Effects of warfarin on biological processes other than haemostasis: A review

Aleksandrov, Aleksandra Popov; Mirkov, Ivana; Ninkov, Marina; Mileusnic, Dina; Demenesku, Jelena; Subota, Vesna; Kataranovski, Dragan; Kataranovski, Milena

doi:10.1016/j.fct.2018.01.019

Cited by 22 publications

(13 citation statements)

References 190 publications

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“…A second interesting class of natural products for scaffold building are coumarins. This class of compound includes anti-coagulants such as warfarin [17], choleretics [18] and even antibiotics such as novobiocin, and several structures are shown in Figure 1. Coumarins are also used extensively as starting materials in drug discovery, and some coumarin derivatives have potent enzyme inhibition activity [19–21].…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

et al. 2018

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Chalcones containing tertiary amine side-chains have potent activity as acetylcholinesterase (AChE) inhibitors. However, the effects of the location of the tertiary amine groups as well as of other groups on AChE and butyrylcholinesterase (BChE) activity have not been reported. Here, we report the synthesis and testing of 36 new coumarin-chalcone hybrids (5d-7j, 9d-11f, 12k-13m) against AChE and BChE. The nature and position of the chalcone substituents had major effects on inhibitory activity as well as selectivity for AChE over BChE. Compounds with para-substituted chalcone fragments in which the substituents were choline-like had potent activity against AChE and poor activity against BChE, while ortho-substituted analogs exhibited an opposite effect. Replacement of the terminal amine groups by amide, alkyl or alkenyl groups abrogated activity. Compound 5e showed potent inhibitory activity [Formula: see text]) and good selectivity for AChE over BChE (ratio 27.4), and a kinetic study showed that 5e exhibited mixed-type inhibition against AChE. Computational docking results indicate that 5e binds to Trp 279, Tyr334 and Trp 84 in AChE, but only to Trp 82 in BChE. Overall, the results show that coumarin-chalcone hybrids with choline-like side-chains have promising activity and selectivity against AChE and be promising therapeutic leads for Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

et al. 2018

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“…The latter is a transporter of biologically active steroids (Hammond 2016). Faced with the lack of pharmacological information on flocoumafen, Warfarin, a parent compound for superwarfarins, will be used for biochemical comparisons due to its widespread use and available literature data (Popov-Aleksandrov et al 2018). One interesting flocoumafen target discovered by virtual screening was MMP-9.…”

Section: Discussionmentioning

confidence: 99%

In Silico Analysis to Identify Molecular Targets for Chemicals of Concern: The Case Study of Flocoumafen, an Anticoagulant Pesticide

Coronado-Posada

Mercado-Camargo

Olívero-Verbel

2021

Enviro Toxic and Chemistry

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Rodenticides are pesticides used worldwide, with little information available regarding health consequences in wildlife and humans. The aim of the present study was to use virtual screening to identify potential targets for flocoumafen, a superwarfarin rodenticide. Blind docking of more than 841 human proteins was carried out employing AutoDock Vina. The strength of the ligand interaction with the proteins was quantified based on the binding affinity score (kcal/mol). Results indicate that flocoumafen could be a promiscuous ligand for diversity of cellular protein targets. The best complexes were obtained for prostaglandin F synthase (−14.2 kcal/mol) and serum albumin (−14.0 kcal/mol) followed by glucocorticoid receptor 2, matrix metalloproteinase-9, nuclear receptor ROR-alpha, and activin receptor type-1, all with values equal or better than −13.5 kcal/mol. Docking method validation based on the root-mean-square deviation showed that flocoumafen had good capability to predict corresponding co-crystallized poses; and molecular dynamics simulations suggested the complex with greater binding affinity was thermodynamically stable. Protein-protein interaction networks built with main protein targets revealed that protein kinase B (AKT1), ribosomal protein S6 kinase B1 (RPS6KB1), phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), retinoid X receptor alpha (RXRA), and protein phosphatase 2 catalytic subunit alpha (PPP2CA) were major hub proteins, whereas the gene ontology analysis reported that cellular response to endogenous stimulus, protein binding, and the TOR complex were the biological processes, molecular function, and cell component enrichments, respectively. These results should motivate more ecotoxicity testing for flocoumafen and other superwarfarins, as well as precautionary legislation to minimize exposure to these highly toxic chemicals.

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“…However, VKAs also limit the vitamin K‐dependent anticoagulants, protein C and protein S, and can have off‐target effects. 32 Another intriguing explanation for these findings comes from studies showing that thrombin promotes T‐cell effector functions. Thrombin has been shown to promote T‐cell proliferation and cytokine production at physiological concentrations.…”

Section: Hemostatic System Components Regulate Innate and Adaptive Tu...mentioning

confidence: 99%

Hemostasis and tumor immunity

Cantrell

Palumbo

2022

Research and Practice in Thrombosis and Haemostasis

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Significant data have accumulated demonstrating a reciprocal relationship between cancer and the hemostatic system whereby cancer promotes life‐threatening hemostatic system dysregulation (e.g., thromboembolism, consumptive coagulopathy), and hemostatic system components directly contribute to cancer pathogenesis. The mechanistic underpinnings of this relationship continue to be defined, but it is becoming increasingly clear that many of these mechanisms involve crosstalk between the hemostatic and immune systems. This is perhaps not surprising given that there is ample evidence for bidirectional crosstalk between the hemostatic and immune systems at multiple levels that likely evolved to coordinate the response to injury, host defense, and tissue repair. Much of the data linking hemostasis and immunity in cancer biology focus on innate immune system components. However, the advent of adaptive immunity‐based cancer therapies such as immune checkpoint inhibitors has revealed that the relationship of hemostasis and immunity in cancer extends to the adaptive immune system. Adaptive immunity‐based cancer therapies appear to be associated with an increased risk of thromboembolic complications, and hemostatic system components appear to regulate adaptive immune functions through diverse mechanisms to affect tumor progression. In this review, the evidence for crosstalk between hemostatic and adaptive immune system components is discussed, and the implications of this relationship in the context of cancer therapy are reviewed. A better understanding of these relationships will likely lead to strategies to make existing adaptive immune based therapies safer by decreasing thromboembolic risk and may also lead to novel targets to improve adaptive immune‐based cancer treatments.

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Effects of warfarin on biological processes other than haemostasis: A review

Cited by 22 publications

References 190 publications

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

In Silico Analysis to Identify Molecular Targets for Chemicals of Concern: The Case Study of Flocoumafen, an Anticoagulant Pesticide

Hemostasis and tumor immunity

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