Synthesis of Moracin C and Its Derivatives with a 2-arylbenzofuran Motif and Evaluation of Their PCSK9 Inhibitory Effects in HepG2 Cells

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key factor in several cardiovascular diseases, as it is responsible for the elevation of circulating low-density lipoprotein cholesterol (LDL-C) levels in blood plasma by direct interaction with the LDL receptor. The development of orally av...

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Detalles Bibliográficos
Autores principales: Masagalli, Jagadeesh Nagarajappa, BasavanaGowda, Melanayakanakatte Kuberappa, Chae, Hee-Sung, Choi, Won Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958322/
https://www.ncbi.nlm.nih.gov/pubmed/33801308
http://dx.doi.org/10.3390/molecules26051327
Descripción
Sumario:Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key factor in several cardiovascular diseases, as it is responsible for the elevation of circulating low-density lipoprotein cholesterol (LDL-C) levels in blood plasma by direct interaction with the LDL receptor. The development of orally available drugs to inhibit this PCSK9-LDLR interaction is a highly desirable objective. Here, we report the synthesis of naturally occurring moracin compounds and their derivatives with a 2-arylbenzofuran motif to inhibit PCSK9 expression. In addition, we discuss a short approach involving the three-step synthesis of moracin C and a divergent method to obtain various analogs from one starting material. Among the tested derivatives, compound 7 (97.1%) was identified as a more potent inhibitor of PCSK9 expression in HepG2 cells than berberine (60.9%). These results provide a better understanding of the structure–activity relationships of moracin derivatives for the inhibition of PCSK9 expression in human hepatocytes.