ORCID Profile
0000-0003-2717-5364
Current Organisations
Curtin University of Technology
,
Perm State Pharmaceutical Academy
,
University of Southern Denmark
,
Westfalische Wilhelms-Universität Munster
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Publications
Amide-functionalized 1,2,4-Triazol-5-amines as Covalent Inhibitors of Blood Coagulation Factor XIIa and Thrombin
Publisher: American Chemical Society (ACS)
Date: 30-11-2022
Novel Potent Proline-Based Metalloproteinase Inhibitors: Design, (Radio)Synthesis, and First in Vivo Evaluation as Radiotracers for Positron Emission Tomography
Publisher: American Chemical Society (ACS)
Date: 13-10-2016
DOI: 10.1021/ACS.JMEDCHEM.6B01291
Abstract: As dysregulation of matrix metalloproteinase (MMP) activity is associated with a wide range of pathophysiological processes like cancer, atherosclerosis, and arthritis, MMPs represent a valuable target for the development of new therapeutics and diagnostic tools. We herein present the chiral pool syntheses, in vitro evaluation, and SAR studies of a series of d- and l-proline- as well as of (4R)-4-hydroxy-l-proline-derived MMP inhibitors possessing general formula 1. Some of the synthesized hydroxamic acids were found to be potent MMP inhibitors with IC
Auranthine, a Benzodiazepinone from Penicillium aurantiogriseum: Refined Structure, Absolute Configuration, and Cytotoxicity
Publisher: American Chemical Society (ACS)
Date: 08-10-2018
DOI: 10.1021/ACS.JNATPROD.8B00187
Abstract: The structure of the known Penicillium aurantiogriseum-derived secondary metabolite auranthine was refined using a combination of synthetic, spectroscopic, and X-ray diffractometric approaches. Thus, auranthine was shown to be a fused quinazolino benzodiazepinedione (2) bearing an acyclic aliphatic nitrile moiety, thereby significantly differing from the originally proposed structure 1 published in 1986. Its absolute configuration was confirmed by CD spectroscopy and DFT calculations. The cultivation of P. aurantiogriseum was optimized, allowing high production of auranthine. The cytotoxicity profile of auranthine and its semisynthetic analogues is reported. The refined structure of auranthine provides a valid target for the total synthesis of this underexplored natural product and its derivatives.
A novel multicomponent microwave-assisted synthesis of 5-aza-adenines
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3RA41932K
Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors
Publisher: Wiley
Date: 04-08-2021
Abstract: Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N‐acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post‐screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor both compounds showed no inhibition of the other tested serine proteases. Selected N‐acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N‐acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.
Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis, antibacterial properties, and docking studies
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.BMC.2019.03.056
Abstract: The Zn
Factor XII(a) inhibitors: a review of the patent literature
Publisher: Informa UK Limited
Date: 27-07-2021
LpxC inhibitors: a patent review (2010-2016)
Publisher: Informa UK Limited
Date: 04-08-2017
DOI: 10.1080/13543776.2017.1360282
Abstract: The Zn
Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants
Publisher: American Chemical Society (ACS)
Date: 22-10-2018
DOI: 10.1021/ACS.JMEDCHEM.8B01087
Abstract: Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which h ers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
A new synthesis of amino substituted azolo[1,3,5]triazines via reaction of N1,N1-dimethyl-N2-azolylformamidines with cyanamide
Publisher: The Japan Institute of Heterocyclic Chemistry
Date: 2013
DOI: 10.3987/COM-12-12601
Structure‐Based Design, Synthesis, and Biological Evaluation of Triazole‐Based smHDAC8 Inhibitors
Publisher: Wiley
Date: 09-01-2020
Acylated 1H-1,2,4-Triazol-5-amines Targeting Human Coagulation Factor XIIa and Thrombin: Conventional and Microscale Synthesis, Anticoagulant Properties, and Mechanism of Action
Publisher: American Chemical Society (ACS)
Date: 22-10-2020
Microwave-Assisted Synthesis, Structure, and Preliminary Biological Evaluation of Novel 6-Methoxy-5,6-dihydro-5-azapurines
Publisher: American Chemical Society (ACS)
Date: 05-04-2023
Synthesis of novel trichloromethyl substituted azolo[1,3,5]triazines1
Publisher: The Japan Institute of Heterocyclic Chemistry
Date: 2012
DOI: 10.3987/COM-12-12542
Synthesis, local anaesthetic and antiarrhythmic activities of N-alkyl derivatives of proline anilides
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.EJMECH.2013.02.003
Abstract: We describe here the design, synthesis and evaluation of in vivo local anaesthetic and antiarrhythmic activities of a series of N-alkylproline anilides. Most of the compounds demonstrated surface anaesthetic activity higher than that of lidocaine, ropivacaine and bupivacaine. We established that the local anaesthetic activity was sensitive to structural variations in the substitution pattern at the aromatic ring and the type of alkyl group at the proline nitrogen atom. Some of the prepared N-alkylproline anilides possessed significant antiarrhythmic activity with higher therapeutic indexes than the reference drugs.
