Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of NBP on concentrations of some purine metabolites in extracellular fluid of rat striatum during global ischemia and reperfusion were studied. Global ischemia was produced by the four-vessel occlusion method. Push-pull cannula was implanted stereotaxically into the striatum of rat and was perfused with Ringer's solution at a flow rate of 2.5 microliters.min-1. The level of adenosine(Ade), inosine(Ino), hypoxanthine(Hyp) and xanthine(Xan) in perfusates were measured with HPLC connected with a UV detector. The results indicate that the levels of ade, ino, hyp and xan were significantly increased (about 3-5 times of initial value) during cerebral ischemia and reperfusion. NBP at the dose of 20 or 40 mg.kg-1 given intra-peritoneally 20 min before ischemia was shown to depress the increase of ade, ino, hyp and xan during ischemia and reperfusion dose dependently. But no change in the level of purine metabolites was found in sham operated rats. It has been known that harmful free radicals were produced when xan and uric acid were formed by xanthine oxidase during reperfusion. This might be important for the development of ischemic injuries. Our findings suggest that the effect of NBP might be beneficial for protection against post-ischemic neuronal damage.
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PMID:[Effect of dl-3-n-butylphthalide (NBP) on purine metabolites in striatum extracellular fluid in four-vessel occlusion rats]. 876 58

O6-alkylguanine-DNA alkyltransferase (AGT) is the main cause of tumor cell resistance to DNA-alkylating agents, so it is valuable to design tumor-targeted AGT inhibitors with hypoxia activation. Based on the existing benchmark inhibitor O6-benzylguanine (O6-BG), four derivatives with hypoxia-reduced potential and their corresponding reduction products were synthesized. A reductase system consisting of glucose/glucose oxidase, xanthine/xanthine oxidase, and catalase were constructed, and the reduction products of the hypoxia-activated prodrugs under normoxic and hypoxic conditions were determined by high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The results showed that the reduction products produced under hypoxic conditions were significantly higher than that under normoxic condition. The amount of the reduction product yielded from ANBP (2-nitro-6-(3-amino) benzyloxypurine) under hypoxic conditions was the highest, followed by AMNBP (2-nitro-6-(3-aminomethyl)benzyloxypurine), 2-NBP (2-nitro-6-benzyloxypurine), and 3-NBG (O6-(3-nitro)benzylguanine). It should be noted that although the levels of the reduction products of 2-NBP and 3-NBG were lower than those of ANBP and AMNBP, their maximal hypoxic/normoxic ratios were higher than those of the other two prodrugs. Meanwhile, we also investigated the single electron reduction mechanism of the hypoxia-activated prodrugs using density functional theory (DFT) calculations. As a result, the reduction of the nitro group to the nitroso was proven to be a rate-limiting step. Moreover, the 2-nitro group of purine ring was more ready to be reduced than the 3-nitro group of benzyl. The energy barriers of the rate-limiting steps were 34-37 kcal/mol. The interactions between these prodrugs and nitroreductase were explored via molecular docking study, and ANBP was observed to have the highest affinity to nitroreductase, followed by AMNBP, 2-NBP, and 3-NBG. Interestingly, the theoretical results were generally in a good agreement with the experimental results. Finally, molecular docking and molecular dynamics simulations were performed to predict the AGT-inhibitory activity of the four prodrugs and their reduction products. In summary, simultaneous consideration of reduction potential and hypoxic selectivity is necessary to ensure that such prodrugs have good hypoxic tumor targeting. This study provides insights into the hypoxia-activated mechanism of nitro-substituted prodrugs as AGT inhibitors, which may contribute to reasonable design and development of novel tumor-targeted AGT inhibitors.
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PMID:Reductive Activity and Mechanism of Hypoxia- Targeted AGT Inhibitors: An Experimental and Theoretical Investigation. 3184