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ACS Med Chem Lett. 2013 Mar 4;4(4):393-6. doi: 10.1021/ml4000832. eCollection 2013 Apr 11.

Benzanilide-Biphenyl Replacement: A Bioisosteric Approach to Quinoline Carboxamide-Type ABCG2 Modulators.

Author information

1
Institute of Organic Chemistry, University of Regensburg , D-93040 Regensburg, Germany ; Departamento de Química, Universidad Nacional de Colombia , Bogotá D.C., Colombia.
2
Institute of Pharmacy, University of Regensburg , D-93040 Regensburg, Germany.
3
Institute of Organic Chemistry, University of Regensburg , D-93040 Regensburg, Germany.

Abstract

Recently reported compounds such as UR-COP78 (6) are among the most potent and selective ABCG2 modulators known so far but are prone to rapid enzymatic cleavage at the central benzanilide moiety. In search for more stable analogues, 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 (I max) over 90% (e.g., UR-COP228 (22a), IC50 591 nM, I max 109%; UR-COP258 (31), IC50 544 nM, I max 112%), though with lower potency and selectivity than 6. The biphenyl analogues are considerably more stable and demonstrate that the benzanilide core is not a crucial structural feature of quinoline carboxamide-type ABCG2 modulators.

KEYWORDS:

ABC transporter; MCF-7 cells; Suzuki coupling; breast cancer resistance protein; solid phase synthesis

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