Synthesis of oleanolic acid derivatives: In vitro, in vivo and in silico studies for PTP-1B inhibition.

Autor: Ramírez-Espinosa JJ; Facultad de Farmacia, Universidad Autónoma del estado de Morelos, Cuernavaca, Morelos 62209, Mexico., Rios MY; Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico., Paoli P; Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, Universitá degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy., Flores-Morales V; Unidad Académica de Ciencias Químicas, Universidad Autónoma de Zacatecas, Zacatecas, Zacatecas 98160, Mexico., Camici G; Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, Universitá degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy., de la Rosa-Lugo V; Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico., Hidalgo-Figueroa S; Facultad de Farmacia, Universidad Autónoma del estado de Morelos, Cuernavaca, Morelos 62209, Mexico., Navarrete-Vázquez G; Facultad de Farmacia, Universidad Autónoma del estado de Morelos, Cuernavaca, Morelos 62209, Mexico., Estrada-Soto S; Facultad de Farmacia, Universidad Autónoma del estado de Morelos, Cuernavaca, Morelos 62209, Mexico. Electronic address: enoch@uaem.mx.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2014 Nov 24; Vol. 87, pp. 316-27. Date of Electronic Publication: 2014 Sep 16.
DOI: 10.1016/j.ejmech.2014.09.036
Abstrakt: 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.
(Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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