RESUMEN
A series of novel five-membered sulfur-containing heterocyclic nucleoside derivatives were designed, synthesized, and evaluated for their anticancer activities in vitro and in vivo. The structure-activity relationship studies revealed that some of them showed obvious antitumor activities in several cancer cell lines. Among them, compound 22o exhibited remarkable antiproliferative activity against HeLa cells and was more potent than cisplatin (IC50 = 2.80 vs 7.99 µM). Furthermore, mechanism studies indicated that 22o inhibited cell metastasis, induced cell apoptosis, decreased mitochondrial membrane potential, and activated autophagy through the PI3K-Akt-mTOR signaling pathway. Moreover, drug affinity responsive target stability and the cellular thermal shift assay revealed that 22o targeted RPS6 and inhibited its phosphorylation. Importantly, 22o inhibited the growth of the HeLa xenograft mouse model with a low systemic toxicity. These results indicated that 22o may serve as potent anticancer agents that merit further attention in future anticancer drug discovery.
Asunto(s)
Antineoplásicos , Proliferación Celular , Nucleósidos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Animales , Relación Estructura-Actividad , Nucleósidos/síntesis química , Nucleósidos/farmacología , Nucleósidos/química , Ratones , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Línea Celular Tumoral , Ratones Desnudos , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Azufre/química , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Tibetan medicine processing ensures the safety of clinical application of Tibetan medicine. It is of great significance to analyze the principles of Tibetan medicine processing in the development, inheritance, and innovation of Tibetan medicine. However, due to the late start of modern Tibetan medicine research and the disciplinary division, the current research on Tibetan medicine processing focuses on the exploration and collation of traditional techniques and the analysis of the processing mechanism of Tibetan medicine through chemical and pharmacological research, but its principles and traditional theories have been rarely reported. In view of this, after analyzing the concept, essence, theories, purposes, and functions of Tibetan medicine processing through the integration of Tibetan medicine, Tibetan pharmacology, and clinical research of Tibetan medicine, this study proposed that the essence of Tibetan medicine processing was to change the "five sources" composition of medicinal materials through physical, chemical, and biological means, or the comprehensive means, and the theoretical principle of Tibetan medicine processing was to change or transform the positive and adverse effects or the obvious and recessive effects by altering the "five sources" composition of the drug to maximize the positive effect and minimize the adverse effect and the damage to the body, thereby achieving the purposes of toxicity reduction, efficacy enhancement, and drug property harmonization represented by sharpening, softening, nourishing, and reasonable compatibility. This study is expected to provide references for the construction of the theoretical system of Tibetan medicine processing, the inheritance of processing techniques, and innovative research.