Abstract
P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure–activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.
Highlights
P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy
One primary mechanism involved in this phenomenon is the over-expression of P-glycoprotein (P-gp), an ATP binding cassette (ABC) transmembrane protein that pumps a great variety of anticancer drugs out from the c ell[5]
This efflux leads to a diminished intracellular concentration and a consequent insensitivity, which is known as multidrug resistance (MDR)[6]
Summary
P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. One primary mechanism involved in this phenomenon is the over-expression of P-glycoprotein (P-gp), an ATP binding cassette (ABC) transmembrane protein that pumps a great variety of anticancer drugs out from the c ell[5] This efflux leads to a diminished intracellular concentration and a consequent insensitivity, which is known as multidrug resistance (MDR)[6]. Considerable attempts have been made to find P-gp-interacting compounds, but clinical trials with three generations of modulators have failed for diverse reasons[5,10], among these, side effects, lack of selectivity, low efficacy and, most important, failures in the design of the trials[11,12] It is a matter of great concern to develop novel chemical entities able to tackle P-gp-mediated outward transport and overcome MDR in cancer cells. Previous reports showed different series of compounds bearing the tetrahydroisoquinoline scaffold with significant activity, at nanomolar range, for reversing P-gp-mediated drug r esistance[18,19,20,21,22]
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