transcriptome and the proteome, a potential antiplatelet protein named pigrin was found. Pigrin was cloned and expressed using P. pastoris GS115. The antiplatelet andantithrombotic bioactivities of pigrin were tested by using aggregometer and the rat arterio-venous shunt thrombosis model, respectively. Thebleeding time of pigrin was measured by a mice tail cutting method. The docking of pigrin and protease-activated receptor 1 (PAR1) or collagen were conducted using the ZDOCK Server. Pigrin was able to selectively inhibit platelet aggregation stimulated by PAR1 agonist and collagen. Pigrin attenuated thrombotic formation in vivo in rat, while did not prolong bleeding time at its effective dosage. There are significant differences in the key residues participating in binding of Pigrin-Collagen complex from Pigrin-PAR1 complex. In conclusion,a novel PAR1 inhibitor pigrin was found from the leech Whitmania pigra. This study helped to elucidate the mechanism of the leech for the treatment of cardiovascular disorder.


Assuntos
Sanguessugas/química , Receptor PAR-1/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Fibrinolíticos/química , Fibrinolíticos/isolamento & purificação , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Perfilação da Expressão Gênica , Sanguessugas/genética , Sanguessugas/metabolismo , Camundongos Endogâmicos ICR , Modelos Moleculares , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Proteômica , Ratos Sprague-Dawley , Glândulas Salivares/química , Glândulas Salivares/metabolismo , Trombose/prevenção & controle
10.
Eur J Med Chem ; 183: 111722, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563807

RESUMO

Thrombosis is a pathological coagulation process and can lead to many serious thrombotic diseases. Here, we report a novel potent antithrombotic compound (6k) based on isosteviol with anticoagulant and antiplatelet activities. 6k selectively inhibited FXa (Ki = 0.015 µM) against a panel of serine proteases and showed excellent anticoagulant activity (significant prolongation of ex vivo PT and aPTT over the vehicle, p < 0.01). 6k also significantly inhibited ADP-induced platelet aggregation in rats relative to the vehicle (p < 0.01). Furthermore, 6k exhibited potent ex vivo and in vivo antithrombotic activity in rats relative to the vehicle (p < 0.01 and p < 0.0001, respectively). Novel structure 6k, with potent antithrombotic activity, is expected to lead a promising approach for the development of antithrombotic agents.


Assuntos
Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Trombose/tratamento farmacológico , Animais , Descoberta de Drogas , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Tempo de Tromboplastina Parcial , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar , Trombina/metabolismo
11.
BMC Complement Altern Med ; 19(1): 236, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481052

RESUMO

BACKGROUND: Syzygium cumini (L.) Skeels. is one of the very popular traditionally used medicinal plants with numerous pharmacological activities including antioxidant, hypoglycemic and anti-inflammatory. However, actions of S. cumini on blood coagulation and other parameters of blood were poorly pharmacologically studied. Therefore, aim of this present investigation is to examine the effects of methanolic extract of S. cumini on blood coagulation and anticoagulation factors in healthy white albino rabbits at different doses. METHODS: Blood samples were drawn twice during this study and biochemical assays were performed to determine the effect on different parameters such as coagulation, anticoagulation, hematological, Protein C (PC) and thrombin antithrombin (TAT) complex and platelet aggregation. RESULTS: The results showed significant increase in RBCs, hemoglobin, hematocrit and platelets counts up to 1.4 × 103/cm, 2.2 g/dl, 6%, 248.2 × 103/cm respectively. While, thrombin and bleeding time were also prolonged in dose dependent manner which is highly significant (p ≤ 0.005) as compared to control. Similarly, highly significantly increased (p ≤ 0.005) in levels of protein C, thrombin antithrombin complex at dose of 500 mg/kg were observed. Whereas, levels of platelets aggregation and fibrinogen were decreased at high doses. CONCLUSION: The obtained findings of hematological and coagulation tests concludes possibly S. cumini possess anticoagulant and antiplatelet effects.


Assuntos
Anticoagulantes/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Syzygium/química , Animais , Anticoagulantes/química , Coagulação Sanguínea/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Folhas de Planta/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Coelhos
12.
Arch Pharm Res ; 42(10): 862-878, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31493264

RESUMO

Ginseng is the most frequently used herbal medicine for immune system stimulation and as an adjuvant with prescribed drugs owing to its numerous pharmacologic activities. It is important to investigate the beneficial effects and interaction of ginseng with therapeutic drugs. This review comprehensively discusses drug metabolizing enzyme- and transporter-mediated ginseng-drug interaction by analyzing in vitro and clinical results with a focus on ginsenoside, a pharmacologically active marker of ginseng. Impact of ginseng therapy or ginseng combination therapy on diabetic patients and of ginseng interaction with antiplatelets and anticoagulants were evaluated based on ginseng origin and ginsenoside content. Daily administration of Korean red ginseng (0.5-3 g extract; dried ginseng > 60%) did not cause significant herb-drug interaction with drug metabolizing enzymes and transporters. Among various therapeutic drugs administered in combination with ginseng, adjuvant chemotherapy, comprising ginseng (1-3 g extract) and anticancer drugs, was effective for reducing cancer-related fatigue and improving the quality of life and emotional scores. Limited information regarding ginsenoside content in each ginseng product and plasma ginsenoside concentration among patients necessitates standardization of ginseng product and establishment of pharmacokinetic-pharmacodynamic correlation to further understand beneficial effects of ginseng-therapeutic drug interactions in future clinical studies.


