RESUMEN
ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse anticancer drugs. In order to investigate their role in resistance, potent and selective ABCG2 modulators have been described in the literature. A leading class of modulators are the tariquidar analogues; however, their susceptibility to hydrolysis limits their applicable use. To overcome this, we synthesized a novel series of chalcone- and ketone-based compounds inspired by reported tariquidar analogues. Compounds were characterized and evaluated for their ABCG2 modulatory activity and ABC transporter selectivity. When compared to transporters ABCB1 and ABCC1, the chalcone-based compounds exhibited selectivity for ABCG2, while the ketone-based compounds showed only a slight preference for ABCG2. From the former series, chalcone 16d (UR-DP48) displayed similar activity to the reference fumitremorgin C, both producing comparable maximal effects. The compound exhibited marked antiproliferative activity, while cytotoxicity was less pronounced for the most active compound 17f from the ketone series. Chalcone-containing tariquidar analogues are promising modulators to aid in functional investigations of ABCG2 transporters.
RESUMEN
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.
RESUMEN
Aiming at structural optimization of potent and selective ABCG2 inhibitors, such as UR-ME22-1, from our laboratory, an efficient solid phase synthesis was developed to get convenient access to this class of compounds. 7-Carboxyisatoic anhydride was attached to Wang resin to give resin bound 2-aminoterephthalic acid. Acylation with quinoline-2- or -6-carbonyl chlorides, coupling with tetrahydroisoquinolinylethylphenylamine derivatives, cleavage of the carboxylic acids from solid support and treatment with trimethylsilydiazomethane gave the corresponding methyl esters. Among these esters highly potent and selective ABCG2 modulators were identified (inhibition of ABCB1 and ABCG2 determined in the calcein-AM and the Hoechst 33342 microplate assay, respectively). Interestingly, compounds bearing triethyleneglycol ether groups at the tetrahydroisoquinoline moiety (UR-COP77, UR-COP78) were comparable to UR-ME22-1 in potency but considerably more efficient (max inhibition 83% and 88% vs 60%, rel. to fumitremorgin c, 100%) These results support the hypothesis that solubility of the new ABCG2 modulators and of the reference compounds tariquidar and elacridar in aqueous media is the efficacy-limiting factor.