RESUMO
Starting from quinazoline 3a, we designed potent and selective ALK5 inhibitors over p38MAP kinase from a rational drug design approach based on co-crystal structures in the human ALK5 kinase domain. The quinazoline 3d exhibited also in vivo activity in an acute rat model of DMN-induced liver fibrosis when administered orally at 5mg/kg (bid).
Assuntos
Receptores de Ativinas/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinazolinas/síntese química , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Ativinas/metabolismo , Animais , Linhagem Celular , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismoRESUMO
The chemotoxicity of iodinated contrast agents is essentially related to the spatial accessibilty of lipophilic and polarizable iodine atoms. This accessibility was examined in iobitridol by HPLC and 1H- and 13C-NMR spectroscopy,taking into account both the static distribution of the hydrophilic groups around the triiodinated benzene ring and in particular the dynamic modulation of this distribution. The aim of this latter parameter is to prevent distortion of the hydrophilic sphere of nonionic agents when faced with a hydrophobic environment. Iobitridol is characterized by 2 tertiary carbamoyl substituents whose high rotation barriers (deltaG*353=27.6 kcal for E/Z-rotation and deltaG*345=17.3 kcal for syn/anti-rotation) stabilize the hydrophilic sphere. The 3rd dihydroxylated anilide substituent does not undergo SMILES rearrangement and provides iobitridol with its even hydrophilic distribution. Iobitridol presents remarkable chemical solubility (>140% m/v) and stability. The iobitridol molecule was specifically designed with the aim of stabilizing the hydrophilic sphere around the triiodinated benzene ring, therefore permanently masking access to the iodine atoms. This new concept represents a further step forward towards the synthesis of new iodinated contrast agents which should be totally inert vis-a-vis biological membranes and proteins.
Assuntos
Meios de Contraste/química , Iohexol/análogos & derivados , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Iohexol/química , Isomerismo , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação MolecularRESUMO
PURPOSE: The regular distribution in space and the stability in time of the hydrophilic sphere surrounding iobitridol were investigated. This is a novel yet important concept in the design of polyiodinated contrast agents since such a sphere is meant to hide their hydrophobic core and thus prevent hydrophobic interactions with biomacromolecules and hence chemotoxicity. METHODS: The methods used were experimental (HPLC, 1H- and 13C-NMR spectroscopy) and computational (calculation of conformational behavior and molecular electrostatic potentials). RESULTS: Iobitridol exists as a mixture of stereoisomers due to hindered rotation around several bonds. High-temperature molecular dynamics established the existence between 0 and 15 kcal/mol of 238 conformers belonging to 14 classes. Most of these conformers have an inaccessible hydrophobic core, and variable temperature molecular dynamics confirmed that the hydrophilic sphere around iobitridol is stable against external disruption. CONCLUSIONS: This study has demonstrated that iobitridol fulfils the physicochemical and structural criteria believed to render a polyiodinated contrast agent inert toward interacting with biomacromolecules.
Assuntos
Meios de Contraste/química , Iohexol/análogos & derivados , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Simulação por Computador , Estabilidade de Medicamentos , Iohexol/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
The origin of the anomalous H8 chemical shifts observed in 1H-NMR spectra of oligonucleotides cross-linked at a GpG sequence with cis-[Pt(NH3)2]2+ has been investigated and clarified. The main contributions that distinguish the H8 resonances of the two platinum-ligating guanines from other GH8 signals and from each other are: (a) the inductive effect of platinum binding which we have recently quantified as a downfield shift of 0.48 +/- 0.07 ppm (M. H. Fouchet, D. Lemaire, J. Kozelka and J.-C. Chottard, unpublished results); (b) the ring-current effect of one GpG guanine on the H8 resonance of the other guanine, which is negative (shielding) for the 5'-H8 and positive (deshielding) for the 3'-H8 in single-stranded adducts, but has the opposite sign in double-stranded adducts; (c) a deshielding polarization effect of the phosphate 5' to the GpG unit. The different signs of the ring-current effects in single-stranded and double-stranded oligonucleotides originate from the orientation of the guanines in the cis-[Pt(NH3)2(Gua)2]2+ moiety (Gua, guanine), which is left-handed helicoidal in single strands and right-handed helicoidal in double strands. In the platinated dinucleotides (cis-[Pt(NH3)2(GpG)]+, cis-[Pt(NH3)2(d(GpG))]+ and cis-[Pt(NH3)2(d(GpG))]), the guanines assume either the left-handed or the right-handed arrangement, depending on the sugar moiety (ribose or deoxyribose), protonation state at N1 and, in the solid state, on crystal forces. This work shows that chemical shifts contain valuable structural information which is complementary to that extracted from correlated spectroscopy and nuclear Overhauser spectroscopy data.
Assuntos
Cisplatino/química , Fosfatos de Dinucleosídeos/química , Oligonucleotídeos/química , Cátions Bivalentes , Reagentes de Ligações Cruzadas , Espectroscopia de Ressonância Magnética , Conformação MolecularRESUMO
The nonamer 5'd(CTCAGCCTC) 3' 1 has been reacted with cis-diamminediaquaplatinum(II) in water at pH 4.2. The major reaction product was shown by enzymatic digestion and 1H NMR to be the d(ApG)cis-Pt(NH3)2 chelate [cis-Pt(NH3)2[d(CTCAGCCTC)-N7(4),N7(5)]] 1-Pt. When mixed with its complementary strand 2, 1-Pt forms a B DNA type duplex 3-Pt with a Tm of 35 degrees C (versus 58 degrees C for the unplatinated duplex). The NMR study of the exchangeable protons of 3-Pt revealed that the helix distortion is localized on the CA*G*-CTG moiety (the asterisks indicating the platinum chelation sites) with a strong perturbation of the A*(4)T(15) base pair related to a large tilt of A*(4).
Assuntos
Cisplatino/química , DNA/química , Oligodesoxirribonucleotídeos/química , Compostos Organoplatínicos/síntese química , Composição de Bases , Sequência de Bases , Espectroscopia de Ressonância Magnética/métodos , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos/síntese química , Compostos Organoplatínicos/química , Espectrofotometria UltravioletaRESUMO
A direct method is described for the resolution of the enantiomers of betaxolol, a novel cardioselective beta-adrenergic blocking agent, using a tris(3,5-dimethylphenylcarbamate)cellulose chiral column. An excellent resolution of the two antipodes is obtained (Rs greater than 2) with high peak symmetries. The method is simple and ideally suited to the routine control of the enantiomeric excess in the bulk drug and the analysis of the enantiomers of betaxolol in hepatocyte suspensions. With modification of the polar modifier in a hexane-based mobile phase, most commercially available beta-blockers can be baseline resolved.