RESUMEN
Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50â¯=â¯0.061⯱â¯0.003⯵M) and intact cell (IC50â¯=â¯0.89⯱â¯0.05⯵M), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.
Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Ureasa/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/citología , Helicobacter pylori/enzimología , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/química , Cinética , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Ureasa/aislamiento & purificación , Ureasa/metabolismoRESUMEN
In order to discover novel derivatives in the anti-tumor field, reported anti-tumor pharmacophores (uridine, uracil, and thymine) were combined with 2-methoxyestradiol, which has been characterized as having excellent biological properties in terms of anti-tumor activity. Thus, 20 hybrids were synthesized through etherification at the 17ß-OH or 3-phenolic hydroxyl group of 2-methoxyestradiol, and evaluated for their biological activities against the human breast adenocarcinoma MCF-7 cell lines, human breast cancer MDA-MB-231 cell lines, and the normal human liver L-O2 cell lines. As a result, all the uridine derivatives and single-access derivatives of uracil/thymine possessed good anti-proliferative activity against tested tumor cells (half maximal inhibitory concentration values from 3.89 to 19.32 µM), while only one dual-access derivative (21b) of thymine possessed good anti-proliferative activity (half maximal inhibitory concentration ≈ 25 µM). Among them, the uridine derivative 11 and the single-access derivative of uracil 12a possessed good anti-proliferative selectivity against tested tumor cells. Furthermore, basic mechanism studies revealed that hybrids 11 and 12a could induce apoptosis in MCF-7 cells through mitochondrial pathway. These hybrids induced morphological changes in MCF-7 cells, causing mitochondrial depolarization. These two hybrids also had the following effects: arrest of the cell cycle at the G2 phase; upregulation of Apaf-1, Bax, and cytochrome c; downregulation of Bcl-2 and Bcl-xL for both mRNA and protein; and increase of the expression for caspase-8 and -9. Finally, apoptotic effector caspase-3 was increased, which eventually caused nuclear apoptosis at least through an intrinsic pathway in the mitochondria. Additionally, hybrids 11 and 12a could specifically bind to estradiol receptor alpha in a dose-dependent manner.
Asunto(s)
2-Metoxiestradiol/análogos & derivados , 2-Metoxiestradiol/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , 2-Metoxiestradiol/síntesis química , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Femenino , Humanos , Células MCF-7 , Modelos MolecularesRESUMEN
Due to the obvious adverse effects of 5-fluorouracil that limit its clinical usefulness and considering the diverse biological activities of pentacyclic triterpenes, twelve pentacyclic triterpene-5-fluorouracil conjugates were synthesized and their antitumor activities were evaluated. The results indicated that all the single substitution targeted hybrids (7a-12a) possessed much better antiproliferative activities than the double substitution targeted hybrids (7b-12b). Hybrid 12a exhibited good antiproliferative activities against all the tested MDR cell lines. Furthermore, it was revealed that 12a could induce intracellular calcium influx, the generation of ROS, arrest the cell proliferation at the G1 phase, and activate the apoptotic signaling caspase-8, which eventually activates the apoptotic effector caspase-3 and causes the later nuclear apoptosis.