Neuroprotective effect of synthetic chalcone derivatives as competitive dual inhibitors against μ-calpain and cathepsin B through the downregulation of tau phosphorylation and insoluble Aβ peptide formation.
A series of chalcone derivatives were synthesized and evaluated for their μ-calpain and cathepsin B inhibitory activities. Among the tested chalcone derivatives, two compounds, 7 and 11, showed potent inhibitory activities against μ-calpain and cathepsin B and were selected for further evaluation. Compounds 7 and 11 showed enzyme inhibitory activities at the cellular level and displayed neuroprotective effects against oxidative stress-induced apoptosis in SH-SY5Y cells, a human neuroblastoma cell line. Moreover, compounds 7 and 11 reduced p25 formation, tau phosphorylation and insoluble Aβ peptide formation. Enzyme kinetic experiments and docking studies revealed that compounds 7 and 11 competitively inhibited both μ-calpain and cathepsin B enzymes.
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
Kyung-Hwa
KH
Jeon
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
Eunyoung
E
Lee
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
Kyu-Yeon
KY
Jun
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
Ji-Eun
JE
Eom
College of Pharmacy, Cha University, 120 Haeryong-ro, Pochon-shi, Gyeongghi-do, 11160, Republic of Korea.
Soo Yeon
SY
Kwak
College of Pharmacy, Cha University, 120 Haeryong-ro, Pochon-shi, Gyeongghi-do, 11160, Republic of Korea. Electronic address: yna7315@cha.ac.kr.
Younghwa
Y
Na
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea. Electronic address: ykwon@ewha.ac.kr.
Youngjoo
Y
Kwon
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry*; D010766:Phosphorylation / Q000187:drug effects; D012995:Solubility; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C098994:amyloid beta-protein (1-43); D016875:tau Proteins; D002599:Chalcone; D002154:Calpain; C449002:mu-calpain; D002401:Cathepsin B
Alzheimer’s disease; Aβ formation; Cathepsin B inhibitor; Chalcone; Tau hyperphosphorylation; μ-Calpain inhibitor