Inhibitory Mechanisms of Lusianthridin on Human Platelet Aggregation

Lusianthridin is a phenanthrene derivative isolated from Dendrobium venustum. Some phenanthrene compounds have antiplatelet aggregation activities via undefined pathways. This study aims to determine the inhibitory effects and potential mechanisms of lusianthridin on platelet aggregation. The results indicated that lusianthridin inhibited arachidonic acid, collagen, and adenosine diphosphate (ADP)-stimulated platelet aggregation (IC50 of 0.02 ± 0.001 mM, 0.14 ± 0.018 mM, and 0.22 ± 0.046 mM, respectively). Lusianthridin also increased the delaying time of arachidonic acid-stimulated and the lag time of collagen-stimulated and showed a more selective effect on the secondary wave of ADP-stimulated aggregations. Molecular docking studies revealed that lusianthridin bound to the entrance site of the cyclooxygenase-1 (COX-1) enzyme and probably the active region of the cyclooxygenase-2 (COX-2) enzyme. In addition, lusianthridin showed inhibitory effects on both COX-1 and COX-2 enzymatic activities (IC50 value of 10.81 ± 1.12 µM and 0.17 ± 1.62 µM, respectively). Furthermore, lusianthridin significantly inhibited ADP-induced suppression of cAMP formation in platelets at 0.4 mM concentration (p < 0.05). These findings suggested that possible mechanisms of lusianthridin on the antiplatelet effects might act via arachidonic acid-thromboxane and adenylate cyclase pathways.

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Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature

Pharmaceuticals ◽

10.3390/ph11040101 ◽

2018 ◽

Vol 11 (4) ◽

pp. 101 ◽

Cited By ~ 26

Author(s):

Alessandra Pannunzio ◽

Mauro Coluccia

Keyword(s):

Arachidonic Acid ◽

Pharmacological Action ◽

Experimental Models ◽

General Context ◽

Cancer Disease ◽

Knowledge Based ◽

Cyclooxygenase 1 ◽

Tumor Phenotype ◽

Cox 2 ◽

Cox 1

Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE2) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway and to the effects of prostaglandins already known for their ability of affecting the tumor phenotype. A knowledge-based choice of the most appropriate tumor cell models, and a major effort in investigating the COX-1 issue in the more general context of arachidonic acid metabolic network by using the systems biology approaches, should be strongly encouraged.

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Synthesis and Antiplatelet Potential Evaluation of 1,3,4-Oxadiazoles Derivatives

Zeitschrift für Physikalische Chemie ◽

10.1515/zpch-2018-1316 ◽

2019 ◽

Vol 233 (12) ◽

pp. 1741-1759

Author(s):

Ayesha Ramzan ◽

Areesha Nazeer ◽

Ahmad Irfan ◽

Abdullah G. Al-Sehemi ◽

Francis Verpoort ◽

...

Keyword(s):

Arachidonic Acid ◽

Antiplatelet Agents ◽

Binding Pocket ◽

Quantitative Structure Activity Relationship ◽

New Drugs ◽

Aggregation Effect ◽

Antiplatelet Aggregation ◽

Cyclooxygenase 1 ◽

Aggregation Inhibition ◽

Cox 1

AbstractA novel series of 2-(3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-aryl-1,3,4-oxadiazoles (4a–4h) has been synthesized from corresponding hydrazones (3a–3h) and evaluated their antiplatelet aggregation effect induced by arachidonic acid and collagen. Spectral data and elemental evaluation were used to confirm the structure of the compounds while molecular docking against cyclooxygenase 1 and 2 (COX1 & COX2) and quantitative structure-activity relationship (QSAR) were performed in describing their antiplatelet potential. All synthesized compound exhibited more than 50% platelet aggregation inhibition against both arachidonic acid and collagen. Antiplatelet activities results showed that 4b and 4f compounds have highest % inhibition against arachidonic acid. High Egap and ionization potential values showed that the compound 4d, 4e and 4f were supposed to be more active and good electron donor while 4b, 4c, 4d, 4e, 4g and 4h might be more active due to more electrophilic sites. Interaction with more than one residues in the binding pocket of COX-1 in comparison with aspirin and ligand efficacy (LE) consequences showed that compounds have excellent action potential for COX-1. Computational evaluations are in good agreement with antiplatelet activities of the compounds. All compounds might be promising antiplatelet agents especially 4b, 4f and helpful in the synthesis of new drugs for the treatment of cardiovascular diseases (CVDs).

