Benzanilide – Biphenyl Replacement: A Bioisosteric Approach to Quinoline Carboxamide-type ABCG2 Modulators

摘要

Recently reported compounds such as UR-COP78 (6) are among the most potent and selective ABCG2 modulators known so far, but prone to rapid enzymatic cleavage at the central benzanilide moiety. In search for more stable analogs, according to a bioisosteric approach, a series of N-(biphenyl-3-yl)quinoline carboxamides was prepared by solid phase and solution phase synthesis. The biphenyl moiety was constructed by Suzuki coupling. Inhibition of ABCB1 and ABCG2 was determined in a calcein-AM and a Hoechst 33342 microplate assay, respectively. Most synthesized compounds selectively inhibited the ABCG2 transporter at submicromolar concentrations with a maximal inhibitory effect (Imax) over 90% (e.g. UR-COP228 (22a): IC50 591 nM, Imax 109%, and UR COP258 (31): IC50 544 nM, Imax 112%), though with lower potency and selectivity than 6. The biphenyl analogs are considerably more stable and demonstrate that the benzanilide core is not a crucial structural feature of quinoline carboxamide-type ABCG2 modulators.