Identification of 1,2,3-triazole derivatives that protect pancreatic β cells against endoplasmic reticulum stress-mediated dysfunction and death through the inhibition of C/EBP-homologous protein expression

Abstract

The C/EBP-homologous protein (CHOP) acts as a mediator of endoplasmic reticulum (ER) stress-induced pancreatic insulin-producing β cell death, a key element in the pathogenesis of diabetes. Chemicals that inhibit the expression of CHOP might therefore protect β cells from ER stress-induced apoptosis and prevent or ameliorate diabetes. Here, we used high-throughput screening to identify a series of 1,2,3-triazole amide derivatives that inhibit ER stress-induced CHOP-luciferase reporter activity. Our SAR studies indicate that compounds with an N,1-diphenyl-5-methyl-1H-1,2,3-triazole-4-carboxamide backbone potently protect β cell against ER stress. Several representative compounds inhibit ER stress-induced up-regulation of CHOP mRNA and protein, without affecting the basal level of CHOP expression. We further show that a 1,2,3-triazole derivative 4e protects β cell function and survival against ER stress in a CHOP-dependent fashion, as it is inactive in CHOP-deficient β cells. Finally, we show that 4e significantly lowers blood glucose levels and increases concomitant β cell survival and number in a streptozotocin-induced diabetic mouse model. Identification of small molecule inhibitors of CHOP expression that prevent ER stress-induced β cell dysfunction and death may provide a new modality for the treatment of diabetes.

Transcription Factor C/EBP Homologous Protein in Health and Diseases

“…Another critical event is that CHOP downregulates p21 to trigger β-cell apoptosis due to glucotoxicity, thus promoting the onset of T2D ( 85 , 178 ). As such, the chemicals that inhibit CHOP expression protect β cells from apoptosis and dysfunction, such as 1,2,3-triazole derivatives ( 179 ).…”

Evaluation of free radical scavenging capacity of methoxy containing-hybrids of thiosemicarbazone-triazole and their influence on glucose transport

“…Triazole derivatives are known to have antifungal, antibacterial, anticancer, antimalaria, anti-inflammatory activities [ 9 – 14 ]. Derivatives of triazole have also been reported to protect pancreatic β cells against endoplasmmic reticulum stress-mediated dysfunction and death [ 15 ]. Hybrid compounds of thiosemicarbozone and triazole have been evaluated for their biological activities against malaria, obesity and diabetes [ 16 – 18 ].…”

Discovery of N‐(2‐(Benzylamino)‐2‐oxoethyl)benzamide analogs as a novel scaffold of pancreatic β‐cell protective agents against endoplasmic reticulum stress

“…We have previously described that compound 1 possesses the structural motif of triazole amide (Figure ) for effective β‐cell protective activity against ER stress (see Table ; Duan et al, ). However, 1 showed less‐desired potency within a narrow range of doses( Duan et al, ) and poor aqueous solubility (see Figure ).…”

“…We have previously described that compound 1 possesses the structural motif of triazole amide (Figure ) for effective β‐cell protective activity against ER stress (see Table ; Duan et al, ). However, 1 showed less‐desired potency within a narrow range of doses( Duan et al, ) and poor aqueous solubility (see Figure ). Since 1,2,3‐triazole is a scaffold frequently present in various structures with multiple bioactivities, such as antimicrobial, antiviral, and antitumor effects, we reasoned that the triazole ring could be the reason for these less‐desirable properties.…”

“…Recently, our group has discovered a novel small molecule 1‐(3‐chloro‐2‐methylphenyl)‐N‐(2,5‐dimethylphenyl)‐5‐methyl‐1H‐1,2,3‐triazole‐4‐carboxamide ( 1 ) (Duan et al, ) that protects β‐cell function and survival against ER stress with maximal activity at 97% and an EC 50 value of about 6 µ m . However, the 1,2,3‐triazole analog exhibited β‐cell protective activity at around 5 ~ 10 µ m and aqueous insolubility, which becomes a hindrance for further drug development.…”