RESUMEN
Synthesis of four compounds belonging to mesoionic class, (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (5a-d) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and non-infected cell lines (Jurkat) are reported. The compounds were obtained by convergent synthesis under microwave irradiation and the cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Results showed IC50 values of all compounds in the range of 1.51-7.70 M in HTLV-1-infected and non-infected cells. Furthermore, it was observed that 5b could induce necrosis after 24 h for Jurkat and MT2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action for 5b could be related to its capacity to intercalate into DNA. Moreover, the preliminary pharmacokinetic profile of the studied compounds (5a-d) was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential and molecular docking calculations. The interaction HSA:5a-d is spontaneous and moderate (Ka ~ 104 M-1) via a ground-state association, without significantly perturbing both the secondary and surface structures of the albumin in the subdomain IIA (site I), indicating feasible biodistribution in the human bloodstream.
Asunto(s)
Antineoplásicos/farmacología , Cloruros/farmacología , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/virología , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular , Dicroismo Circular , Ensayos de Selección de Medicamentos Antitumorales , Virus Linfotrópico T Tipo 1 Humano , Humanos , Concentración 50 Inhibidora , Células Jurkat , Espectroscopía de Resonancia Magnética , Microondas , Simulación del Acoplamiento Molecular , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo , Albúmina Sérica Humana/química , Distribución TisularRESUMEN
In the title di-hydro-dioxin, C31H28O5, the dioxane ring has a chair conformation, whereas each of the pyran and dioxine rings has an envelope conformation with methyl-ene and quaternary C atoms, respectively, being the flap atoms. The phenyl rings are cis and form a dihedral angle of 82.11â (10)°. The molecular structure is stabilized by C-Hâ¯O contacts. In the crystal packing, supra-molecular layers parallel to (101) are sustained by C-Hâ¯π inter-actions.
RESUMEN
Laser flash photolysis (LFP) studies, atoms in molecules (AIM) studies, and density functional theory (DFT) calculations have been performed in order to study the mechanism of the hydrogen abstraction by alpha-diketones in the presence of phenols. Laser irradiation of a degassed solution of 1,2-diketopyracene in acetonitrile resulted in the formation of a readily detectable transient with absorption at 610 nm, but with very low absorptivity. This transient decays with a lifetime of around 2 micros. The quenching rate constant for substituted phenols, kq, ranged from 1.10x10(8) L mol-1 s-1 (4-cyanophenol) to 3.87x10(9) L mol-1 s-1 (4-hydroxyphenol). The Hammett plot for the reaction of the triplet of 1,2-diketopyracene with phenols gave a reaction constant rho=-0.9. DFT calculations (UB3LYP/6-311++G**//UB3LYP/6-31G*) of the triplet complex ketone-phenol revealed that hydrogen transfer has predominantly occurred and that the reaction with alpha-diketones are generally 7 kcal/mol less endothermic than the respective reactions of the monoketones. These results together with the geometries obtained from the DFT calculations, natural bond order (NBO) analysis, and AIM results indicate that hydrogen abstraction for alpha-diketones is facilitated by the electrophilicity of the ketone, instead of neighboring group participation by the second carbonyl group.