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Molecules 2013, 18(10), 13043-13060; doi:10.3390/molecules181013043
Article

Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor

1, 1, 1, 1, 1, 1, 1, 2, 3, 1, 1, 1, 1 and 1,*
Received: 29 August 2013; in revised form: 11 October 2013 / Accepted: 12 October 2013 / Published: 21 October 2013
(This article belongs to the Special Issue Steroids)
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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.
Keywords: cholanic acid; amino acid conjugates; EphA2 antagonists; structure-activity relationships cholanic acid; amino acid conjugates; EphA2 antagonists; structure-activity relationships
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Russo, S.; Incerti, M.; Tognolini, M.; Castelli, R.; Pala, D.; Hassan-Mohamed, I.; Giorgio, C.; De Franco, F.; Gioiello, A.; Vicini, P.; Barocelli, E.; Rivara, S.; Mor, M.; Lodola, A. Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor. Molecules 2013, 18, 13043-13060.

AMA Style

Russo S, Incerti M, Tognolini M, Castelli R, Pala D, Hassan-Mohamed I, Giorgio C, De Franco F, Gioiello A, Vicini P, Barocelli E, Rivara S, Mor M, Lodola A. Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor. Molecules. 2013; 18(10):13043-13060.

Chicago/Turabian Style

Russo, Simonetta; Incerti, Matteo; Tognolini, Massimiliano; Castelli, Riccardo; Pala, Daniele; Hassan-Mohamed, Iftiin; Giorgio, Carmine; De Franco, Francesca; Gioiello, Antimo; Vicini, Paola; Barocelli, Elisabetta; Rivara, Silvia; Mor, Marco; Lodola, Alessio. 2013. "Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor." Molecules 18, no. 10: 13043-13060.



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