Development of resveratrol-curcumin hybrids as potential therapeutic agents for inflammatory lung diseases.
Acute lung injury (ALI) is a major cause of acute respiratory failure in critically-ill patients. Resveratrol and curcumin are proven to have potent anti-inflammatory efficacy, but their clinical application is limited by their metabolic instability. Here, a series of resveratrol and the Mono-carbonyl analogs of curcumin (MCAs) hybrids were designed and synthesized by efficient aldol construction strategy, and then screened for anti-inflammatory activities in vitro and in vivo. The results showed that the majority of analogs effectively inhibited the LPS-induced production of IL-6 and TNF-α. Five analogs, a9, a18, a19, a20 and a24 exhibited excellent anti-inflammatory activity in a dose-dependent manner along with low toxicity in vitro. Structure activity relationship study revealed that the electron-withdrawing groups at meta-position and methoxyl group (OCH3) at the para position of the phenyl ring were important for anti-inflammatory activities. The most promising compound a18 decreased LPS induced TNF-α, IL-6, IL-12, and IL-33 mRNA expression. Additionally, a18 significantly protected against LPS-induced acute lung injury in the in vivo mouse model. The research of resveratrol and MCAs hybrids could bring insight into the treatment of inflammatory diseases and compound a18 may serve as a lead compound for the development of anti-ALI agents.
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China.
Jialing
J
Pan
Department of Respiration, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Tingting
T
Xu
Department of Respiration, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Fengli
F
Xu
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China.
Yali
Y
Zhang
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China.
Zhiguo
Z
Liu
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China.
Wenbo
W
Chen
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China.
Weitao
W
Fu
Department of Respiration, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Yuanrong
Y
Dai
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China. Electronic address: aabye1100@aliyun.com.
Yunjie
Y
Zhao
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China; Wenzhou University, 1210 University Town, Wenzhou, Zhejiang 325035, China. Electronic address: chemime@163.com.
Jianpeng
J
Feng
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China.
Guang
G
Liang
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000627:therapeutic use*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D012333:RNA, Messenger; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D003474:Curcumin; D000077185:Resveratrol
Acute lung injury; Anti-inflammatory; MCAs; Parallel; Resveratrol