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 dehydrodibenzopyridoannulenes (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. Source
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. Source
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. Source
Elenkov I.J.,Glaxosmithkline |
Elenkov I.J.,Fidelta Ltd. |
Hrvacic B.,Glaxosmithkline |
Hrvacic B.,Fidelta Ltd. |
And 22 more authors.
Croatica Chemica Acta | Year: 2013
A series of variously substituted furochromenes, hemiacetals 2, acetals 3, and rearranged compounds 4, were synthesized from variously substituted 4-hydroxycoumarins and evaluated in several in vitro assays, inhibition of mast cell degranulation induced by the activation of Fce receptor type I or calcium ionophore and leukotriene B4 (LTB4) inhibition. The most active derivatives, 3p and 4p (8-iso-propyl substitution in coumarin ring) and 3r (5-methyl-8-chloro substitution), showed significant inhibition of mast cell degranulation (Fctriggered) and LTB4, and exhibited significant local anti-inflammatory activity in PMA induced ear edema in CD1 mice, with potency equal (compounds 3p and 4p) or better (compound 3r) in comparison with zileuton, a reference drug used. It might be a promising direction for developing novel drugs as potential agents for the treatment of allergies and other inflammatory diseases. Source
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. Source