RESUMEN
In the present work, 103 novel acyclic nucleosides were designed, synthesized, and evaluated for their anticancer activities in vitro and in vivo. The structure-activity relationship (SAR) studies revealed that most target compounds inhibited the growth of colon cancer cells in vitro, of which 3-(6-chloro-9H-purin-9-yl)dodecan-1-ol (9b) exhibited the most potent effect against the HCT-116 and SW480 cells with IC50 values of 0.89 and 1.15 µM, respectively. Furthermore, all of the (R)-configured acyclic nucleoside derivatives displayed more potent anticancer activity compared to their (S)-counterparts. Mechanistic studies revealed that compound 9b triggered apoptosis in the cancer cell lines via depolarization of the mitochondrial membrane and effectively inhibited colony formation. Importantly, compound 9b inhibited the growth of the SW480 xenograft in a mouse model with low systemic toxicity. These results indicated that acyclic nucleoside compounds are viable as potent and effective anticancer agents, and compound 9b may serve as a promising lead compound that merits further attention in future anticancer drug discovery.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Nucleósidos de Purina/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Estructura Molecular , Nucleósidos de Purina/síntesis química , Nucleósidos de Purina/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The base contents of liver deoxyribonucleic acid (DNA) of rats living at an altitude of 2.3 km were determined by reversed-phase high performance liquid chromatography. At first, 0.05 mol/L KH2PO4(pH 4.0) was used to dissolve the DNA acid hydrolysis products with 8-bromoguanosine (Br8G) as an internal standard. Then the DNA hydrolysis products with Br8G were chromatographed on a Supelcosil LC-18 column with UV detection at 254 nm and eluted by the mobile phase of MeOH-0.05 mol/L KH2PO4(pH 4.0) (20:80, V/V) at the flow rate of 0.8 mL/min. Under these conditions, several bases were separated effectively. From the results, the relatively constant proportions of the bases in DNA were found. The contents were 17.4% of cytosine (C), 28.8% of adenine (A), 23.3% of guanine (G) and 25.3% of thymine (T). RSDs of the determination of these bases were 1.7%, 1.5%, 1.3% and 2.1%, respectively. At the same time the methylation level of liver DNA of the rats determined by the internal standard method was 6.2%.
