3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones as potent Nrf2/ARE inducers in human cancer cells and AOM-DSS treated mice.
Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation, and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1, and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1β, and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. Forty-one derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization.
State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.
Mei-Yang
MY
Xi
Jian-Min
JM
Jia
Hao-Peng
HP
Sun
Zhong-Ying
ZY
Sun
Jie-Wei
JW
Jiang
Ya-Jing
YJ
Wang
Min-Ye
MY
Zhang
Jun-Feng
JF
Zhu
Li-Li
LL
Xu
Zheng-Yu
ZY
Jiang
Xin
X
Xue
Ming
M
Ye
Xi
X
Yang
Yuan
Y
Gao
Lei
L
Tao
Xiao-Ke
XK
Guo
Xiao-Li
XL
Xu
Qing-Long
QL
Guo
Xiao-Jin
XJ
Zhang
Rong
R
Hu
Qi-Dong
QD
You
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000236:Adenoma / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061745:Antioxidant Response Elements / Q000235:genetics*; D001397:Azoxymethane; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D051547:Heme Oxygenase-1 / Q000378:metabolism; D056945:Hep G2 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
C586838:3-(2-(3-fluorophenyl)-2-oxoethylidene)-2,3,6,7-tetrahydro-1H-pyrazino(2,1-a)isoquinolin-4(11bH)-one; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D053583:Interleukin-1beta; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016264:Dextran Sulfate; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D001397:Azoxymethane