Assuntos
Anticoagulantes/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ginsenosídeos/farmacologia , Hipoglicemiantes/farmacologia , Neoplasias/tratamento farmacológico , Panax/química , Inibidores da Agregação de Plaquetas/farmacologia , Anticoagulantes/química , Antineoplásicos Fitogênicos/química , Diabetes Mellitus/tratamento farmacológico , Ginsenosídeos/química , Interações Ervas-Drogas , Humanos , Hipoglicemiantes/química , Inibidores da Agregação de Plaquetas/química
13.
Future Med Chem ; 11(16): 2051-2062, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31538518

RESUMO

Aim: The current limitations of antiplatelet therapy promote the search for new antithrombotic agents. Here we describe novel platelet aggregation inhibitors that combine pyridazinone and coumarin scaffolds in their structure. Results: The target compounds were synthesized in good yield from maleic anhydride, following a multistep strategy. The in vitro studies demonstrated significant antiplatelet activity in many of these compounds, with IC50 values in the low micromolar range, revealing that the activity was affected by the substitution pattern of the two selected cores. Additional studies point out their effect as inhibitors of glycoprotein (Gp) IIb/IIIa activation. Conclusion: This novel hybrid structure can be considered a good prototype for the development of potent platelet aggregation inhibitors.


Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Desenho de Fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Humanos , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Piridazinas/química , Piridazinas/farmacologia
14.
Nutrients ; 11(10)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554252

RESUMO

Silymarin is a traditional drug and food supplement employed for numerous liver disorders. The available studies indicate that its activities may be broader, in particular due to claimed benefits in some cardiovascular diseases, but the contributions of individual silymarin components are unclear. Therefore, we tested silymarin flavonolignans as pure diastereomers as well as their sulfated metabolites for potential vasorelaxant and antiplatelet effects in isolated rat aorta and in human blood, respectively. Eleven compounds from a panel of 17 tested exhibited a vasorelaxant effect, with half maximal effective concentrations (EC50) ranging from 20 to 100 µM, and some substances retained certain activity even in the range of hundreds of nM. Stereomers A were generally more potent as vasorelaxants than stereomers B. Interestingly, the most active compound was a metabolite-silychristin-19-O-sulfate. Although initial experiments showed that silybin, 2,3-dehydrosilybin, and 2,3-dehydrosilychristin were able to substantially block platelet aggregation, their effects were rapidly abolished with decreasing concentration, and were negligible at concentrations ≤100 µM. In conclusion, metabolites of silymarin flavonolignans seem to have biologically relevant vasodilatory properties, but the effect of silymarin components on platelets is low or negligible.


Assuntos
Aorta/efeitos dos fármacos , Flavonolignanos/química , Flavonolignanos/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Humanos , Masculino , Estrutura Molecular , Ratos , Vasodilatadores
15.
Bioconjug Chem ; 30(9): 2349-2357, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31429535

RESUMO

Activated platelets have a high affinity for tumor cells, and consequently, they can protect tumor cells from environmental stress and immune attacks. Therefore, preventing platelet-tumor cell interaction can lead to the elimination of circulating tumor cells via natural killer cells and finally metastasis inhibition. It is also shown that CREKA (Cys-Arg-Glu-Lys-Ala), a tumor-homing pentapeptide, targets fibrin-fibronectin complexes that are found on the tumor stroma and the vessel walls. In this study, we linked CREKA to Ticagrelor, a reversible antagonist of the P2Y12 receptor on platelets. In vitro experiments indicated that CREKA-Ticagrelor could not only inhibit the platelet-induced migration of tumor cells with an invasive phenotype but also prevent tumor-platelet interaction. In vivo antitumor and antimetastasis results of this drug showed that CREKA-Ticagrelor could specifically target the tumor tissues within 24 h post intravenous injection and suppress lung metastasis. Meanwhile, by having this antiplatelet drug targeted, its side effects were minimized, and bleeding risk was decreased. Thus, CREKA-Ticagrelor offers an efficient antimetastatic agent.


Assuntos
Peptídeo Hidrolases/química , Peptídeo Hidrolases/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Ticagrelor/química , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/prevenção & controle , Peptídeo Hidrolases/efeitos adversos , Peptídeo Hidrolases/farmacocinética , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Segurança , Distribuição Tecidual , Cicatrização/efeitos dos fármacos
16.
Future Med Chem ; 11(14): 1757-1775, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31288579

RESUMO

Platelet aggregation is the central event in hemostasis and thrombosis. Up to now, many agents inhibiting platelet aggregation have been approved for the treatment of thrombotic disorders. In this review, we mainly summarized the progress in the research of platelet aggregation inhibitors based on different design strategies. The advantage and challenge of corresponding targets are also discussed in this article. We hope more platelet aggregation inhibitors with efficacy and safety will be discovered in the future.


