TARGETING OVEREXPRESSED EFFECTORS IN CANCER PROGRESSION/INFLAMMATION: SYNTHESIS AND BINDING OF A DITOPIC MOLECULE
Barbara Richichi
1
Marco Bartoloni
1
Elisa Dragoni
1
Claudio Luchinat
2
Marco Fragai
2
Blanca E. Domìnguez
4
Sabine André
3
Hans-Joachim Gabius
3
Ana Ardá
4
Jesús Jiménez-Barbero
4
Cristina Nativi
11Dipartimento di Chimica "Ugo Schiff", Università di Firenze, Sesto Fiorentino, Firenze
2Magnetic Resonance Center, CERM, Sesto Fiorentino, Firenze
3Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University, Munchen
4Centro de Investigationes Biològicas, CSIC, Madrid
Matrix Metallopreoteinases1(MMPs) are Ca2+- and Zn2+-dependent proteases that play multifaceted roles in physiology such as angiogenesis or connective tissue remodelling. Their association to disease processes, e.g. in arthritis, heart failure and tumor invasion, makes them an attractive target for therapeutic interventions. In the cellular context, upregulation has been noted by tissue effectors associated with tumor progression, i.e. galectins2,3. Moreover, MMPs can process galectins in tumors and sites of inflammation, hereby affecting their activity profile in angiogenesis in breast cancer and bone metastases4. This interplay between two dysregulated proteins, connected to favour disease progression, tempts to be exploited by devising a strategy for blocking activities in an attractively cooperative manner.
This communication presents an innovative approach in to inhibit MMPs by developing a new class of ditopic molocules5, shown in the figure. Binding to galectins is a means for local increase of MMP inhibitor concentration, both effectors thus blocked. The spacer length between the carbohydrate part and the inhibitory scaffold enables simultaneous interaction with MMP and galectin5.
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5. M. Bartoloni, B. E. Domìnguez, E. Dragoni, B. Richichi, M. Fragai, S. André, H. J. Gabius, A. Ardà, C. Luchinat, J. Jiménez-Barbero, C. Nativi, Chemistry, 2013, 19(6), 1896-1902.
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