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One-Step Synthesis of Chiral Oxindole-type Analogues with Potent Anti-inflammatory and Analgesic Activities.

Sun Y, Liu J, Jiang X, Sun T, Liu L, Zhang X, Ding S, Li J, Zhuang Y, Wang Y, Wang R - Sci Rep (2015)

Bottom Line: Moreover, Q4c alleviated pain in mouse models with comparable activity to morphine.Further investigation suggested that nitric oxide signaling pathway is involved in the anti-inflammatory and analgesic activities of Q4c.Notably, this is the first time that chiral oxindole-type analogues have been identified to be both anti-inflammatory and analgesic, and our study also paved the way for future development of oxindoles as drug candidates in this field.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China, 510006.

ABSTRACT
Here we report a facile approach to synthesize highly optically active oxindole-type analogues with both high yield and enantioselectivity. This single-step synthesis strategy represents a substantial improvement upon existing methods that are often involved with multi-step routes and have suboptimal atomic economy. One such compound, namely Q4c, showed remarkable in vivo anti-inflammatory activity with efficiency approaching to that of a steroidal compound dexamethasone. Moreover, Q4c alleviated pain in mouse models with comparable activity to morphine. Further investigation suggested that nitric oxide signaling pathway is involved in the anti-inflammatory and analgesic activities of Q4c. Notably, this is the first time that chiral oxindole-type analogues have been identified to be both anti-inflammatory and analgesic, and our study also paved the way for future development of oxindoles as drug candidates in this field.

No MeSH data available.


Related in: MedlinePlus

Mechanism of actions of Q4c.(A) The effect of Q4c on LPS-stimulated NO release from primary peritoneal macrophages. Nitrite levels were assessed by Griess reagent. Data are shown as mean ± SEM (n = 5). Significant difference between LPS and test groups are indicated, **p < 0.01; ***p < 0.001.(B) The effect of iNOS antagonist SMT on the in vivo anti-inflammatory activity of Q4c. Data are shown as mean ± SEM (n = 7). Significant difference from vehicle, *p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001. Significant difference between Q4c treatments in the absence and presence of SMT, #p < 0.05. Statistical analysis was performed by two-way ANOVA, followed by Tukey’s post-tests.
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f5: Mechanism of actions of Q4c.(A) The effect of Q4c on LPS-stimulated NO release from primary peritoneal macrophages. Nitrite levels were assessed by Griess reagent. Data are shown as mean ± SEM (n = 5). Significant difference between LPS and test groups are indicated, **p < 0.01; ***p < 0.001.(B) The effect of iNOS antagonist SMT on the in vivo anti-inflammatory activity of Q4c. Data are shown as mean ± SEM (n = 7). Significant difference from vehicle, *p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001. Significant difference between Q4c treatments in the absence and presence of SMT, #p < 0.05. Statistical analysis was performed by two-way ANOVA, followed by Tukey’s post-tests.

Mentions: To explore how Q4c exerts its anti-inflammatory and analgesic activities, we next examined the signaling pathways that may be involved in its function. Our previous study suggested that nitric oxide synthase (NOS) signaling pathway was involved in the anti-inflammatory activity of JP-8 g, another spirooxindole compound14. Therefore, we sought to determine the effect of Q4c on LPS-stimulated nitric oxide (NO) release in isolated primary macrophages. As seen in Fig. 5A, Q4c suppressed NO release in a dose-dependent manner. Q4c of 10 μM achieved more than 50% suppression. To confirm the role of NOS signaling pathway, we evaluated the effect of NOS inhibitors on the anti-inflammatory activity of Q4c using mouse paw swelling model. It was observed that 30 mg/kg of inducible NOS (iNOS) inhibitor SMT significantly (p < 0.05) reduced the anti-inflammatory activity of Q4c 5–24 h after carrageenan injection (Fig. 5B). In contrast, NF-kB inhibitor BAY 11–7082 did not appear to affect the in vivo activity of Q4c (Supplementary Fig. 7). This is consistent with our previous findings that NOS pathway, but not NF-κB pathway, is involved in the anti-inflammatory activity of spirooxindole compounds15.


