Aromatic 2-(Thio)ureidocarboxylic Acids As a New Family of Modulators of Multidrug Resistance-Associated Protein 1: Synthesis, Biological Evaluation, and Structure−Activity Relationships

Abstract

Four series of aromatic carboxylic acids were prepared with a urea or thiourea moiety at the neighboring position to the carboxyl group and benzene or thiophene as aromatic scaffold. Using a calcein AM assay, these compounds were evaluated as inhibitors of multidrug resistance-associated protein 1 (MRP1) and selected compounds were examined toward P-glycoprotein (P-gp) as well as breast cancer resistance protein (BCRP) to assess selectivity for MRP1. Two 2-thioureidobenzo[b]thiophene-3-carboxylic acids (48, 49) were identified as particularly potent inhibitors of MRP1, with IC50 values of around 1 microM. The structural features of this new family of nontoxic MRP1 inhibitors include a (thio)urea disubstituted with preferentially two alkyl groups at the terminal nitrogen and an additional fused aromatic ring.

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

“…In 2009, our working group also presented aromatic 2‐(thio)ureidocarboxylic acids as novel lead for MRP1 inhibition, using the cDNA‐transfected human ovarian carcinoma cell line 2008/MRP1 and the calcein AM assay. The benzene moiety led only to weak inhibitors in the moderately low double‐digit concentration range, while a naphthyl partial structure (compound 16; Figure ) showed at least moderate inhibitory activity (IC 50 = 5.38 μM).…”

Thiorhodamines containing amide and thioamide functionality as inhibitors of the ATP-binding cassette drug transporter P-glycoprotein (ABCB1)

“…Recent studies have shown that thiourea functionality imparted greater inhibitory activity toward MRP1 in a series of drug derivatives relative to P-gp or BCRP, which is consistent with different types of binding. 43 …”

Targeting the Achilles Heel of Multidrug-Resistant Cancer by Exploiting the Fitness Cost of Resistance

“…A number of MRP1 modulators whose mechanism of inhibition is poorly characterized have been reported. 95,96 In many cases, including the reference inhibitor leukotriene antagonist MK571, studies suggest that the mechanism of action relies on competitive inhibition. 97,98 Although MK571 was able to completely reverse vincristine resistance of MRP1-overexpressing cells, the required concentrations were too high to be used in vivo.…”