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Kuder K.J.,Jagiellonian University | Lazewska D.,Jagiellonian University | Kaleta M.,Jagiellonian University | Latacz G.,Jagiellonian University | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2017

As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2-21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6-8 (K i =8.8-23.4nM range) and among them piperidine derivative 6 with K i =8.8nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50 =157 and 164nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2-4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30mg/kg at 0.5h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate "drug-likeness" of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed. © 2017.


Bateman A.,Wellcome Trust Sanger Institute | Agrawal S.,Institute of Bioinformatics and Applied Biotechnology IBAB | Agrawal S.,BioCOS Life science Private Ltd | Birney E.,European Bioinformatics Institute | And 28 more authors.
RNA | Year: 2011

During the last decade there has been a great increase in the number of noncoding RNA genes identified, including new classes such as microRNAs and piRNAs. There is also a large growth in the amount of experimental characterization of these RNA components. Despite this growth in information, it is still difficult for researchers to access RNA data, because key data resources for noncoding RNAs have not yet been created. The most pressing omission is the lack of a comprehensive RNA sequence database, much like UniProt, which provides a comprehensive set of protein knowledge. In this article we propose the creation of a new open public resource that we term RNAcentral, which will contain a comprehensive collection of RNA sequences and fill an important gap in the provision of biomedical databases. We envision RNA researchers from all over the world joining a federated RNAcentral network, contributing specialized knowledge and databases. RNAcentral would centralize key data that are currently held across a variety of databases, allowing researchers instant access to a single, unified resource. This resource would facilitate the next generation of RNA research and help drive further discoveries, including those that improve food production and human and animal health. We encourage additional RNA database resources and research groups to join this effort. We aim to obtain international network funding to further this endeavor.


Sterjev Z.,Institute of Pharmaceutical Chemistry | Trencevska G.K.,University of Sfax | Cvetkovska E.,University of Sfax | Petrov I.,University of Sfax | And 8 more authors.
Neuropsychiatric Disease and Treatment | Year: 2012

The ABCB1 gene encodes the P-glycoprotein (Pgp) protein, which is thought to transport various antiepileptic drugs. The single nucleotide polymorphism (SNP) (C3435T) in exon 26 of this gene correlates with the altered expression levels of P-glycoprotein, range of drug response and clinical conditions. In order to investigate the influence of this polymorphism on the susceptibility to and efficacy of carbamazepine therapy, we evaluated the allelic frequency and genotype distribution of this variant in 162 epilepsy patients from the Republic of Macedonia. Statistically significant differences were detected neither in the allelic frequency and genotype distribution between carbamazepine-resistant and carbamazepine-responsive epilepsy patients nor between the subgroups of carbamazepine (CBZ)-responsive patients treated with different CBZ doses. However, the T-allele was enriched in CBZ-responsive patients who required higher maintenance CBZ doses, This observation was substantiated by the findings that the median total plasma levels were the lowest in patients with CC (20 μmol/L) followed by CT (23 μmol/L) and TT (29 μmol/L) genotypes. Patients with a CC genotype also had a higher likelihood of response compared to patients with CT or TT genotypes over a wide range (400-1000 mg/day) of initial doses of CBZ. The T allele showed a reduced expression of ∼5% compared to the C allele in peripheral blood mononuclear cells in heterozygotes for the variant. This difference might be translated into ∼10% difference in homozygotes for the variant, which would explain the trend towards a dose-dependent efficacy of the CBZ treatment in patients with different genotypes. A larger prospective study is warranted to clarify the clinical utility of a genotypespecific individualized CBZ therapy. © 2012 Sterjev et al, publisher and licensee Dove Medical Press Ltd.


