2(3)-Aryl-thio(oxy)-methylquinoxaline Derivatives: A New Class of P-Glycoprotein-Mediated Drug Efflux Inhibitors

Antonio      Carta; Sandra      Piras; Giuseppe      Paglietti; Sabrina      Pricl; Paolo   La   Colla; Bernardetta      Busonera; Roberta      Loddo

Abstract

A series of quinoxalines variously substituted, namely 3-arylthiomethyl-1,6-dimethylquinoxalin-2-ones (6a-f), 3-arylthiomethyl-1-benzyl-7-trifluoromethylquinoxalin-2-ones (8a-g) and 2-arylthiomethyl-3-benzyloxy-6-trifluoromethylquinoxalines (10a,b,e-h), were synthesized and compared with previous arylphenoxymethylquinoxalines (1a-f, 2af and 3a-b). The purpose was to verify whether the replacement of oxygen with sulphur atom and the insertion of different substituents on the phenyl side chain were able to improve the capability to inhibit the Pgp pump and restore the antiproliferative activity of clinically useful drugs, such as doxorubicin (Doxo), vincristine (VCR) and etoposide (VP16), in drugresistant human nasopharyngeal carcinoma KB cells (KBwt, KBMDR, KB7D and KBV20C). Furthermore, 2,3-bis(aryloxymethyl)- 6-trifluoromethylquinoxalines (13a-c) were designed with the objective to evaluate the capability of the double side chain to potentiate the antiproliferative activity of the drugs tested. Biological assays showed that title compounds were, in general, endowed with good activity as Pgp inhibitors. In particular compound 3a, bearing 2-CONHPh substituent on phenoxymethyl side chain, resulted the most effective, while the double side chain (compound 13c) gives the ability to inhibit a different MRP pump (a membrane glycoprotein named mrp). Furthermore, we can conclude that replacement of oxygen with sulphur atom did not improve the biological activity.

Keywords: 2(3)-aryl-thio(oxy)-methylquinoxalines, antiproliferative activity, multidrug resistance, P-glycoprotein inhibitors, MRP pump, doxorubicin, vincristine, etoposide