Solid phase synthesis of tariquidar-related modulators of ABC transporters preferring breast cancer resistance protein (ABCG2).

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Puentes CO, Hocherl P, Kuhnle M, Bauer S, Burger K, Bernhardt G, Buschauer A, Konig B

Solid phase synthesis of tariquidar-related modulators of ABC transporters preferring breast cancer resistance protein (ABCG2).

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3654-7. doi: 10.1016/j.bmcl.2011.04.094. Epub 2011 Apr 28.

PubMed ID

21570282 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Elacridar	ATP-binding cassette sub-family G member 2	IC 50 (nM)	127	N/A	N/A	Details
Elacridar	P-glycoprotein 1	IC 50 (nM)	193	N/A	N/A	Details