title: The design, synthesis, and biological evaluation of novel YC-1 derivatives as potent anti-hepatic fibrosis agents.
abstract: 1-Benzyl-3-(substituted aryl)-5-methylfuro[3,2-c]pyrazole (YC-1) is a well-known synthetic compound with various satisfactory pharmacological activities, such as the activation of soluble guanylate cyclase (sGC) and the inhibition of hypoxia-induced factor-1α (HIF-1α). Recently, YC-1 has been demonstrated to have a potent activity on anti-fibrotic activity. However, the mechanism underlying its anti-fibrotic activity is still largely unknown. To this end, we presented here the design and synthesis of YC-1 and its novel derivatives, as well as the evaluation of their anti-fibrotic effects on activated human hepatic stellate cells (HSCs) LX-2. Moreover, the possible underlying mechanism of anti-fibrotic activity was also investigated for the first time by means of a CCK-8 assay, cell apoptosis analysis, and western blot analysis. Our study revealed that YC-1 and its derivatives suppressed activated LX-2 cell viability and induced cell apoptosis in a time- and dose-dependent manner. Western blot data demonstrated that these derivatives not only decreased the expression of α-smooth muscle actin (α-SMA), but also increased the expression of caspase-3, resulting in cell apoptosis. These findings strongly indicated that YC-1 and its derivatives, especially AC, could significantly inhibit LX-2 cell activation and induce LX-2 cell apoptosis by inhibiting α-SMA protein expression and promoting caspase-3 expression, respectively. In summary, our findings suggested that YC-1 derivatives might be potential agents for hepatic fibrosis therapy.
authors.affiliation: Research Centre for Chemical Biology, Department of Chemistry, Yanbian University, Yanji 133002, P. R. China. hsinzh@yahoo.com wuxue@ybu.edu.cn.
authors.forename: Juan
authors.initials: J
authors.lastname: Xiao
authors.forename: Chunmei
authors.initials: C
authors.lastname: Jin
authors.forename: Zhixue
authors.initials: Z
authors.lastname: Liu
authors.forename: Shujing
authors.initials: S
authors.lastname: Guo
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
mesh_terms: D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000199:Actins; D007191:Indazoles; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D053148:Caspase 3