One-Step Synthesis of Chiral Oxindole-type Analogues with Potent Anti-inflammatory and Analgesic Activities.
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.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China, 510006.|Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, China, 730000.
Yulong
Y
Sun
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China, 200031.
Jia
J
Liu
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China, 510006.
Xianxing
X
Jiang
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, China, 730000.
Tao
T
Sun
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, China, 730000.
Luping
L
Liu
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, China, 730000.
Xiaoyuan
X
Zhang
Anesthesia department of Gansu Provincial Hospital, China, 730000.
Shaoli
S
Ding
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, China, 730000.
Jingyi
J
Li
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, China, 730000.
Yan
Y
Zhuang
Key Laboratory for Reproductive Medicine and Embryo, The Reproductive Medicine Research Center of the First Hospital of Lanzhou University, Gansu, China, 730000.
Yiqing
Y
Wang
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China, 510006.|Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, China, 730000.
Rui
R
Wang
D000700:Analgesics / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002351:Carrageenan / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000078183:Oxindoles; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D000078183:Oxindoles; C022960:2-oxindole; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2