Discovery of novel, potent, isosteviol-based antithrombotic agents

Chen, Peng; Zhang, Dianwen; Li, Meng; Wu, Qiong; Lam, Yuko P. Y.; Guo, Yan; Chen, Chen; Bai, Nan; Malhotra, Shipra; Li, Wei; O’Connor, Peter B.; Fu, Hongzheng

doi:10.1016/j.ejmech.2019.111722

Cited by 12 publications

(14 citation statements)

References 54 publications

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“…To obtain washed platelets, PRP was centrifuged at 1400 g for 15 min. 37,38 The precipitates obtained was washed twice with CGS buffer (sodium chloride, D-glucose, sodium citrate) and suspended in modified tyrode's buffer (143 mM NaCl, 5.4 mM KCl, 5 mM HEPES, 0.25 mM Na2HPO4, 0.5 mM MgCl2, 1.8 mM CaCl2, pH 7.4). The final platelet counts in PRP/washed platelets were adjusted to 2×10 8 cell/mL after counting under optical microscope.…”

Section: Platelet Preparationmentioning

confidence: 99%

The Synergistic Effect of Ginkgo biloba Extract 50 and Aspirin Against Platelet Aggregation

Huo

et al. 2021

DDDT

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We aimed to investigate potential synergistic antiplatelet effects of Ginkgo biloba extract (GBE50) in combination with aspirin using in vitro models. Methods: Arachidonic acid (AA), platelet activating factor (PAF), adenosine 5ʹ-diphosphate (ADP) and collagen were used as inducers. The antiplatelet effects of GBE50, aspirin and 1:1 combination of GBE50 and aspirin were detected by microplate method using rabbit platelets. Synergy finder 2.0 was used to analyze the synergistic antiplatelet effect. The compounds in GBE50 were identified by UPLC-Q/TOF-MS analysis and the candidate compounds were screened by TCMSP database. The targets of candidate compounds and aspirin were obtained in TCMSP, CCGs, Swiss target prediction database and drugbank. Targets involving platelet aggregation were obtained from GenCLiP database. Compound-target network was constructed and GO and KEGG enrichment analyses were performed to identify the critical biological processes and signaling pathways. The levels of thromboxane B2 (TXB2), cyclic adenosine monophosphate (cAMP) and PAF receptor (PAFR) were detected by ELISA to determine the effects of GBE50, aspirin and their combination on these pathways. Results: GBE50 combined with aspirin inhibited platelet aggregation more effectively. The combination displayed synergistic antiplatelet effects in AA-induced platelet aggregation, and additive antiplatelet effects occurred in PAF, ADP and collagen induced platelet aggregation. Seven compounds were identified as candidate compounds in GBE50. Enrichment analyses revealed that GBE50 could interfere with platelet aggregation via cAMP pathway, AA metabolism and calcium signaling pathway, and aspirin could regulate platelet aggregation through AA metabolism and platelet activation. ELISA experiments showed that GBE50 combined with aspirin could increase cAMP levels in resting platelets, and decreased the levels of TXB2 and PAFR. Conclusion:Our study indicated that GBE50 combined with aspirin could enhance the antiplatelet effects. They exerted both synergistic and additive effects in restraining platelet aggregation. The study highlighted the potential application of GBE50 as a supplementary therapy to treat thrombosis-related diseases.

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Section: Platelet Preparationmentioning

confidence: 99%

The Synergistic Effect of Ginkgo biloba Extract 50 and Aspirin Against Platelet Aggregation

Huo

et al. 2021

DDDT

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“…Subsequently, this group (Chen et al, 2019) screened the reported compounds (Chang et al, 2009;Wu et al, 2009;Zhu et al, 2013) and synthesized a series of isobutanol derivatives, in which: the introduction of ethyl acetate at 19-C would elevate the activity of the derivatives; The activity of introducing oximes at 16-c would be superior to that of introducing carbonyl and hydroxyl groups. So, they selected compound 21 (IC 50 = 2.7 ± 0.3 μM) as the leading compound, and further modifications were finished.…”

Section: Fxa Inhibitors From Natural Productsmentioning

confidence: 99%

Discovery and development of Factor Xa inhibitors (2015–2022)

Zheng

Dai

et al. 2023

Front. Pharmacol.

