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Cikos A.,Fidelta Ltd. | Triballeau N.,Galapagos SASU | Hubbard P.A.,BioFocus DPI Ltd. | Hubbard P.A.,Cedars Sinai Medical Center | And 7 more authors.
Organic Letters | Year: 2016

A conformational study of branimycin was performed using single-crystal X-ray crystallography to characterize the solid-state form, while a combination of NMR spectroscopy and molecular modeling was employed to gain information about the solution structure. Comparison of the crystal structure with its solution counterpart showed no significant differences in conformation, confirming the relative rigidity of the tricyclic system. However, these experiments revealed that the formerly proposed stereochemistry of branimycin at 17-C should be revised. (Chemical Equation Presented). © 2016 American Chemical Society.


PubMed | Institute for Medical Research and Occupational Health, Fidelta Ltd. and University of Zagreb
Type: | Journal: Toxicology and applied pharmacology | Year: 2016

A well-considered treatment of acute nerve agents poisoning involves the exogenous administration of butyrylcholinesterase (BChE, EC 3.1.1.8) as a stoichiometric bioscavenger efficient in preventing cholinergic crises caused by acetylcholinesterase (AChE, EC 3.1.1.7) inhibition. An additional improvement in medical countermeasures would be to use oximes that could reactivate BChE as well to upgrade bioscavenging from stoichiometric to oxime-assisted catalytic. Therefore, in this paper we investigated the potency of 39 imidazolium and benzimidazolium oximes (36 compounds synthesized for the first time) to be considered as the reactivators specifically designed for reactivation of phosphylated human BChE. Their efficiency in the reactivation of paraoxon-, VX-, and tabun-inhibited human BChE, as well as human AChE was tested and compared with the efficiencies of HI-6 and obidoxime, used in medical practice today. A comprehensive analysis was performed for the most promising oximes defining kinetic parameters of reactivation as well as interactions with uninhibited BChE. Furthermore, experimental data were compared with computational studies (docking, QSAR analysis) as a starting point in future oxime structure refinement. Considering the strict criteria set for in vivo applications, we determined the cytotoxicity of lead oximes on two cell lines. Among the tested oxime library, one imidazolium compound was selected for preliminary in vivo antidotal study in mice. The obtained protection in VX poisoning outlines its potential in development oxime-assisted OP-bioscavenging with BChE.


PubMed | University of Namur, BioFocus DPI Ltd., Fidelta Ltd., Galapagos and Galapagos SASU
Type: Journal Article | Journal: Organic letters | Year: 2016

A conformational study of branimycin was performed using single-crystal X-ray crystallography to characterize the solid-state form, while a combination of NMR spectroscopy and molecular modeling was employed to gain information about the solution structure. Comparison of the crystal structure with its solution counterpart showed no significant differences in conformation, confirming the relative rigidity of the tricyclic system. However, these experiments revealed that the formerly proposed stereochemistry of branimycin at 17-C should be revised.


Djakovic S.,University of Zagreb | Kodrin I.,University of Zagreb | Smrecki V.,Ruder Boskovic Institute | Novak P.,University of Zagreb | And 4 more authors.
Tetrahedron | Year: 2014

In this study we present a synthesis and conformational analysis of 1′-acetylferrocene amino acid derivatives of type Ac-Fn-CO-AA-Y (Fn=ferrocene-1,1-diyl; AA=Gly, Ala or Val; Y=OMe or NHMe) as a simple model for parallel β-helical peptides. Derivatives with only one amino acid adopt a reduced number of total conformations and allow a more exact analysis of intramolecular hydrogen bonds (IHB) close to the ferrocene unit. Conformational analysis of these bioconjugates was performed by a combination of spectroscopic techniques (IR, NMR and CD) and corroborated by solution-phase DFT calculations. The investigation of ester conjugates 1-3 indicates the coexistence of non-bonded (an open forms) and hydrogen bonded NHa group forming a 7-membered ring (γ-turn). The amide derivatives 4-6 with an additional NHb hydrogen bond donor are mostly constituted of conformers with a 10-membered ring (β-turn) as a single IHB pattern or the β-turn accompanied by a 7-membered ring (γ-turn) containing NHa group. The exchange of the amino acid side-chain does not significantly affect the conformational properties and IHB pattern of the studied conjugates 1-6. © 2014 Elsevier Ltd. All rights reserved.


