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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

The in vivo anti-inflammatory and analgesic activity of Q4c.(A) Carrageenan-induced paw inflammation model (n = 7). (B) Xylene-induced ear inflammation model (n = 10). (C) Tail flick pain model (n = 6). (D) Acetic acid twist body pain model (n = 6). Data are expressed as mean ± SEM. Statistical evaluation was performed by two-way ANOVA, followed by Tukey post-tests (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001).
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f4: The in vivo anti-inflammatory and analgesic activity of Q4c.(A) Carrageenan-induced paw inflammation model (n = 7). (B) Xylene-induced ear inflammation model (n = 10). (C) Tail flick pain model (n = 6). (D) Acetic acid twist body pain model (n = 6). Data are expressed as mean ± SEM. Statistical evaluation was performed by two-way ANOVA, followed by Tukey post-tests (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001).

Mentions: We next evaluated the time- and dose-dependency of the anti-inflammatory activity of Q4c using mouse paw inflammation model. Swelling of paws was efficiently induced by carrageenan injection during the entire 48 h period and peaked at 4–6 h (Fig. 4A, vehicle). A reference drug dexamethasone (DEX) showed significant suppression (p < 0.001, Tukey’s post-tests) of paw swelling at 4–24 h after carrageenan injection. Q4c of doses ranging from 6.25 to 25.0 mg/kg inhibited the progression of inflammation with efficacy comparable to that of DEX. Similarly, Q4c showed potent anti-inflammatory activity on mouse ear inflammation with the highest dose (50.0 mg/kg) as potent as 5.0 mg/kg DEX (Fig. 4B).


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)

The in vivo anti-inflammatory and analgesic activity of Q4c.(A) Carrageenan-induced paw inflammation model (n = 7). (B) Xylene-induced ear inflammation model (n = 10). (C) Tail flick pain model (n = 6). (D) Acetic acid twist body pain model (n = 6). Data are expressed as mean ± SEM. Statistical evaluation was performed by two-way ANOVA, followed by Tukey post-tests (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: The in vivo anti-inflammatory and analgesic activity of Q4c.(A) Carrageenan-induced paw inflammation model (n = 7). (B) Xylene-induced ear inflammation model (n = 10). (C) Tail flick pain model (n = 6). (D) Acetic acid twist body pain model (n = 6). Data are expressed as mean ± SEM. Statistical evaluation was performed by two-way ANOVA, followed by Tukey post-tests (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001).
Mentions: We next evaluated the time- and dose-dependency of the anti-inflammatory activity of Q4c using mouse paw inflammation model. Swelling of paws was efficiently induced by carrageenan injection during the entire 48 h period and peaked at 4–6 h (Fig. 4A, vehicle). A reference drug dexamethasone (DEX) showed significant suppression (p < 0.001, Tukey’s post-tests) of paw swelling at 4–24 h after carrageenan injection. Q4c of doses ranging from 6.25 to 25.0 mg/kg inhibited the progression of inflammation with efficacy comparable to that of DEX. Similarly, Q4c showed potent anti-inflammatory activity on mouse ear inflammation with the highest dose (50.0 mg/kg) as potent as 5.0 mg/kg DEX (Fig. 4B).

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