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As a pathological coagulation process, thrombus can lead to many serious diseases, including ischemic stroke, acute myocardial infarction (AMI), acute coronary syndrome (ACS), and deep venous thrombosis (DVT). And anticoagulant drugs are one of the most effective ways to prevent and treat these diseases. Although macromolecular anticoagulant drugs such as low molecular weight heparins (LMWHs) are widely used in the clinic, their characteristics of requiring injectable use hinder their further promotion in the clinic, and the disadvantages of oral anticoagulant drugs, such as warfarin and dabigatran etexilate, which can easily cause bleeding adverse effects, are also not addressed. Factor Xa (FXa) has gained attention because it lies at the intersection of the coagulation cascade pathways, whereas subsequently introduced Factor Xa inhibitors such as rivaroxaban and apixaban, among others, have gained market popularity because of their high potency for anticoagulation and high specificity for Factor Xa when administered orally. But some of the drawbacks that these Factor Xa inhibitors have simultaneously such as fewer indications and the lack of an effective reversal drug when bleeding occurs are urgently addressed. The development of new Factor Xa inhibitors therefore becomes one means of addressing these questions. This article summarizes the small molecule Factor Xainhibitors developed from 2015 to 2022, classifies them according to their scaffolds, focuses on the analysis of their structure-activity relationships, and provides a brief assessment of them.

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“…Otherwise, a given variable should be excluded due to no effect or a deterioration of the performance of the network. Chen et al reported that 19-ethyl ester and 16-oxime groups are the key to anticoagulant activity [10]. Moreover, it has been observed that oxime ether derivatives possessing a thiophene group or a 3-methyloxetane group exhibit excellent in vitro activity against human FXa.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…On the basis of the observations mentioned above and structure-activity relationships established in the present investigation, 26 new oxime ether isosteviol derivatives were designed, containing moieties with saturated and unsaturated alicyclic and heterocyclic four-and five-membered rings with sulphur, oxygen, or nitrogen atoms (Table 3). anticoagulant activity [10]. Moreover, it has been observed that oxime ether derivatives possessing a thiophene group or a 3-methyloxetane group exhibit excellent in vitro activity against human FXa.…”

Section: Molecular Modelingmentioning

confidence: 99%

Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation

et al. 2023

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Direct oral anticoagulants are an important and relatively new class of synthetic anticoagulant drugs commonly used for the pharmacotherapy of thromboembolic disorders. However, they still have some limitations and serious side effects, which continuously encourage medicinal chemists to search for new active compounds acting as human-activated coagulation factor X (FXa) inhibitors. Isosteviol is a nontoxic hydrolysis product of naturally occurring stevioside and possesses a wide range of therapeutic properties, including anticoagulant activity. The present contribution describes the in silico design of novel oxime ether isosteviol derivatives as well as a molecular modeling approach based on QSAR analysis and a docking simulation for searching for novel isosteviol-based compounds as potential FXa inhibitors. The elaborated ANN model, encompassing topological and geometrical information, exhibited a significant correlation with FXa-inhibitory activity. Moreover, the docking simulation indicated six of the most promising isosteviol-like compounds for further investigation. Analysis showed that the most promising derivatives contain heterocyclic, aromatic, five-membered moieties, with substituents containing chlorine or fluorine atoms. It is anticipated that the findings reported in the present work may provide useful information for designing effective FXa inhibitors as anticoagulant agents.

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Discovery of novel, potent, isosteviol-based antithrombotic agents

Cited by 12 publications

References 54 publications

The Synergistic Effect of Ginkgo biloba Extract 50 and Aspirin Against Platelet Aggregation

The Synergistic Effect of Ginkgo biloba Extract 50 and Aspirin Against Platelet Aggregation

Discovery and development of Factor Xa inhibitors (2015–2022)

Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation

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