One-Step Synthesis of Chiral Oxindole-type Analogues with Potent Anti-inflammatory and Analgesic Activities.

Sun Y, Liu J, Jiang X, Sun T, Liu L, Zhang X, Ding S, Li J, Zhuang Y, Wang Y, Wang R - Sci Rep (2015)

Mechanism of actions of Q4c.(A) The effect of Q4c on LPS-stimulated NO release from primary peritoneal macrophages. Nitrite levels were assessed by Griess reagent. Data are shown as mean ± SEM (n = 5). Significant difference between LPS and test groups are indicated, **p < 0.01; ***p < 0.001.(B) The effect of iNOS antagonist SMT on the in vivo anti-inflammatory activity of Q4c. Data are shown as mean ± SEM (n = 7). Significant difference from vehicle, *p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001. Significant difference between Q4c treatments in the absence and presence of SMT, #p < 0.05. Statistical analysis was performed by two-way ANOVA, followed by Tukey’s post-tests.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4555174&req=5

f5: Mechanism of actions of Q4c.(A) The effect of Q4c on LPS-stimulated NO release from primary peritoneal macrophages. Nitrite levels were assessed by Griess reagent. Data are shown as mean ± SEM (n = 5). Significant difference between LPS and test groups are indicated, **p < 0.01; ***p < 0.001.(B) The effect of iNOS antagonist SMT on the in vivo anti-inflammatory activity of Q4c. Data are shown as mean ± SEM (n = 7). Significant difference from vehicle, *p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001. Significant difference between Q4c treatments in the absence and presence of SMT, #p < 0.05. Statistical analysis was performed by two-way ANOVA, followed by Tukey’s post-tests.
Mentions: To explore how Q4c exerts its anti-inflammatory and analgesic activities, we next examined the signaling pathways that may be involved in its function. Our previous study suggested that nitric oxide synthase (NOS) signaling pathway was involved in the anti-inflammatory activity of JP-8 g, another spirooxindole compound14. Therefore, we sought to determine the effect of Q4c on LPS-stimulated nitric oxide (NO) release in isolated primary macrophages. As seen in Fig. 5A, Q4c suppressed NO release in a dose-dependent manner. Q4c of 10 μM achieved more than 50% suppression. To confirm the role of NOS signaling pathway, we evaluated the effect of NOS inhibitors on the anti-inflammatory activity of Q4c using mouse paw swelling model. It was observed that 30 mg/kg of inducible NOS (iNOS) inhibitor SMT significantly (p < 0.05) reduced the anti-inflammatory activity of Q4c 5–24 h after carrageenan injection (Fig. 5B). In contrast, NF-kB inhibitor BAY 11–7082 did not appear to affect the in vivo activity of Q4c (Supplementary Fig. 7). This is consistent with our previous findings that NOS pathway, but not NF-κB pathway, is involved in the anti-inflammatory activity of spirooxindole compounds15.

Bottom Line: Moreover, Q4c alleviated pain in mouse models with comparable activity to morphine.Further investigation suggested that nitric oxide signaling pathway is involved in the anti-inflammatory and analgesic activities of Q4c.Notably, this is the first time that chiral oxindole-type analogues have been identified to be both anti-inflammatory and analgesic, and our study also paved the way for future development of oxindoles as drug candidates in this field.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China, 510006.

ABSTRACT
Here we report a facile approach to synthesize highly optically active oxindole-type analogues with both high yield and enantioselectivity. This single-step synthesis strategy represents a substantial improvement upon existing methods that are often involved with multi-step routes and have suboptimal atomic economy. One such compound, namely Q4c, showed remarkable in vivo anti-inflammatory activity with efficiency approaching to that of a steroidal compound dexamethasone. Moreover, Q4c alleviated pain in mouse models with comparable activity to morphine. Further investigation suggested that nitric oxide signaling pathway is involved in the anti-inflammatory and analgesic activities of Q4c. Notably, this is the first time that chiral oxindole-type analogues have been identified to be both anti-inflammatory and analgesic, and our study also paved the way for future development of oxindoles as drug candidates in this field.

No MeSH data available.


Related in: MedlinePlus