新型抗纤维化药物五脂酮A的合成及药效验证OA

Objective To design and synthesize the specific metabolite of schisandrin A,an anti-renal fibrosis active ingredient of Schisandrae Chinensis Fructus,schisanlignone A,and evaluate its toxicity and anti-renal fibrosis activity in vitro and in vivo.Methods The target metabolite schisanlignone A was synthesized via a 10-step synthetic route and characterized the structures of the synthesized compounds.Zebrafish model of acute kidney injury and NIH/3T3 cells were used to evaluate its anti-renal fibrosis activity in vitro and in vivo.Results The results of CCK8 assay showed that the effect of schisanlignone A on the viability of NIH/3T3 cells induced by TGF-β1 was less than that of schisandrin A,and schisanlignone A had low toxicity.RT-qPCR analysis in NIH/3T3 cells demonstrated that both schisandrin A and schisanlignone A significantly suppressed the expression of fibrosis-associated genes,including CDH2,COL1A2,and α-SMA,compared to the model group.Consistent with these findings,in vivo experiments using a zebrafish model revealed that both compounds also downregulated the expression of COL1A1A.Notably,schisanlignone A exhibited a more pronounced inhibitory effect on COL1A1A expression than schisandrin A.Furthermore,both compounds moderately improved the survival rate and enhanced tissue repair capacity in zebrafish following kidney injury induction.Conclusion Compound schisanlignone A is a potential,low-toxic anti-renal fibrosis drug,and demonstrated superior efficacy and reduced toxicity compared to its parent drug,schisandrinA.