HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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.
AuthorsCristian Ochoa Puentes, Peter Höcherl, Matthias Kühnle, Stefanie Bauer, Kira Bürger, Günther Bernhardt, Armin Buschauer, Burkhard König
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 12 Pg. 3654-7 (Jun 15 2011) ISSN: 1464-3405 [Electronic] England
PMID21570282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: