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Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.

Lan Z, Xu X, Xu W, Li J, Liang Z, Zhang X, Lei M, Zhao C - Drug Des Devel Ther (2015)

Bottom Line: This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone.Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains.In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.

ABSTRACT
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus

Effect of 3d on H2O2-induced cytotoxicity in HT22 cells.Notes: Data were expressed as the mean ± SD of each group of cells from four separate experiments. Data were analyzed by one-way analysis of variance (ANOVA) followed by Newman-keuls test: #P<0.05 vs the H2O2-treated group.Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; SD, standard deviation.
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f8-dddt-9-3377: Effect of 3d on H2O2-induced cytotoxicity in HT22 cells.Notes: Data were expressed as the mean ± SD of each group of cells from four separate experiments. Data were analyzed by one-way analysis of variance (ANOVA) followed by Newman-keuls test: #P<0.05 vs the H2O2-treated group.Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; SD, standard deviation.

Mentions: A growing body of evidence suggested that oxidative stress plays an important role in ischemic stroke reperfusion injury,44,45 which can exacerbate ischemic brain damage through the generation of ROS, such as superoxide anions (O2•−), hydroxyl radicals (OH•), and NO, and H2O2. Hydroxyl radicals (OH•) can damage DNA and have high cytotoxicity.46,47 NBP can reduce damage of oxidative stress. Thus, we hypothesized that 3d might have antioxidative stress effect. To verify this hypothesis, we investigated its scavenging activities in murine HT22 cells, which are commonly used for the analysis of diseases related to oxidative neuronal cell death.48–52 The influence of H2O2 on HT22 cell survival was measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and confirmed by microscopic evaluation. The 100 µM 3d remarkably increased the H2O2-treated HT22 viability percentage (74.25%), compared with 51.45% of only H2O2-treated HT22 cells. The neuroprotective effect of 3d exceeded that of NBP and Eda (71.55% and 69.87%, respectively) at the same dosage (Figure 8). The results implied that 3d could protect HT22 cells from H2O2-induced cytotoxicity damage and might be a free radical scavenger.


Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.

Lan Z, Xu X, Xu W, Li J, Liang Z, Zhang X, Lei M, Zhao C - Drug Des Devel Ther (2015)

Effect of 3d on H2O2-induced cytotoxicity in HT22 cells.Notes: Data were expressed as the mean ± SD of each group of cells from four separate experiments. Data were analyzed by one-way analysis of variance (ANOVA) followed by Newman-keuls test: #P<0.05 vs the H2O2-treated group.Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492651&req=5

f8-dddt-9-3377: Effect of 3d on H2O2-induced cytotoxicity in HT22 cells.Notes: Data were expressed as the mean ± SD of each group of cells from four separate experiments. Data were analyzed by one-way analysis of variance (ANOVA) followed by Newman-keuls test: #P<0.05 vs the H2O2-treated group.Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; SD, standard deviation.
Mentions: A growing body of evidence suggested that oxidative stress plays an important role in ischemic stroke reperfusion injury,44,45 which can exacerbate ischemic brain damage through the generation of ROS, such as superoxide anions (O2•−), hydroxyl radicals (OH•), and NO, and H2O2. Hydroxyl radicals (OH•) can damage DNA and have high cytotoxicity.46,47 NBP can reduce damage of oxidative stress. Thus, we hypothesized that 3d might have antioxidative stress effect. To verify this hypothesis, we investigated its scavenging activities in murine HT22 cells, which are commonly used for the analysis of diseases related to oxidative neuronal cell death.48–52 The influence of H2O2 on HT22 cell survival was measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and confirmed by microscopic evaluation. The 100 µM 3d remarkably increased the H2O2-treated HT22 viability percentage (74.25%), compared with 51.45% of only H2O2-treated HT22 cells. The neuroprotective effect of 3d exceeded that of NBP and Eda (71.55% and 69.87%, respectively) at the same dosage (Figure 8). The results implied that 3d could protect HT22 cells from H2O2-induced cytotoxicity damage and might be a free radical scavenger.

Bottom Line: This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone.Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains.In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.

ABSTRACT
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus