title: Synthesis of oleanolic acid derivatives: In vitro, in vivo and in silico studies for PTP-1B inhibition.
abstract: Non-insulin dependent diabetes mellitus is a multifactorial disease that links different metabolic routes; a point of convergence is the enzyme PTP-1B which turns off insulin and leptin receptors involved in glucose and lipid metabolism, respectively. Pentacyclic acid triterpenes such as oleanolic acid (OA) have proved to be excellent PTP-1B inhibitors, thus, the purpose of current work was to generate a series of derivatives that improve the pharmacological effect of OA. Our findings suggest that the presence of the carboxylic acid and/or its corresponding reduction product carbinol derivative (H-bond donor) in C-28 is required to maintain the inhibitory activity; moreover, this is further enhanced by ester or ether formation on C-3. The most active derivatives were cinnamoyl ester (6) and ethyl ether (10). Compound 6 showed potent in vitro inhibitory activity and significantly decrease of blood glucose levels on in vivo experiments. Meanwhile, 10 showed contrasting outcomes, since it was the compound with higher inhibitory activity and selectivity over PTP-1B and has improved interaction with site B, according with docking studies, the in vivo antidiabetic effect was similar to oleanolic acid. In conclusion, oleanolic acid derivatives have revealed an enhanced inhibitory effect over PTP-1B activity by increasing molecular interactions with either catalytic or allosteric sites and producing a hypoglycaemic effect on non insulin dependent diabetes mellitus rat model.
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Ramírez-Espinosa
authors.affiliation: Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors.forename: Maria Yolanda
authors.initials: MY
authors.lastname: Rios
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, Universitá degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoli
authors.affiliation: Unidad Académica de Ciencias Químicas, Universidad Autónoma de Zacatecas, Zacatecas, Zacatecas 98160, Mexico.
authors.forename: Virginia
authors.initials: V
authors.lastname: Flores-Morales
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, Universitá degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Camici
authors.affiliation: Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors.forename: Vianey
authors.initials: V
authors.lastname: de la Rosa-Lugo
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: Hidalgo-Figueroa
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del estado de Morelos, Cuernavaca, Morelos 62209, Mexico. Electronic address: enoch@uaem.mx.
authors.forename: Samuel
authors.initials: S
authors.lastname: Estrada-Soto
mesh_terms: D000818:Animals; D001665:Binding Sites; D060326:Chemistry Techniques, Synthetic; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D062105:Molecular Docking Simulation; D009828:Oleanolic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D009828:Oleanolic Acid; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Antidiabetic; Docking; Oleanolic acid derivatives; PTP1B inhibition; Pentacyclic acid triterpenes