Mondal M.,University of Groningen | Radeva N.,Institute of Pharmaceutical Chemistry | Koster H.,Institute of Pharmaceutical Chemistry | Park A.,Institute of Pharmaceutical Chemistry | And 4 more authors.
Angewandte Chemie - International Edition | Year: 2014

Structure-based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein-bound library member(s) by saturation-transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization. The dynamic duo: The combination of de novo structure-based design and dynamic combinatorial chemistry has been applied to the identification of novel acylhydrazone-based inhibitors for the aspartic protease endothiapepsin. 1H-STD-NMR spectroscopy has been used to identify the binders from the dynamic combinatorial libraries. Proposed binding modes of the most potent inhibitors have been confirmed by X-ray crystallography. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | University of Groningen and Institute of Pharmaceutical Chemistry
Type: Journal Article | Journal: Angewandte Chemie (International ed. in English) | Year: 2016

Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.


Naruhn S.,University of Marburg | Toth P.M.,Institute of Pharmaceutical Chemistry | Adhikary T.,University of Marburg | Kaddatz K.,University of Marburg | And 6 more authors.
Molecular Pharmacology | Year: 2011

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a ligand-regulated nuclear receptor with essential functions in metabolism and inflammation. We have synthesized a new derivative [methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (ST247) structurally related to the published PPARβ/δ inhibitory ligand methyl 3-(N-(2-methoxy-4-(phenylamino)phenyl)sulfamoyl)thiophene-2- carboxylate (GSK0660). ST247 has a higher affinity to PPARβ/δ than GSK0660, and at equimolar concentrations, it more efficiently 1) induces the interaction with corepressors both in vitro and in vivo, 2) inhibits the agonist-induced transcriptional activity of PPARβ/δ, and 3) downregulates basal level expression of the peroxisome proliferator responsive element-driven PPARβ/δ target gene ANGPTL4. Methyl 3-(N-(4-(tert-butylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (PT-S58), another high-affinity derivative from our series, also efficiently inhibits agonist-induced transcriptional activation, but in contrast to ST247, it does not enhance the interaction of PPARβ/δ with corepressors. PT-S58 rather prevents corepressor recruitment triggered by the inverse agonist ST247. These findings classify ST247 as an inverse agonist, whereas PT-S58 is the first pure PPARβ/δ antagonist described to date. It is noteworthy that ST247 and PT-S58 are also effective on PPRE-independent functions of PPARβ/δ: in monocytic cells, both ligands modulate expression of the activation marker CCL2 in the opposite direction as an established PPARβ/δ agonist. The possibility to differentially modulate specific functions of PPARβ/δmakes these novel compounds invaluable tools to advance our understanding of PPARβ/δ biology. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.


Shi H.-B.,Chemical Engineering College | Shi H.-B.,Institute of Pharmaceutical Chemistry | Hu W.-X.,Zhejiang University of Technology | Zhang W.-M.,Institute of Pharmaceutical Chemistry | Wu Y.-F.,Institute of Pharmaceutical Chemistry
Journal of Chemical Research | Year: 2016

A series of 21 new tri- and tetra-cyclic thiosemicarbazone derivatives were prepared via the condensation of morpholine, piperazine or N-(4-methoxyphenyl)piperazine with seven methyl hydrazine-carbodithioate derivatives of 5-acetyl-2-arylamino-4-methylthiazoles under microwave irradiation. All compounds were tested for their cytotoxic activity in vitro against human gastric, lung and breast cancer cell lines. The results showed that some of the compounds displayed moderate anticancer activity. The most potent compound, a morpholinosubstituted analogue, exhibited significant activity against human breast cancer cells.


Thieme T.M.,Institute of Pharmaceutical Chemistry | Steri R.,Institute of Pharmaceutical Chemistry | Proschak E.,Institute of Pharmaceutical Chemistry | Paulke A.,Institute of Pharmaceutical Chemistry | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Peroxisome proliferator-activated receptor γ (PPARγ) is involved in glucose and lipid homeostasis. PPARγ agonists are in clinical use for the treatment of type 2 diabetes. Lately, a new class of selective PPARγ modulators (SPPARγMs) was developed, which are believed to show less side effects than full PPARγ agonists. We have previously shown that α-substitution of pirinixic acid, a moderate agonist of PPARα and PPARγ, leads to low micromolar active balanced dual agonists of PPARα and PPARγ. Herein we present modifications of pirinixic acid leading to subtype-selective PPARγ agonists and furthermore the development of a selective PPARγ modulator guided by molecular docking studies. © 2010 Elsevier Ltd. All rights reserved.


