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Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor
Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze 27/A, Parma I-43124, Italy
TES Pharma S.r.l., Via P. Togliatti, 20, Loc Taverne, Corciano 06073, Italy
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1, Perugia 06123, Italy
* Author to whom correspondence should be addressed.
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
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
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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.
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.
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.