RESUMEN
Alzheimer's disease and oxidative stress are connected. In the present communication, we report the use of a MnII -based superoxide dismutase (SOD) mimic ([MnII (L)]+ , 1+ ) as a pro-drug candidate to target CuII -associated events, namely, CuII -induced formation of reactive oxygen species (ROS) and modulation of the amyloid-ß (Aß) peptide aggregation. Complexâ 1+ is able to remove CuII from Aß, stop ROS and prevent alteration of Aß aggregation as would do the corresponding free ligand LH. Using 1+ instead of LH in further biological applications would have the double advantage to avoid the cell toxicity of LH and to benefit from its proved SOD-like activity.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cobre/química , Modelos Moleculares , Profármacos/química , Superóxido Dismutasa/química , Péptidos beta-Amiloides/química , Concentración de Iones de Hidrógeno , Cinética , Oxidación-Reducción , Estrés Oxidativo , Agregado de Proteínas , Unión Proteica , Conformación Proteica , Especies Reactivas de Oxígeno/química , TermodinámicaRESUMEN
Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzyme have been found to play a role in promoting growth in colon cancer cell lines. The di-tert-butyl phenol class of compounds has been found to inhibit both COX-2 and 5-LOX enzymes with proven effectiveness in arresting tumor growth. In the present study, the structural analogs of 2,6 di-tert-butyl-p-benzoquinone (BQ) appended with hydrazide side chain were found to inhibit COX-2 and 5-LOX enzymes at micromolar concentrations. Molecular docking of the compounds into COX-2 and 5-LOX protein cavities indicated strong binding interactions supporting the observed cytototoxicities. The signaling interaction between endogenous hyaluronan and CD44 has been shown to regulate COX-2 activities through ErbB2 receptor tyrosine kinase (RTK) activation. In the present studies it has been observed for the first time, that three of our COX/5-LOX dual inhibitors inhibit proliferation upon hydrazide substitution and prevent the activity of pro-angiogenic factors in HCA-7, HT-29, Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressed in colon cancer cells, through inhibition of the hyaluronan/CD44v6 cell survival pathway. Since there is a substantial enhancement in the antiproliferative activities of these compounds upon hydrazide substitution, the present work opens up new opportunities for evolving novel active compounds of BQ series for inhibiting colon cancer.
Asunto(s)
Antineoplásicos/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Ciclohexanonas/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/metabolismo , Hidrazinas/farmacología , Inhibidores de la Lipooxigenasa/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Ciclohexanonas/síntesis química , Ciclohexanonas/química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Modelos Moleculares , Estructura Molecular , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Copper conjugates of Schiff base derivatives of nimesulide (1), a well-known cyclooxygenase-2 (COX-2) inhibitor, were synthesized, structurally characterized and evaluated for their COX selectivity indices and cytotoxicities on pancreatic tumor, BxPC-3 (COX-2 positive) and MiaPaCa (COX-2 negative) cell lines. Copper conjugates exhibit distorted square planar geometries as revealed by the single crystal X-ray structure determination of Cu(L1)(2) and show significant growth inhibition in both cell lines (IC50 values 3-26 microM for COX-2 positive and 5-9 microM for COX-2 negative cell line) than the parent nimesulide (35 microM for COX-2 positive and >100 microM for COX-2 negative cell line). The mechanistic pathway for the biological activity involves inhibition of vascular endothelial growth factor (VEGF) and COX inhibition, as well as down regulation of antiapoptotic Bcl-2 and Bcl-(XL) proteins.
Asunto(s)
Cobre/química , Ciclooxigenasa 2/química , Proteínas Proto-Oncogénicas c-bcl-2/química , Bases de Schiff , Sulfonamidas/química , Factor A de Crecimiento Endotelial Vascular/química , Animales , Línea Celular Tumoral , Proliferación Celular , Espectroscopía de Resonancia por Spin del Electrón , Humanos , Modelos Moleculares , Espectrofotometría InfrarrojaRESUMEN
SOD-mimics are small complexes that reproduce the activity of superoxide dismutases, natural proteins that catalytically dismutate the superoxide anion. Activated macrophages, which produce ROS and RNS fluxes, constitute a relevant model to challenge antioxidant activity in a cellular context and were used to test a Mn-complex which was shown to efficiently alter the flow of O(2)(-), ONOO(-) and H(2)O(2).