Palej Jakopovic I.,Fidelta Ltd. | Kapic S.,Fidelta Ltd. | Alihodzic S.,Fidelta Ltd. | Sunjic V.,Croatian Academy of science and Arts
Arkivoc | Year: 2015

Most ether-bond forming reactions based on traditional methods or modifications thereof require strongly acidic or basic conditions and often harsh reaction conditions. Reduction of esters to ethers has been regarded as an impracticable method, generally affording alcohols as the principal products. Only recently, original, mostly catalytic methods for reduction of esters to ethers have been reported, which proceed under mild conditions and are compatible with many functional groups present in the substrate ester molecule. These reactions are considered as a valuable alternative to traditional methods, and specific protocols have been reported. An account of the progress in this synthetic methodology is given. © ARKAT-USA, Inc.


Zimmermann B.,Ruder Boskovic Institute | Zimmermann B.,Norwegian University of Life Sciences | Baranovic G.,Ruder Boskovic Institute | Gembarovski D.,Galapagos Research Center | Gembarovski D.,Fidelta Ltd.
Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy | Year: 2014

The UV/Vis titration measurements, vibrational and NMR spectroscopy of isomeric dehydrodibenzopyrido[15]annulenes (DBPA) 1 and 2 clearly show that under proper conditions these macrocycles can achieve fast, quantitative and unselective binding of metal ions. The macrocycle 1 is an example of a hindered amine 2,6-bis(R)pyridine and its isomer 2 of a non-hindered amine 3,5-bis(R)pyridine. The protonation stoichiometry for both 1 and 2 was assumed to be DBPA:H+= 1:1 and the formation constants log K = 4.77 ± 0.02 for 1, and log K = 6.78 ± 0.08 for 2 were obtained that well agree with those obtained under similar conditions for a macrocycle containing bipyridine units. The protonation of 2 gave the estimated stoichiometry of 2:H+= 1:1 while the stoichiometric protonation of macrocycle 1 could not be achieved and the lower stability of the ion pair containing 1H+is most likely due to the inaccessibility of the nitrogen atom of 1 to the counterions and solvent molecules. The structures and electronic absorption spectra of 1 and 2, as well as the structures and spectra of 1H+and 2H+, i.e. the species formed by protonation of the pyridine nitrogen, were calculated with the time-dependent DFT method with a B3LYP functional and a 6-31+G(d) basis set. The solvent effects were incorporated by means of the polarizable continuum model (PCM). The agreement of the calculated absorption data for the parent and protonated species with the observed spectra is rather satisfactory. Vibrational IR and Raman spectra of 1, 2, 1H+and 2H+in vacuo were calculated at the B3LYP/cc-pVTZ level of theory. Macrocycles 1 and 2, and their products protonated by trifluoromethanesulfonic acid (1HOTf and 2HOTf) were also characterized by temperature-dependent FTIR technique known as two dimensional IR correlation analysis. Quite large difference in degradation temperature between macrocycle 1 and 2 and their protonated complexes was measured, indicating that inclusion of proton leads to significant thermal stabilization of dehydroannulene ring. © 2014 Elsevier B.V. All rights reserved.


Bakic M.T.,University of Zagreb | Bakic M.T.,Ruder Boskovic Institute | Jadresko D.,Ruder Boskovic Institute | Hrenar T.,University of Zagreb | And 9 more authors.
RSC Advances | Year: 2015

New fluorescent calix[4]arene derivatives 1, 2, and 3 were synthesized by introducing phenanthridine moieties at a lower calixarene rim. It was shown that due to the prominent fluorescence of compounds 1 and 3, they could be considered as potential sensitive fluorimetric cation sensors. Complexation of the prepared compounds with alkali-metal cations was studied at 25 °C in acetonitrile-dichloromethane and methanol-dichloromethane solvent mixtures (φ = 0.5) by means of fluorimetric, spectrophotometric, potentiometric, and microcalorimetric titrations as well as NMR spectroscopy. The stability constants of the corresponding complexes were determined, as were the enthalpies and entropies of the complexation reactions. In addition, equilibrium constants of ion-pairing reactions between alkali-metal cations and several anions in the solvents used were measured conductometrically. It was found that the cation-binding affinity of ligand 1 with four phenanthridine subunits was much higher than that of 2 and 3, with the complex stabilities in all cases being significantly lower in methanol-dichloromethane mixture compared to that in acetonitrile-dichloromethane. These findings were thoroughly discussed by taking into account the determined thermodynamic complexation data, structural properties of the ligand and free and complexed cations, as well as the solvation abilities of the solvents examined. The conclusions made in that way were corroborated by the results of the molecular dynamics simulations of the systems studied. An attempt to get an insight into the possible structures of the alkali-metal cation complexes with ligand 1 was made by carrying out the corresponding density functional theory calculations. © 2015 The Royal Society of Chemistry.


