HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Synthesis and structure-activity relationships of amino acid conjugates of cholanic acid as antagonists of the EphA2 receptor.

Abstract
The Eph-ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas the introduction of aromatic amino acids reduces the potency in displacement studies. The b-alanine derivative 4 was able to disrupt EphA2-ephrinA1 interaction in the micromolar range and to dose-dependently inhibit EphA2 activation on PC3 cells. These findings may help the design of novel EphA2 antagonists active on cancer cell lines.
AuthorsSimonetta Russo, Matteo Incerti, Massimiliano Tognolini, Riccardo Castelli, Daniele Pala, Iftiin Hassan-Mohamed, Carmine Giorgio, Francesca De Franco, Antimo Gioiello, Paola Vicini, Elisabetta Barocelli, Silvia Rivara, Marco Mor, Alessio Lodola
JournalMolecules (Basel, Switzerland) (Molecules) Vol. 18 Issue 10 Pg. 13043-60 (Oct 21 2013) ISSN: 1420-3049 [Electronic] Switzerland
PMID24152675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cholic Acids
  • Receptor, EphA1
  • Receptor, EphA2
  • cholanic acid
Topics
  • Binding Sites
  • Cell Line, Tumor
  • Cholic Acids (chemical synthesis, chemistry, pharmacology)
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational (drug effects)
  • Protein Structure, Secondary
  • Receptor, EphA1 (antagonists & inhibitors, chemistry, metabolism)
  • Receptor, EphA2 (antagonists & inhibitors, chemistry, metabolism)
  • Structure-Activity Relationship

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: