Anti-Diabetic Activity of Glycyrrhetinic Acid Derivatives FC-114 and FC-122: Scale-Up, In Silico, In Vitro, and In Vivo Studies
Por:
Alvarez-Almazan, Samuel, Solis-Dominguez, Luz Cassandra, Duperou-Luna, Paulina, Fuerte-Gomez, Teresa, Gonzalez-Andrade, Martin, Aranda-Barradas, Maria E., Palacios-Espinosa, Juan Francisco, Perez-Villanueva, Jaime, Matadamas-Martinez, Felix, Miranda-Castro, Susana Patricia, Mercado-Marquez, Crisoforo, Cortes-Benitez, Francisco
Publicada:
1 ago 2023
Resumen:
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 a-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/a-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 a-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.
Filiaciones:
Alvarez-Almazan, Samuel:
Laboratory of Biotechnology, Unidad de Posgrado, Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Cuautitlán Campus 1, Cuautitlán Izcalli, 54740, Mexico
Solis-Dominguez, Luz Cassandra:
Laboratory of Biotechnology, Unidad de Posgrado, Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Cuautitlán Campus 1, Cuautitlán Izcalli, 54740, Mexico
Duperou-Luna, Paulina:
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
Fuerte-Gomez, Teresa:
Laboratory of Biotechnology, Unidad de Posgrado, Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Cuautitlán Campus 1, Cuautitlán Izcalli, 54740, Mexico
Gonzalez-Andrade, Martin:
Laboratory of Biosensors and Molecular Modelling, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Aranda-Barradas, Maria E.:
Laboratory of Biotechnology, Unidad de Posgrado, Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Cuautitlán Campus 1, Cuautitlán Izcalli, 54740, Mexico
Palacios-Espinosa, Juan Francisco:
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
Perez-Villanueva, Jaime:
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
Matadamas-Martinez, Felix:
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
Miranda-Castro, Susana Patricia:
Laboratory of Biotechnology, Unidad de Posgrado, Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Cuautitlán Campus 1, Cuautitlán Izcalli, 54740, Mexico
Mercado-Marquez, Crisoforo:
Isolation and Animal Facility Unit, Facultad de Estudios Superiores Cuautitlán 28, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, 54714, Mexico
Cortes-Benitez, Francisco:
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
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