RESUMEN
HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated. Among the synthesized hybrid compounds, compound 16b showed the potent HDAC inhibitory activity at a low nanomolar level and exhibited antiproliferative activity toward cancer cell lines including MCF-7 (breast), HCT-116 (colon), and DU-145 (prostate) cancer cells at a low micromolar level. Moreover, compound 16a showed HDAC6-selectivity 20-fold over HDAC1.
Asunto(s)
Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo II/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/metabolismo , Inhibidores de Topoisomerasa II/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/química , Células HCT116 , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/genética , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Humanos , Células MCF-7 , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
We developed novel nucleoside-based topoisomerase II selective inhibitors and showed that small structural units, such as catechols, are essential for DNA topoisomerase II inhibitory activity. Moreover, nucleoside analogues containing TBS and 1,3-dithian moieties had potent and selective DNA topoisomerase II inhibitory activities. In further experiments, compound 25b having a beta configuration of the thymine moiety showed relatively strong growth inhibitory activity against cancer cell lines, and was more potent against all cancer cell lines than compound 26b, which carries a thymine moiety in the alpha configuration.
Asunto(s)
Diseño de Fármacos , Nucleótidos/antagonistas & inhibidores , Inhibidores de Topoisomerasa II/farmacología , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectrometría de Masas , Espectroscopía de Protones por Resonancia Magnética , Espectrofotometría Infrarroja , Inhibidores de Topoisomerasa II/químicaRESUMEN
The use of a quenching gas, isobutene, with a low vapor pressure was investigated to enhance the utility of hyperpolarized (129) Xe (HP Xe) MRI. Xenon mixed with isobutene was hyperpolarized using a home-built apparatus for continuously producing HP Xe. The isobutene was then readily liquefied and separated almost totally by continuous condensation at about 173 K, because the vapor pressure of isobutene (0.247 kPa) is much lower than that of Xe (157 kPa). Finally, the neat Xe gas was continuously delivered to mice by spontaneous inhalation. The HP Xe MRI was enhanced twofold in polarization level and threefold in signal intensity when isobutene was adopted as the quenching gas instead of N2 . The usefulness of the HP Xe MRI was verified by application to pulmonary functional imaging of spontaneously breathing mice, where the parameters of fractional ventilation (ra ) and gas exchange (fD ) were evaluated, aiming at future extension to preclinical studies. This is the first application of isobutene as a quenching gas for HP Xe MRI.
Asunto(s)
Alquenos/farmacocinética , Aumento de la Imagen/métodos , Pulmón/fisiología , Imagen por Resonancia Magnética/métodos , Intercambio Gaseoso Pulmonar/fisiología , Isótopos de Xenón/farmacocinética , Administración por Inhalación , Alquenos/administración & dosificación , Animales , Medios de Contraste , Gases , Interpretación de Imagen Asistida por Computador/métodos , Pulmón/diagnóstico por imagen , Masculino , Ratones , Ratones Endogámicos , Radiofármacos/administración & dosificación , Radiofármacos/farmacología , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Isótopos de Xenón/administración & dosificaciónRESUMEN
The feasibility of ventilation imaging with hyperpolarized (HP) (129) Xe MRI has been investigated for quantitative and regional assessment of ventilation in spontaneously breathing mice. The multiple breath ventilation imaging technique was modified to the protocol of spontaneous inhalation of HP (129) Xe delivered continuously from a (129) Xe polarizer. A series of (129) Xe ventilation images was obtained by varying the number of breaths before the (129) Xe lung imaging. The fractional ventilation, r, was successfully evaluated for spontaneously breathing mice. An attempt was made to detect ventilation dysfunction in the emphysematous mouse lung induced by intratracheal administration of porcine pancreatic elastase (PPE). As a result, the distribution of fractional ventilation could be visualized by the r map. Significant dysfunction of ventilation was quantitatively identified in the PPE-treated group. The whole-lung r value of 0.34 ± 0.01 for control mice (N = 4) was significantly reduced, to 0.25 ± 0.07, in PPE-treated mice (N = 4) (p = 0.038). This study is the first application of multiple breath ventilation imaging to spontaneously breathing mice, and shows that this methodology is sensitive to differences in the pulmonary ventilation. This methodology is expected to improve simplicity as well as noninvasiveness when assessing regional ventilation in small rodents.