Assuntos
Desenho de Fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Plaquetas/efeitos dos fármacos , Humanos , Estrutura Molecular , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química
17.
Drug Dev Ind Pharm ; 45(9): 1515-1522, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31267803

RESUMO

Optimization of electrospray ionization (ESI) parameters is routinely carried out by one factor at a time (OFAT) or auto-tune software (ATS). Design of experiments (DOE) approach has been reported to be an excellent alternative to OFAT or ATS. Box-Behnken Design (BBD) was successfully used to optimize ESI parameters like nebulizing gas flow rate, desolvation line temperature, heat block temperature, and drying gas flow rate for [M + H]+ intensity of Clopidogrel bisulfate (CLP) and Ticlopidine (TLP). BBD model was found to be significant with p < .0001 for both CLP and TLP. The predicted and optimized (OL) ESI parameters were used for chromatographic analysis and were compared against three levels of ESI parameters, i.e. low level (LL), medium level (ML), and high level (HL). The OL ESI parameters were subjected to chromatographic analysis and its mean peak area was significantly higher than mean peak area for LL, ML, and HL ESI in case of CLP and TLP (p < .001). However, no significant difference was observed between the mean peak area for ML and OL of TLP. Thus, BBD can be considered with 29 trials to optimize four mass spectrometric parameters. The liquid chromatographic parameters percentage of methanol, percentage of formic acid and flow rate were also optimized using BBD. However, the optimized method did not significantly influence the peak response over the non-optimized method.


Assuntos
Inibidores da Agregação de Plaquetas/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Química Farmacêutica , Cromatografia Líquida de Alta Pressão/métodos , Clopidogrel/análise , Clopidogrel/química , Modelos Químicos , Inibidores da Agregação de Plaquetas/química , Sensibilidade e Especificidade , Ticlopidina/análise , Ticlopidina/química
18.
Int J Mol Sci ; 20(11)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163690

RESUMO

Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10-80 µM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2-PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases.


Assuntos
Plaquetas/metabolismo , Trombose/etiologia , Trombose/prevenção & controle , Umbeliferonas/uso terapêutico , Biomarcadores , Plaquetas/efeitos dos fármacos , Humanos , Fosfolipase C gama/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Umbeliferonas/química , Umbeliferonas/farmacologia
19.
J Enzyme Inhib Med Chem ; 34(1): 999-1009, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072143

RESUMO

This study explored the possible bioactive ingredients and target protein of Rostellularia procumbens (L.) Nees. The results of optical turbidimetry revealed that the ethyl acetate extraction obtained from R. procumbens (L.) Nees could inhibit platelet aggregation. Gene chip was used to investigate differentially expressed genes. According to the results of the gene chip, the targets of compounds isolated from the ethyl acetate extraction were predicted by network pharmacology. Computational studies revealed that chinensinaphthol methyl ether and neojusticin B may target the integrin αIIbß3 protein. The results of Prometheus NT.48 and microscale thermophoresis suggested that the molecular interactions between the two compounds with purified integrin αIIbß3 protein in the optimal test conditions were coherent with the docking results. To our best knowledge, this is the first report to state that chinensinaphthol methyl ether and neojusticin B target the integrin αIIbß3 protein.


Assuntos
Acanthaceae/química , Derivados de Benzeno/farmacologia , Dioxolanos/farmacologia , Éteres/farmacologia , Lignanas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/isolamento & purificação , Dioxolanos/química , Dioxolanos/isolamento & purificação , Relação Dose-Resposta a Droga , Éteres/química , Éteres/isolamento & purificação , Humanos , Lignanas/química , Lignanas/isolamento & purificação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação , Testes de Função Plaquetária , Relação Estrutura-Atividade
20.
Langmuir ; 35(21): 6898-6904, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31050437

RESUMO

Dopamine surface chemistry has been of great interest because of its universal coating property and ability to transform nonadhesive molecules into adhesive molecules. Catechol oxidation and intramolecular cyclization underlie the unique property of dopamine (DA) surface chemistry and provide clues for developing new surface modification reagents such as norepinephrine, 5-pyrogallol-2-aminoethane, and perfluorinated DA derivatives. Based on these inspiring properties, a fast and universal surface chemistry technique using 4-(3-aminopropyl)-benzene-1,2-diol (3-catecholpropanamine, CPA) is reported herein. A single carbon insertion in the aliphatic chain of DA gives rise to the significantly accelerated intermolecular assembly and surface coating of CPA. The effect of CPA conjugation on an anticoagulant polysaccharide coating is also investigated. The use of CPA instead of DA to make polysaccharide coating materials improves the coating rate, while maintaining excellent antiplatelet performance on the coated surface.


Assuntos
Plaquetas/metabolismo , Materiais Revestidos Biocompatíveis/química , Dopamina/química , Inibidores da Agregação de Plaquetas/química , Humanos , Propriedades de Superfície
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