Alkynyl Gold(I) complexes derived from 3-hydroxyflavones as multi-targeted drugs against colon cancer

Mármol, Inés (Universidad de Zaragoza) ; Castellnou, Pilar ; Álvarez, Raquel ; Gimeno, M. Concepción (Universidad de Zaragoza) ; Rodríguez-Yoldi, M.Jesús (Universidad de Zaragoza) ; Cerrada, Elena (Universidad de Zaragoza)

Resumen: The design of multi-targeted drugs has gained considerable interest in the last decade thanks to their advantages in the treatment of different diseases, including cancer. The simultaneous inhibition of selected targets from cancerous cells to induce their death represents an attractive objective for the medicinal chemist in order to enhance the efficiency of chemotherapy. In the present work, several alkynyl gold(I) phosphane complexes derived from 3-hydroxyflavones active against three human cancer cell lines, colorectal adenocarcinoma Caco-2/TC7, breast adenocarcinoma MCF-7 and hepatocellular carcinoma HepG2, have been synthesized and characterized. Moreover, these compounds display high selective index values towards differentiated Caco-2 cells, which are considered as a model of non-cancerous cells. The antiproliferative effect of the most active complexes [Au(L2b)PPh3] (3b) and [Au(L2c)PTA] (4c) on Caco-2 cells, seems to be mediated by the inhibition of the enzyme cyclooxygenase-1/2 and alteration of the activities of the redox enzymes thioredoxin reductase and glutathione reductase. Both complexes triggered cell death by apoptosis, alterations in cell cycle progression and increased of ROS production. These results provide support for the suggestion that multi-targeting approach involving the interaction with cyclooxygenase-1/2 and the redox enzymes that increases ROS production, enhances cell death in vitro. All these results indicate that complexes [Au(L2b)PPh3] and [Au(L2c)PTA] are promising antiproliferative agents for further anticancer drug development.

Idioma: Inglés

DOI: 10.1016/j.ejmech.2019.111661

Año: 2019

Publicado en: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 183 (2019), 111661 [14 pp.]
ISSN: 0223-5234

Factor impacto JCR: 5.572 (2019)

Categ. JCR: CHEMISTRY, MEDICINAL rank: 5 / 61 = 0.082 (2019) - Q1 - T1

Factor impacto SCIMAGO: 1.144 - Drug Discovery (Q1) - Pharmacology (Q1) - Organic Chemistry (Q1) - Medicine (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B16-R17
Financiación: info:eu-repo/grantAgreement/ES/DGA/E07-17R
Financiación: info:eu-repo/grantAgreement/ES/ISCIII-CIBERObn/CB06-03-1012
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2016-75816-C2-1-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2016-75441-R
Financiación: info:eu-repo/grantAgreement/EUR/SUDOE/INTERREG/Redvalue-SOE1-PI-E0123

Tipo y forma: Article (PostPrint)

Área (Departamento): Área Química Inorgánica (Dpto. Química Inorgánica)
Área (Departamento): Área Fisiología (Dpto. Farmacología y Fisiolog.)