Landek G.,Glaxosmithkline | Ozimec Landek I.,Glaxosmithkline | Ozimec Landek I.,Fidelta Ltd | Pesic D.,Glaxosmithkline | And 2 more authors.
Monatshefte fur Chemie | Year: 2013

The dynamic properties of planar chiral 1-hydroxymethyl-substituted dibenzo[b,f]thieno[3,4-d]-fused oxepine and thiepine derivatives have been investigated by use of variable-temperature nuclear magnetic resonance spectroscopy combined with line-shape analysis, chiral column chromatography, and molecular modelling. NMR data and computational studies revealed the height of the energy barrier for ring inversion in thiepine derivatives was sufficient to enable the existence of a pair of conformational enantiomers at ambient temperature. Their resolution was achieved by chiral column high-performance liquid chromatography (HPLC). The absolute conformation of the enantiomers is proposed. This is the first chromatographic separation of planar chiral enantiomers of [b,d,f]-fused thiepine derivatives. Graphical Abstract: [Figure not available: see fulltext.] © 2013 Springer-Verlag Wien.


Brajsa K.,Fidelta Ltd. | Trzun M.,Fidelta Ltd. | Zlatar I.,Fidelta Ltd. | Jelic D.,Fidelta Ltd.
Periodicum Biologorum | Year: 2016

Background and purpose: Producing of reliable information about pharmacological activity of new chemical entities is essential in early stages of drug discovery and development. There is a continuous need for improvement of existing in vitro technologies, in order to get more accurate and more predictive biological data (and for compounds selection) in pre-clinical screening methods and models. Materials and methods: Two-dimensional (2D) cell cultures, in comparison with original tissues, does not fully reproduce in vivo cell growth and differentiation. Therefore, significant efforts have been made toward the development of more realistic three-dimensional (3D) in vitro cell culture models that would better mimic tissue physiology. Results: Two-dimensional (2D) cell cultures, in comparison with original tissues, does not fully reproduce in vivo cell growth and differentiation. Therefore, significant efforts have been made toward the development of more realistic three-dimensional (3D) in vitro cell culture models that would better mimic tissue physiology. Basic concepts and advantages of 3D cell cultures, as well as different approaches in technologies that enable the cell growth in 3D will be presented here. Possible applications of 3D cell culture in drug discovery will be discussed, and example of formation of spherical growth of three different human breast cancer cells (MDAMB- 231, SK-BR-3 and T-47D cells) in 3D format will be shown. Conclusions: Although biological significance of obtained data from 2D and 3D cell cultures is still poorly understood, discrepancy of compunds activity illustrated importance of implementation 3D cell culture assays in early part of drug discovery process. © 2016, Croatian Society of Natural Sciences. All rights reserved.


PubMed | Fidelta Ltd. and University of Zagreb
Type: | Journal: European journal of medicinal chemistry | Year: 2016

Benzimidazo[1,2-a]quinolines and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles with amino chains on the different positions have been evaluated by 2D and 3D assays on the human breast cancer cells. Pentacyclic derivatives were synthesized by microwave assisted amination to study the influence of the thiophene substructure on antitumor activity in comparison to tetracyclic analogues. The results obtained from 2D assay reveals that the antitumor activity is strongly dependent on the nature and position of amino chains. Tetracyclic derivatives displayed selective activity on SK-BR-3 with the 2-amino substituted derivatives as the most active ones while pentacyclic derivatives 6-16 and 21-25 showed more pronounced activity on T-47D. The evaluation of antitumor activity in the 3D assay pointed out that some of the tetracyclic and pentacyclic amino substituted derivatives showed selective activity on the MDA-MB-231cell line. Influence of physico-chemical properties of the compounds on antiproliferative activity have been investigated by multivariate statistical methods. As a measure of lipophilicity, experimental Chrom LogD values have been determined and number of structural parameters have been calculated for investigated compounds. Main factors contributing to the antiproliferative effect for both 2D and 3D cell cultures are found to be basicity, lipophilicity, molecular weight and number of H-bond donors.

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