Rational design of phenyl thiophene (pyridine) derivatives that overcome P-glycoprotein mediated MDR in MCF-7/ADR cell

Abstract

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) has become an important hindrance in the clinical treatment of malignant tumors. In this paper, based on our lead compound 5m and strategies of bioisosteric replacement and alkoxy effect, phenylthiophene and phenylpyridine derivatives were designed as chemosensitizers for front-line antineoplastic agents and overcomes P-gp mediated MDR in MCF-7/ADR cell. Generally, 4-phenylthiophene-2-carboxamide derivative 60 has been screened and obtained with optimal activity against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 1.02 μM, RF = 49.9 with 5 μM 60 treated). The results of western blot and Rh123 accumulation assays showed that 60 effectively inhibited P-gp efflux function but not its expression. It is noted that compound 60 is a potentially broad-spectrum chemosensitizer in combination with commonly used anti-tumor drugs, such as doxorubicin, paclitaxel, daunorubicin and vincristine with RF value of 20–80.