Pyrazole-Based Thrombin Inhibitors with a Serine-Trapping Mechanism of Action: Synthesis and Biological Activity
Publisher: MDPI AG
Date: 28-10-2022
DOI: 10.3390/PH15111340
Abstract: New antithrombotic drugs are needed to combat thrombosis, a dangerous pathology that causes myocardial infarction and ischemic stroke. In this respect, thrombin (FIIa) represents an important drug target. We herein report the synthesis and biological activity of a series of 1H-pyrazol-5-amine-based thrombin inhibitors with a serine-trapping mechanism of action. Among synthesized compounds, flexible acylated 1H-pyrazol-5-amines 24e, 34a, and 34b were identified as potent 16–80 nM thrombin inhibitors, which showed practically no off-targeting effect against other physiologically relevant serine proteases. To prove that synthesized compounds are covalent thrombin inhibitors, the most potent derivative 24e (FIIa IC50 = 16 nM) was studied in a mass-shift assay, where it has been shown that 24e transfers its acyl moiety (pivaloyl) to the catalytic Ser195 of thrombin. Performed herein docking studies also confirmed the covalent mechanism of thrombin inhibition by synthesized compounds. Acylated aminopyrazoles found during this study showed only limited effects on plasma coagulation in activated partial thrombin time (aPTT) and prothrombin time (PT) in vitro assays. However, such thrombin inhibitors are expected to have virtually no effect on bleeding time and can be used as a starting point for developing a safer alternative to traditional non-covalent anticoagulants.
Cover Feature: Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors (ChemMedChem 24/2021)
Publisher: Wiley
Date: 14-12-2021
Platelet functional abnormalities in pediatric patients with kaposiform hemangioendothelioma/Kasabach-Merritt phenomenon
Publisher: American Society of Hematology
Date: 25-08-2023
DOI: 10.1182/BLOODADVANCES.2022009590
Abstract: Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of infancy that is commonly associated with a life-threatening thrombocytopenic condition, Kasabach-Merritt phenomenon (KMP). Platelet CLEC-2, tumor podoplanin interaction is considered the key mechanism of platelet clearance in these patients. Here, we aimed to assess platelet functionality in such patients. Three groups of 6 to 9 children were enrolled: group A with KHE/KMP without hematologic response (HR) to therapy group B with KHE/KMP with HR and group C with healthy children. Platelet functionality was assessed by continuous and end point flow cytometry, low-angle light scattering analysis (LaSca), fluorescent microscopy of blood smears, and ex vivo thrombi formation. Platelet integrin activation in response to a combination of CRP (GPVI agonist) and TRAP-6 (PAR1 agonist), as well as calcium mobilization and integrin activation in response to CRP or rhodocytin (CLEC-2 agonist) alone, were significantly diminished in groups A and B. At the same time, platelet responses to ADP with or without TRAP-6 were unaltered. Thrombi formation from collagen in parallel plate flow chambers was also noticeably decreased in groups A and B. In silico analysis of these results predicted diminished amounts of CLEC-2 on the platelet surface of patients, which was further confirmed by immunofluorescence microscopy and flow cytometry. In addition, we also noted a decrease in GPVI levels on platelets from group A. In KHE/KMP, platelet responses induced by CLEC-2 or GPVI activation are impaired because of the diminished number of receptors on the platelet surface. This impairment correlates with the severity of the disease and resolves as the patient recovers.