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Anti-Platelet Aggregation and Anti-Cyclooxygenase Activities for a Range of Coffee Extracts (Coffea arabica)

Molecules ◽

10.3390/molecules26010010 ◽

2020 ◽

Vol 26 (1) ◽

pp. 10

Author(s):

Nuntouchaporn Hutachok ◽

Pongsak Angkasith ◽

Chaiwat Chumpun ◽

Suthat Fucharoen ◽

Ian J. Mackie ◽

...

Keyword(s):

Platelet Aggregation ◽

Biological Activities ◽

Total Phenolic ◽

Inhibitory Effects ◽

Phenolic Contents ◽

Inhibition Of Platelet Aggregation ◽

Dependent Inhibition ◽

Cox 2 ◽

Activation Pathways ◽

Cox 1

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.

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Anti-Platelet Aggregation and Anti-Cyclooxygenase Activities for a Range of Coffee Extracts (Coffea arabica)

10.20944/preprints202011.0706.v1 ◽

2020 ◽

Author(s):

Nuntouchporn Hutachok ◽

Pongsak Angkasith ◽

Chaiwat Chumpun ◽

Suthat Fucharoen ◽

Ian Mackie ◽

...

Keyword(s):

Platelet Aggregation ◽

Biological Activities ◽

Total Phenolic ◽

Inhibitory Effects ◽

Phenolic Contents ◽

Inhibition Of Platelet Aggregation ◽

Dependent Inhibition ◽

Cox 2 ◽

Activation Pathways ◽

Cox 1

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 colourimetry, 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.

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Design, Synthesis, Docking Study and Antiplatelet Evaluation of New Thiosemicarbazide Derivatives Derived from Captopril

Oriental Journal Of Chemistry ◽

10.13005/ojc/350246 ◽

2019 ◽

Vol 35 (2) ◽

pp. 829-838

Author(s):

Hiba Najeh Al-Saad ◽

Ammar Abdul Razzak Mahmood ◽

Redha I. Al-Bayati

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Binding Energy ◽

Enzyme Inhibitor ◽

Adenosine Diphosphate ◽

Docking Study ◽

Molecular Docking Study ◽

Percent Inhibition ◽

Thiosemicarbazide Derivatives ◽

Cox 1

A series of thiosemicarbazide derivatives of captopril, a well-known angiotensin-converting enzyme inhibitor ACEI, have been synthesized by reaction of hydrazide of captopril with different phenylisothiocyanate substituents. The synthesized compounds were characterized using FTIR, 1HNMR and CHNS analysis. The final derivatives were tested for antiplatelet activity using multiplate analyzer and adenosine diphosphate (ADP), arachidonic acid (AA), and collagen, as platelet aggregation inducers. Among tested compounds, derivative 7 and 10 were the most potent inhibitors of platelet aggregation induced by arachidonic acid, with percent inhibition (97.14±0 and 95.71±2.02) and IC50 (2.7 and 1.21μgml), respectively. Molecular docking study was performed using purino receptor P2Y12, COX-1, and glycoprotein llbllla as the target protein, compound 7 has a potential to become as a lead molecule for COX-1 inhibitor with binding energy (-10.67) Kcal/mol. Also, compound 6 was found as the best inhibitor for the glycoprotein IIa/IIIb with percent inhibition (83.9±2.8), and binding energy (-10.05) Kcal/mol.

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Inhibitory effects of H2-receptor antagonists on platelet function in vitro

Human & Experimental Toxicology ◽

10.1191/096032799678847069 ◽

1999 ◽

Vol 18 (8) ◽

pp. 487-492 ◽

Cited By ~ 10

Author(s):

K Nakamura ◽

H Kariyazono ◽

T Shinkawal ◽

T Yamaguchi ◽

T Yamashita ◽

...

