Anti-Diabetic Activity of Glycyrrhetinic Acid Derivatives FC-114 and FC-122: Scale-Up, In Silico, In Vitro, and In Vivo Studies
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Published:2023-08-15
Issue:16
Volume:24
Page:12812
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Álvarez-Almazán Samuel1ORCID, Solís-Domínguez Luz Cassandra1, Duperou-Luna Paulina2, Fuerte-Gómez Teresa1, González-Andrade Martin3ORCID, Aranda-Barradas María E.1ORCID, Palacios-Espinosa Juan Francisco2ORCID, Pérez-Villanueva Jaime2ORCID, Matadamas-Martínez Félix2, Miranda-Castro Susana Patricia1ORCID, Mercado-Márquez Crisóforo4, Cortés-Benítez Francisco2ORCID
Affiliation:
1. Laboratory of Biotechnology, Unidad de Posgrado, Facultad de Estudios Superiores Cuautitlán Campus 1, Universidad Nacional Autónoma de México, Cuautitlán Izcalli 54740, Mexico 2. Laboratory of Synthesis and Isolation of Bioactive Substances, Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana–Xochimilco (UAM–X), Mexico City 04960, Mexico 3. Laboratory of Biosensors and Molecular Modelling, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico 4. Isolation and Animal Facility Unit, Facultad de Estudios Superiores Cuautitlán 28, Universidad Nacional Autónoma de México, Cuautitlán Izcalli 54714, Mexico
Abstract
Type 2 diabetes (T2D) is one of the most common diseases and the 8th leading cause of death worldwide. Individuals with T2D are at risk for several health complications that reduce their life expectancy and quality of life. Although several drugs for treating T2D are currently available, many of them have reported side effects ranging from mild to severe. In this work, we present the synthesis in a gram-scale as well as the in silico and in vitro activity of two semisynthetic glycyrrhetinic acid (GA) derivatives (namely FC-114 and FC-122) against Protein Tyrosine Phosphatase 1B (PTP1B) and α-glucosidase enzymes. Furthermore, the in vitro cytotoxicity assay on Human Foreskin fibroblast and the in vivo acute oral toxicity was also conducted. The anti-diabetic activity was determined in streptozotocin-induced diabetic rats after oral administration with FC-114 or FC-122. Results showed that both GA derivatives have potent PTP1B inhibitory activity being FC-122, a dual PTP1B/α-glucosidase inhibitor that could increase insulin sensitivity and reduce intestinal glucose absorption. Molecular docking, molecular dynamics, and enzymatic kinetics studies revealed the inhibition mechanism of FC-122 against α-glucosidase. Both GA derivatives were safe and showed better anti-diabetic activity in vivo than the reference drug acarbose. Moreover, FC-114 improves insulin levels while decreasing LDL and total cholesterol levels without decreasing HDL cholesterol.
Funder
Consejo Nacional de Humanidades Ciencias y Tecnologías División de Ciencias Biológicas y de la Salud UAM-Xochimilco
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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