A one-pot, three-component, microwave-promoted synthesis of 2-amino-substituted 7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazines
Publisher: Elsevier BV
Date: 10-2013
Development of Novel Quinoxaline-Based κ-Opioid Receptor Agonists for the Treatment of Neuroinflammation
Publisher: American Chemical Society (ACS)
Date: 13-12-2018
DOI: 10.1021/ACS.JMEDCHEM.8B01609
Abstract: Neuroinflammatory disorders, such as multiple sclerosis or experimental autoimmune encephalomyelitis (EAE), an established mouse model mimicking part of the human pathology, are characterized by inflammatory infiltrates containing T helper 1 (T
Semisynthetic Approach toward Biologically Active Derivatives of Phenylspirodrimanes from S. chartarum
Publisher: American Chemical Society (ACS)
Date: 28-11-2022
Diuretic activity and toxicity of some Verbascum nigrum extracts and fractions
Publisher: Informa UK Limited
Date: 30-09-2014
DOI: 10.3109/13880209.2013.822001
Abstract: Verbascum nigrum L. (Scrophulariaceae) is a perennial plant used in folk medicine for the treatment of kidney diseases due to its presumable diuretic properties. We investigated the diuretic activity and toxicity of extracts from different parts of V. nigrum and identified a group of compounds responsible for the biological effect. Five ethanol extracts from herb, roots, flowers, leaves and stems as well as five fractions of polar compounds isolated from herb of V. nigrum were orally administrated as a single dose of 50 mg/kg to rats. Urinary excretion and electrolyte content were measured at 3 and 6 h after the treatment. The acute toxicity of the V. nigrum extracts and fractions was evaluated in mice. All extracts, except the one prepared from the roots, showed a significant increase of the urine output within first 3 h after their administration. The extract from stems was the most active, inducing urine output of 14.6 ± 0.8 ml/kg BW versus 5.2 ± 1.4 ml/kg BW of the control. It also demonstrated saluretic activity with a natriuretic index 4.1 and a kaliuretic index 3.8. The diuretic activity was correlated with the flavonoid content in the plant organs. Flavonoid fractions demonstrated significant activity the higher content of flavonoids (expressed as hesperidin) translated into more pronounced diuretic (35.9 ± 2.1 ml/kg BW) and saluretic effects (natriuretic index 4.5 and kaliuretic index 5.4). The diuretic activity of traditionally used V. nigrum was validated experimentally. The pharmacological effect was attributed to flavonoids, which accumulated in aerial parts of the plant, mainly in stems.
Replacement of the Benzylpiperidine Moiety with Fluorinated Phenylalkyl Side Chains for the Development of GluN2B Receptor Ligands
Publisher: Wiley
Date: 14-11-2018
Abstract: The 4-benzylpiperidine moiety is a central structural element of potent N-methyl-d-aspartate (NMDA) receptor antagonists containing the GluN2B subunit. To obtain novel GluN2B ligands suitable for positron emission tomography, the benzylpiperidine moiety was replaced with fluorinated ω-phenylalkylamino groups. For this purpose three primary propyl- and butylamines 7 a-c and one butyraldehyde 7 d bearing a fluorine atom and an ω-phenyl moiety were prepared in 3- to 7-step syntheses. Compounds 7 a-d were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4-benzylpiperidine moiety. Although benzoxazol-2-ones and indoles with a benzylpiperidine moiety show high GluN2B affinity, the corresponding fluorophenylalkylamine derivatives did not result in high Glu2B affinity. Moderate GluN2B affinity was observed for a 3-(fluoroalkyl)-substituted tetrahydro-1H-3-benzazepine (K
Related Organisations
Related Funding Activities
Development Of Small-molecule Inhibitors Of Blood Coagulation Factor XIIa As Novel Anticoagulants
Start Date: 2021
End Date: End date not available
Funder: German Research Foundation
View Funded Activity