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.
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Authors | Cristian Ochoa Puentes, Peter Höcherl, Matthias Kühnle, Stefanie Bauer, Kira Bürger, Günther Bernhardt, Armin Buschauer, Burkhard König |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 21
Issue 12
Pg. 3654-7
(Jun 15 2011)
ISSN: 1464-3405 [Electronic] England |
PMID | 21570282
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
- ABCG2 protein, human
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
- Antineoplastic Agents
- Neoplasm Proteins
- Quinolines
- tariquidar
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Topics |
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
(antagonists & inhibitors)
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Breast Neoplasms
(drug therapy)
- Cell Line, Tumor
- Combinatorial Chemistry Techniques
- Dose-Response Relationship, Drug
- Female
- Humans
- Inhibitory Concentration 50
- Molecular Structure
- Neoplasm Proteins
(antagonists & inhibitors)
- Protein Transport
(drug effects)
- Quinolines
(chemical synthesis, chemistry, pharmacology)
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