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Platelet Function ◽

Chemical Structure ◽

Adenosine Diphosphate ◽

Imidazole Ring ◽

Inhibitory Effects ◽

Receptor Antagonists ◽

Induced Aggregation

1 To evaluate in vitro inhibitory effects of four types of histamine H2-receptor antagonist (H2-receptor antagonists), famotidine, roxatidine, cimetidine and ranitidine, on platelet function, we examined aggregating potency and P-selectin levels with agonist-induced aggregation. Ranitidine and cimetidine inhibited, in concentration of 0.35 mM, the secondary aggregation induced by 5 pM adenosine diphosphate (ADP), the aggregation induced by 1,g/mL collagen and 3 gM arachidonic acid. All of H2-receptor antagonists inhibited, in concentration of 1.4 mm, the aggregation induced by ADP, collagen and arachidonic acid. Ranitidine and cimetidine reduced markedly, in same concentration, P-selectin levels after induction of aggregation by 5 gm ADP, 1 ig/xmL collagen and 3 gM arachidonic acid. When classified by the strength of inhibitory action, ranitidine and cimetidine were strong, followed by famotidine and roxatidine. 2 It is considered that inhibitory effects of H.-receptor antagonists on platelet function are weaker than those of acetylsalicylic acid (ASA), since ASA inhibited platelet aggregation in concentration of 100 MM. 3 No relationship was observed between inhibitory effects of H2-receptor antagonists on platelet aggregation induced by above agonists and the presence or absence of imidazole ring in the chemical structure.

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New pyrimidines and triazolopyrimidines as antiproliferative and antioxidants with cyclooxygenase-1/2 inhibitory potential

Future Medicinal Chemistry ◽

10.4155/fmc-2018-0285 ◽

2019 ◽

Vol 11 (13) ◽

pp. 1583-1603

Author(s):

Ashraf M Omar ◽

Heba A Abd El Razik ◽

Aly A Hazzaa ◽

Maryam AZ El-Attar ◽

Maha A El Demellawy ◽

...

Keyword(s):

Free Radicals ◽

Inhibitory Activity ◽

Docking Studies ◽

Cyclooxygenase 1 ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Cox 2 ◽

Inhibitory Potential ◽

Cox 1 ◽

Mcf 7

Aim: Cyclooxygenase-2 (COX-2) inhibition and scavenging-free radicals are important targets in cancer treatment. Materials & methods: Sulfanylpyrimidines and triazolopyrimidines were synthesized and evaluated as anticancer and antioxidant COX-1/2 inhibitors. Results: Compound 7 showed the same growth inhibitory activity as 5-fluorouracil against MCF-7. Compound 6f displayed broad-spectrum anticancer activity against the four tested cancer cell lines. Compounds 5b, 6a, 6c, 6d and 8 were found to be more active antioxidants than trolox. Compounds 6a, 6c, 6f and 8 revealed high COX-2 inhibitory activity and selectivity, which was confirmed by docking studies. Conclusion: Compound 6f could be considered as promising anticancer and antioxidant structural lead with COX-2 inhibition that deserve further derivatization and investigation.

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Stronger inhibitory effects of ticagrelor plus aspirin compared with clopidogrel plus aspirin on arachidonic acid induced platelet aggregation in patients with acute coronary syndrome with PCI

Journal of the Pakistan Medical Association ◽

10.47391/jpma.029 ◽

2020 ◽

pp. 1-7

Author(s):

Zhichao Dong ◽

Hengbo Zhai ◽

Lifei Pan ◽

Bo Zhang

Keyword(s):

Acute Coronary Syndrome ◽

Arachidonic Acid ◽

Platelet Aggregation ◽

Adenosine Diphosphate ◽

Platelet Inhibition ◽

Inhibit Platelet Aggregation ◽

Inhibitory Effects ◽

Coronary Syndrome ◽

Adp Receptor

Abstract Antagonists of the adenosine diphosphate (ADP) receptor, P2Y12 may inhibit platelet aggregation resulting from stimulation with arachidonic acid (AA). The potent P2Y12 blocker, ticagrelor has greater anti-platelet effects than clopidogrel. We explored the effects of ticagrelor versus clopidogrel on mean maximum aggregation ratios (MAR%) in response to AA stimulation in patients receiving conventional aspirin dosages. A total of 613 acute coronary syndrome (ACS) patients were followed from October 2017 to October 2018. At the 1- and 6-month follow-up visit, mean AA-MAR% was lower in the ticagrelor group when compared with the clopidogrel group (28.9% vs. 31.7%, 28.4% vs. 31.0%, P<0.001 and P=0.001, respectively). BARC1-2 bleeding occurred with greater frequency with ticagrelor rather than clopidogrel treated patients (29.3% vs. 9.5%, P<0.001; 23.5% vs. 9.3%, P<0.001). Excessive platelet inhibition and decreased AA-MAR% were considered the main reasons for the severe subcutaneous/dermal bleeding in ticagrelor treated patients. Continuous...

