代谢功能障碍相关的脂肪性肝病(MAFLD)提出了重大的全球健康挑战,其特征是肝脏脂肪的积累和影响相当一部分的世界人口。尽管它普遍存在,MAFLD的有效治疗方法有限。丙酮酸激酶(PKL)的肝脏特异性同工型已被确定为开发MAFLD疗法的有希望的靶标。尿磷脂C,PKL的变构抑制剂,在初步研究中显示出潜力。在这个基础上扩展,我们的研究通过合成基于砜的尿石素类似物来描述尿石素C的构效关系。我们的结果强调,掺入砜部分会导致大量的PKL抑制,与额外的儿茶酚部分进一步增强这种效果。尽管肝脏细胞系有适度的改善,在HepG2细胞裂解物中观察到抑制显著增加。具体来说,化合物15d,9d,15e,18a,12d,和15a显示有希望的IC50值范围为4.3µM至18.7µM。值得注意的是,化合物15e不仅显示PKL活性和三酰甘油(TAG)含量的降低,而且显示有效的细胞摄取。这些发现将化合物15e定位为药物MAFLD治疗的有希望的候选物。保证进一步的研究和研究。
Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC50 values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.