Carbonyl-heterobimetallic Ru(II)/Fe(II)-complexes containing polypyridyl ligands: Synthesis, characterization, cellular viability assays and interactions with biomolecules.

This paper describes on the interaction studies of carbonyl heterobimetallic compounds of Ru(II)/Fe(II) containing polypyridyl ligands, with general formula ct-[RuCl(CO)(N-N)(dppf)]PF6, N-N = 1,10-phenanthroline (phen) 5; dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) 6; dipyrido[3,2-a:2',3'-c]phenazine (dppz) 7; dipyrido[3,2-f:2',3'-h]quinoxalino[2,3-b]quinoxaline (dpqQX) 8 and dppf = 1,1'-bis(diphenylphosphino) ferrocene], with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA). Also, it describes the cellular viability assays of these complexes in tumorigenic and non-tumorigenic cell lines. The carbonyl complexes 5-8 and their respective precursors with formula cis-[RuCl2(N-N)(dppf)], N-N = phen (1), dpq (2), dppz (3) and dpqQX (4), were characterized by elemental analysis and spectroscopic techniques (FTIR, UV-vis, 1H and 31P{1H} NMR). Also, a cyclic voltammetry study was performed for all complexes. The crystal structure of the complex 3 is presented and discussed. Spectrofluorimetric titrations shows spontaneous and strong interaction of 5-8 with BSA, through a static quenching mechanism, resulting in binding constants in the order of 104-106 L mol-1, at 310 K. Viscosity measurements and circular dichroism spectra prompts interactions of 5-8 with ct-DNA via non-classical intercalations or by an electrostatic pathway. MTT assays in breast tumor cells MDA-MB-231 and in non-tumorigenic cells MCF-10A and V79-4 cell lines revealed IC50 values ranging from 0.19 to 1.11 µmol L-1, 1.07-3.18 µmol L-1 and 1.29-3.85 µmol L-1 respectively, for complexes 5-8.

Diaminomaleonitrile derivatives as new potential antichagasic compounds: a study of structure-activity relationships.

Background: Schiff bases are synthetically accessible compounds that have been used in medicinal chemistry. Methods & results: In this work, 27 Schiff bases derived from diaminomaleonitrile were synthesized in high yields (80-98%). Molecular docking studies suggested that the Schiff bases interact with the catalytic site of cruzain. The most active cruzain inhibitor, analog 13 (IC50 = 263 nM), was predicted to form an additional hydrophobic contact with Met68 in the binding site of the enzyme. A strong correlation between the IC50 values and ChemScore binding energies was observed (R = 0.99). Kernel-based 2D quantitative structure-activity relationship models for the whole dataset yielded sound correlation coefficients (R2 = 0.844; Q2 = 0.719). Conclusion: These novel and potent cruzain inhibitors are worthwhile starting points in further Chagas disease drug discovery programs.

Is breaking of a hydrogen bond enough to lead to drug resistance?

Drug resistance is a serious problem in cancer, viral, bacterial, fungal and parasitic diseases. Examination of crystal structures of protein-drug complexes is often not enough to explain why a certain mutation leads to drug resistance. As an example, the crystal structure of the kinase inhibitor dasatinib bound to the Abl1 kinase shows a hydrogen bond between the drug and residue Thr315 and very few contacts between the drug and residues Val299 and Phe317, yet mutations in those residues lead to drug resistance. In the first case, it is tempting to suggest that the loss of a hydrogen bond leads to drug resistance, whereas in the other two cases it is not known why mutations lead to drug resistance in the first place. We carried out extensive molecular dynamics (MD) simulations and free energy calculations to explain drug resistance to dasatinib from a molecular point of view and show that resistance is due to a multitude of subtle effects. Importantly, our calculations could reproduce the experimental values for the binding energies upon mutations in all three cases and shed light on their origin.

Enfermedad de Behçet. Reflexiones sobre su diagnóstico y tratamiento / Behçet's disease. Reflections on its diagnosis and treatment

La enfermedad de Behçet se considera una entidad multisistémica identificada por aftas orales y genitales, lesiones cutáneas, artritis, manifestaciones gastrointestinales, neurológicas y oculares, pertenece al conjunto de afecciones consideradas autoinmunes en la que se puede afectar a cualquier vaso sanguíneo del organismo, para su diagnóstico se sugieren un grupo de criterios que examina regularmente un comité internacional de especialistas en las que deben incluir aftas periódicas en boca y genitales acompañados de hipopion y uveítis, su tratamiento en la actualidad se dirige a disminuir la actividad del sistema inmune y tiene como objetivo reducir los síntomas y prevenir las complicaciones(AU)

Behçet's disease is considered a multisystemic entity identified by oral and genital thrush, skin lesions, arthritis, gastrointestinal, neurological and ocular manifestations, belongs to the set of conditions considered autoimmune in which any blood vessel of the organism can be affected, for its Diagnosis is suggested a group of criteria that regularly examines an international committee of specialists in which they must include periodic canker sores in the mouth and genitals accompanied by hypopion and uveitis, their treatment is currently aimed at decreasing the activity of the immune system and aims reduce symptoms and prevent complications(AU)