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Design, Synthesis and Pharmacological Evaluation of Novel Antiinflammatory and Analgesic O-Benzyloxime Compounds Derived From Natural Eugenol

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180620145609 ◽

2019 ◽

Vol 16 (10) ◽

pp. 1157-1166

Author(s):

Rodrigo César da Silva ◽

Fabiano Veiga ◽

Fabiana Cardoso Vilela ◽

André Victor Pereira ◽

Thayssa Tavares da Silva Cunha ◽

...

Keyword(s):

Formalin Test ◽

Docking Studies ◽

Paw Edema ◽

Inhibitory Effects ◽

Structural Pattern ◽

Design Synthesis ◽

Drug Candidates ◽

Anti Inflammatory ◽

Analgesic Activities ◽

Cox 1

Background: : A new series of O-benzyloximes derived from eugenol was synthesized and was evaluated for its antinociceptive and anti-inflammatory properties. Methods: : The target compounds were obtained in good global 25-28% yields over 6 steps, which led us to identify compounds (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-(4- (methylthio)benzyloxime (8b), (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- bromobenzyloxime (8d) and (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- (methylsulfonyl)benzyloxime (8f) as promising bioactive prototypes. Results:: These compounds have significant analgesic and anti-inflammatory effects, as evidenced by formalin-induced mice paw edema and carrageenan-induced mice paw edema tests. In the formalin test, compounds 8b and 8f evidenced both anti-inflammatory and direct analgesic activities and in the carrageenan-induced paw edema, with compounds 8c, 8d, and 8f showing the best inhibitory effects, exceeding the standard drugs indomethacin and celecoxib. Conclusion: : Molecular docking studies have provided additional evidence that the pharmacological profile of these compounds may be related to inhibition of COX enzymes, with slight preference for COX-1. These results led us to identify the new O-benzyloxime ethers 8b, 8d and 8f as orally bioactive prototypes, with a novel structural pattern capable of being explored in further studies aiming at their optimization and development as drug candidates.

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Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level Functional and modelling studies

Thrombosis and Haemostasis ◽

10.1160/th09-01-0057 ◽

2009 ◽

Vol 102 (08) ◽

pp. 336-346 ◽

Cited By ~ 35

Author(s):

Marilena Crescente ◽

Gisela Jessen ◽

Stefania Momi ◽

Hans-Dieter Höltje ◽

Paolo Gresele ◽

...

Keyword(s):

Salicylic Acid ◽

Platelet Aggregation ◽

Gallic Acid ◽

Molecular Modelling ◽

In Silico Docking ◽

Cyclooxygenase 1 ◽

Modelling Studies ◽

Cox 1

SummaryWhile resveratrol and quercetin possess antiplatelet activity, little is known on the effect of gallic acid on platelets.We studied the interactions of these three different polyphenols among themselves and with aspirin, at the level of platelet cyclooxygenase-1 (COX-1). Both functional (in vitro and in vivo) and molecular modelling approaches were used. All three polyphenols showed comparable antioxidant activity (arachidonic acid [AA]-induced intraplatelet ROS production); however, resveratrol and quercetin, but not gallic acid, inhibited AA-induced platelet aggregation. Gallic acid, similarly to salicylic acid, the major aspirin metabolite, prevented inhibition of AA-induced platelet function by aspirin but, at variance with salicylic acid, also prevented inhibition by the other two polyphenols. Molecular modelling studies, performed by in silico docking the polyphenols into the crystal structure of COX-1, suggested that all compounds form stable complexes into the COX-1 channel, with slightly different but functionally relevant interaction geometries. Experiments in mice showed that gallic acid administered before aspirin, resveratrol or quercetin fully prevented their inhibitory effect on serum TxB2. Finally, a mixture of resveratrol, quercetin and gallic acid, at relative concentrations similar to those contained in most red wines, did not inhibit platelet aggregation, but potentiated sub-inhibitory concentrations of aspirin. Gallic acid interactions with other polyphenols or aspirin at the level of platelet COX-1 might partly explain the complex,and possibly contrasting, effects of wine and other components of the Mediterranean diet on platelets and on the pharmacologic effect of lowdose aspirin.

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