RESUMEN
18-ß-Glycyrrhetinic acid (GA; 1) and many of its derivatives are cytotoxic in cancer cells. The current study aims to characterize the anticancer effects of 17 novel 1 derivatives. On the basis of these studies, N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b) appeared to be the most potent compound, with IC(50)in vitro growth inhibitory concentrations in single-digit micromolarity in a panel of 8 cancer cell lines. Compound 6b is cytostatic and displays similar efficiency in apoptosis-sensitive versus apoptosis-resistant cancer cell lines through, at least partly, the inhibition of the activity of a cluster of a dozen kinases that are implicated in cancer cell proliferation and in the control of the actin cytoskeleton organization. Compound 6b also inhibits the activity of the 3 proteolytic units of the proteasome. Compound 6b thus represents an interesting hit from which future compounds could be derived to improve chemotherapeutic regimens that aim to combat cancers associated with poor prognoses.
Asunto(s)
Antineoplásicos/síntesis química , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/síntesis química , Compuestos de Fenilurea/síntesis química , Inhibidores de Proteasoma , Inhibidores de Proteínas Quinasas/síntesis química , Animales , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Ácido Glicirretínico/farmacología , Humanos , Ratones , Modelos Moleculares , PPAR gamma/antagonistas & inhibidores , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
The adults of the leaf beetle Platyphora kollari (Chrysomelidae) are able to metabolise the oleanane triterpene beta-amyrin (1) into the glycoside 3-O-beta-D: -glucopyranosyl-(1-->4)-beta-D: -glucuronopyranosyl-hederagenin (2) that is stored in their defensive glands. The aim of this study was to test the hypothesis that oleanolic acid (3) is an intermediate in the conversion of 1 into 2 and to check whether the sequestration of pentacyclic triterpenes is selective in favour of beta-amyrin (1). To this end, adults of P. kollari were fed with Ipomoea batatas leaf disks painted with a solution of [2,2,3-(2)H(3)]oleanolic acid or [2,2,3-(2)H(3)]alpha-amyrin and the secretion of their defensive glands analysed by HPLC-ESIMS. The data presented in this work indicated that the first step of the transformation of beta-amyrin (1) into the sequestered glycoside 2 is its oxidation into oleanolic acid (3) and that this conversion is selective but not specific in favour of beta-amyrin (1).