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1.
Org Biomol Chem ; 12(28): 5235-42, 2014 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-24920241

RESUMEN

Herein, we report optically pure modified acyclic nucleosides as ideal probes for aptamer modification. These new monomers offer unique advantages in exploring the role played in thrombin inhibition by a single residue modification at key positions of the TBA structure.


Asunto(s)
Antitrombinas/síntesis química , Aptámeros de Nucleótidos/síntesis química , Nucleósidos/química , Trombina/antagonistas & inhibidores , Antitrombinas/química , Aptámeros de Nucleótidos/química , Dicroismo Circular , G-Cuádruplex , Modelos Moleculares , Imitación Molecular , Rotación Óptica , Estereoisomerismo , Termodinámica , Trombina/química
2.
J Exp Clin Cancer Res ; 35(1): 167, 2016 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-27770821

RESUMEN

BACKGROUND: Embelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-κB signaling pathway. Synthetic structural modification yielded the derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id), an embelin constrained analogue, with improved efficiency against 5-LOX in human neutrophils and anti-inflammatory activity in vivo. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms. METHODS: U87MG and LN229 cells were plated in 96-wells and treated with increasing concentrations of RF-Id. Cell viability was evaluated by MTT assay. The effects of the compounds on cell cycle, apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array and evaluating caspase cascade and NFκB pathway by western blotting technique. RESULTS: Here, we found that RF-Id induced a stronger inhibition of GBM cell growth than treatment with embelin. Flow cytometry analysis showed that RF-Id induced about 30 % apoptosis and a slight increase of autophagy after 72 h on U87-MG cells. Moreover, the compound induced an increase in the percentage of cells in G2 and S phase that was paralleled by an increase of p21 and p27 expression but no significant changes of the mitochondrial membrane potential; array analysis showed a significant upregulation of CASP8 and a downregulation of IAP family and NFκB genes in cells treated with RF-Id. RF-Id induced a significant cleavage of caspases 8, 9, 3 and 7, blocked c-IAP2/XIAP interaction by inducing XIAP degradation and inhibited NFκB pathway. CONCLUSIONS: RF-Id induced a caspase-dependent apoptosis in GBM cells by inhibiting IAP family proteins and NFκB pathway and represents a promising lead compound for designing a new class of anti-cancer drugs with multiple targets.


Asunto(s)
Benzoquinonas/farmacología , Neoplasias Encefálicas/metabolismo , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Glioblastoma/metabolismo , Proteínas Inhibidoras de la Apoptosis/metabolismo , Araquidonato 5-Lipooxigenasa/metabolismo , Ácido Araquidónico/metabolismo , Autofagia , Benzoquinonas/síntesis química , Benzoquinonas/química , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Humanos , Ácido Linoleico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
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