Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0337)
Name
Clausenamide
Synonyms
Clausenamide; 103541-15-7; (+)-Clausenamide; 109905-95-5; (-)-Clausenamide; (3R,4S,5S)-3-hydroxy-5-[(R)-hydroxy(phenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one; 3-hydroxy-5-[hydroxy(phenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one; ( )-Clausenamide; (3R,4S,5S)-3-Hydroxy-5-((R)-hydroxyphenylmethyl)-1-methyl-4-phenylpyrrolidin-2-one; (3R,4S,5S)-3-HYDROXY-5-[(R)-HYDROXY-PHENYL-METHYL]-1-METHYL-4-PHENYL-P YRROLIDIN-2-ONE; Zetaclausenamide; CHEMBL508970; SCHEMBL6369855; DTXSID10908462; 2-Pyrrolidinone,3-hydroxy-5-((R)-hydroxyphenylmethyl)-1-methyl-4-phenyl-, (3R,4S,5S)-rel; DL-Xylonic acid, 3,4-dideoxy-4-(methylamino)-3-phenyl-5-C-phenyl-, gamma-lactam, (S*)-

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Structure
Formula
C18H19NO3
IUPAC Name
(3R,4S,5S)-3-hydroxy-5-[(R)-hydroxy(phenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one
Canonical SMILES
CN1C(C(C(C1=O)O)C2=CC=CC=C2)C(C3=CC=CC=C3)O
InChI
InChI=1S/C18H19NO3/c1-19-15(16(20)13-10-6-3-7-11-13)14(17(21)18(19)22)12-8-4-2-5-9-12/h2-11,14-17,20-21H,1H3/t14-,15-,16+,17+/m0/s1
InChIKey
WGYGSZOQGYRGIP-MWDXBVQZSA-N
PubChem CID
128412
Full List of Ferroptosis Target Related to This Drug
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Injury of intra-abdominal organs ICD-11: NB91
 Disease Info 
Responsed Regulator Kelch-like ECH-associated protein 1 (KEAP1) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Pathways in cancer hsa05200
Cell Process Cell ferroptosis
In Vitro Model HepaRG cells Hepatocellular carcinoma Homo sapiens CVCL_9720
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
BEL-7402 cells Endocervical adenocarcinoma Homo sapiens CVCL_5492
In Vivo Model
Male C57BL/6 mice aged 8-10 weeks were purchased from Guangdong Experimental Animal Center (Guangzhou, China). The animals were maintained on a 12 h light-dark cycle in a regulated temperature and humidity environment for 1 week before drug administration. (+)-CLA (50 mg/kg/day, i.g.) or fer-1 (2.5 umol/kg/day, i.p.)were administered for 7 consecutive days. To induce liver injury, mice were injected with erastin (100 mg/kg/day, i.p., twice a day) on both the 6th and 7th day, or a single dose of APAP (600 mg/kg/day, i.p.) on the 7th day after overnight food deprivation. The serum and livers were obtained for analysis.

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Response regulation (+)-clausenamide ((+)-CLA) specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability. Thus, (+)-CLA protects against acetaminophen-induced hepatotoxicity via inhibiting ferroptosis and activating the Keap1/Nrf2 pathway in a Cys-151-dependent manner.
References
Ref 1 (+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis. Cell Death Dis. 2020 Sep 19;11(9):781. doi: 10.1038/s41419-020-02961-5.