Jenkins D.,Weatherall Institute of Molecular Medicine | Caubit X.,Institut Universitaire de France | Dimovski A.,Institute of Pharmaceutical Chemistry | Matevska N.,Institute of Pharmaceutical Chemistry | And 6 more authors.
Nephrology Dialysis Transplantation | Year: 2010

Background. Congenital pelvi-ureteric junction obstruction (PUJO) affects 0.3 of human births. It may result from aberrant smooth muscle development in the renal pelvis, resulting in hydronephrosis. Mice that are null mutant for the Teashirt3 (Tshz3) gene exhibit congenital PUJO with defective smooth muscle differentiation and absent peristalsis in the proximal ureter.Methods. Given the phenotype of Tshz3 mutant mice, we considered that Teashirt genes, which code for a family of transcription factors, might represent candidate genes for human PUJO. To evaluate this possibility, we used in situ hydridization to analyse the three mammalian Tshz genes in mouse embryonic ureters and determined whether TSHZ3 was expressed in the human embryonic ureter. TSHZ2 and TSHZ3 were sequenced in index cases with non-syndromic PUJO.Results. Tshz2 and Tshz3 genes were detected in mouse ureters and TSHZ3 was expressed in the human embryonic renal pelvis. Direct sequencing of TSHZ2 and TSHZ3 did not identify any mutations in an initial cohort of 48 PUJO index cases, excluding these genes as a major cause of this condition. A polymorphic missense change (E469G) in TSHZ3 was identified at a residue highly conserved throughout evolution in all Teashirt proteins, although subsequently no significant difference between the E469G allele frequency in Albanian and Macedonian PUJO index cases (3.2) versus 633 control individuals (1.7) was found (P = 0.18).Conclusions. Mutations in TSHZ2 and TSHZ3 are not a major cause of PUJO, at least in Albanian and Macedonian populations. Expression of these genes in the human fetal ureter emphasizes the importance of analysing these genes in other groups of patients with renal tract malformations.


PubMed | Institute of Pharmaceutical Chemistry
Type: | Journal: Neuropsychiatric disease and treatment | Year: 2012

The ABCB1 gene encodes the P-glycoprotein (Pgp) protein, which is thought to transport various antiepileptic drugs. The single nucleotide polymorphism (SNP) (C3435T) in exon 26 of this gene correlates with the altered expression levels of P-glycoprotein, range of drug response and clinical conditions. In order to investigate the influence of this polymorphism on the susceptibility to and efficacy of carbamazepine therapy, we evaluated the allelic frequency and genotype distribution of this variant in 162 epilepsy patients from the Republic of Macedonia. Statistically significant differences were detected neither in the allelic frequency and genotype distribution between carbamazepine-resistant and carbamazepine-responsive epilepsy patients nor between the subgroups of carbamazepine (CBZ)-responsive patients treated with different CBZ doses. However, the T-allele was enriched in CBZ-responsive patients who required higher maintenance CBZ doses, This observation was substantiated by the findings that the median total plasma levels were the lowest in patients with CC (20 mol/L) followed by CT (23 mol/L) and TT (29 mol/L) genotypes. Patients with a CC genotype also had a higher likelihood of response compared to patients with CT or TT genotypes over a wide range (400-1000 mg/day) of initial doses of CBZ. The T allele showed a reduced expression of ~5% compared to the C allele in peripheral blood mononuclear cells in heterozygotes for the variant. This difference might be translated into ~10% difference in homozygotes for the variant, which would explain the trend towards a dose-dependent efficacy of the CBZ treatment in patients with different genotypes. A larger prospective study is warranted to clarify the clinical utility of a genotypespecific individualized CBZ therapy.

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