Category Archives: Eur J Med Chem

Molecular insight into specific 14-3-3 modulators: Inhibitors and stabilisers of protein-protein interactions of 14-3-3.

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Molecular insight into specific 14-3-3 modulators: Inhibitors and stabilisers of protein-protein interactions of 14-3-3.
Eur J Med Chem. 2017 Apr 24;136:573-584
Authors: Hartman AM, Hirsch AKH
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Enzyme kinetics and inhibition of histone acetyltransferase KAT8.

Enzyme kinetics and inhibition of histone acetyltransferase KAT8.
Eur J Med Chem. 2015 Oct 22;105:289-296
Authors: Wapenaar H, van der Wouden PE, Groves MR, Rotili D, Mai A, Dekker FJ
Abstract
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Novel analogs of antitumor agent calixarene 0118: Synthesis, cytotoxicity, click labeling with 2-[(18)F]fluoroethylazide, and in vivo evaluation.

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Novel analogs of antitumor agent calixarene 0118: Synthesis, cytotoxicity, click labeling with 2-[(18)F]fluoroethylazide, and in vivo evaluation.

Eur J Med Chem. 2015 Jan 7;89:279-95

Authors: Läppchen T, Dings RP, Rossin R, Simon JF, Visser TJ, Bakker M, Walhe P, van Mourik T, Donato K, van Beijnum JR, Griffioen AW, Lub J, Robillard MS, Mayo KH, Grüll H

Abstract
Calixarene 0118 is a potent anti-angiogenic agent that effectively inhibited tumor growth in preclinical studies, and is currently being evaluated in a phase I clinical trial. We have designed two close mimetics of calixarene 0118 containing a terminal alkynyl-functional group, and developed an optimized semi-automated procedure for radiolabeling with 2-[(18)F]fluoroethylazide using click chemistry. Following semi-preparative HPLC purification and formulation, the lower-rim modified analog [(18)F]6 and the equatorially labeled [(18)F]13 were obtained in >97% radiochemical purity and overall decay-corrected isolated radiochemical yields of 18.7 ± 2.7% (n = 4) and 10.2 ± 5.0% (n = 4), respectively, in a total synthesis time of about 2 h. Preliminary in vivo studies in nude mice bearing human tumor xenografts revealed highest accumulation of both tracers in the liver, followed by spleen, kidney, lung and bone, with no substantial uptake in the tumor. Still, these first-in-class radiotracers are a valuable tool for pharmacokinetic profiling and improvement of calixarene-based anti-angiogenic therapeutics in the future, as similar radiolabeling strategies may be applied to other compounds in the calixarene series. The cold reference compounds of the radiotracers were characterized in terms of cytotoxicity and anti-proliferative effects on HUVEC cells and on MA148 human ovarian carcinoma cells, along with the respective precursors, a small series of 0118 analogs modified with short-chain linear alkyl substituents, and a PEG3-spaced calixarene dimer. While all of the new analogs proved at least equipotent to parent 0118, some of them inhibited HUVEC and MA148 cell growth almost 4- and 10-fold more effectively, rendering these analogs promising candidates for further evaluation in anti-angiogenic cancer therapy.

PMID: 25462244 [PubMed – indexed for MEDLINE]

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New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design.

New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design.

Eur J Med Chem. 2015 Mar 19;95:136-152

Authors: Barrera Guisasola EE, Andujar SA, Hubin E, Broersen K, Kraan IM, Méndez L, Delpiccolo CM, Masman MF, Rodríguez AM, Enriz RD

Abstract
A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer’s disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.

PMID: 25805447 [PubMed – as supplied by publisher]

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Identification of 6-benzyloxysalicylates as a novel class of inhibitors of 15-lipoxygenase-1.

Identification of 6-benzyloxysalicylates as a novel class of inhibitors of 15-lipoxygenase-1.

Eur J Med Chem. 2015 Mar 5;94:265-275

Authors: Eleftheriadis N, Thee S, Te Biesebeek J, van der Wouden P, Baas BJ, Dekker FJ

Abstract
Lipoxygenases metabolize polyunsaturated fatty acids into signalling molecules such as leukotrienes and lipoxins. 15-lipoxygenase-1 (15-LOX-1) is an important mammalian lipoxygenase and plays a crucial regulatory role in several respiratory diseases such as asthma, COPD and chronic bronchitis. Novel potent and selective inhibitors of 15-LOX-1 are required to explore the role of this enzyme in drug discovery. In this study we describe structure activity relationships for 6-benzyloxysalicylates as inhibitors of human 15-LOX-1. Kinetic analysis suggests competitive inhibition and the binding model of these compounds can be rationalized using molecular modelling studies. The most potent derivative 37a shows a Ki value of 1.7 μM. These structure activity relationships provide a basis to design improved inhibitors and to explore 15-LOX-1 as a drug target.

PMID: 25771032 [PubMed – as supplied by publisher]

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6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site.

6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site.

Eur J Med Chem. 2012 Jan;47(1):337-44

Authors: Ghizzoni M, Wu J, Gao T, Haisma HJ, Dekker…

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