Role of a Preorganized Scaffold Presenting Four Residues of a GM-3 Lactone Mimetic on Melanoma Progression

Barbara Richichi; Giuseppina Comito; Olivier Renaudet; Michele Fiore; A Marra; B Stecca; L Pasquato; P Chiarugi; C Nativi

doi:10.1021/acsmedchemlett.5b00283

Role of a Preorganized Scaffold Presenting Four Residues of a GM-3 Lactone Mimetic on Melanoma Progression

ACS Med Chem Lett. 2015 Nov 10;7(1):28-33. doi: 10.1021/acsmedchemlett.5b00283. eCollection 2016 Jan 14.

Authors

Barbara Richichi¹, Giuseppina Comito², Olivier Renaudet³, Michele Fiore⁴, A Marra⁵, B Stecca⁶, L Pasquato⁷, P Chiarugi², C Nativi⁸

Affiliations

¹ Department of Chemistry "Ugo Schiff″, University of Florence , via della Lastruccia, 13 50019 Sesto F.no (FI), Italy.
² Department of Experimental and Clinical Biomedical Sciences, Biochemistry, Human Health Medical School, University of Florence , viale Morgagni 50, 50134 Firenze, Italy.
³ Université Grenoble-Alpes, and CNRS, DCM, 38000 Grenoble, France; Institut Universitaire de France, 103 Boulevard Saint-Michel, 75005 Paris, France.
⁴ Université Grenoble-Alpes, and CNRS, DCM , 38000 Grenoble, France.
⁵ Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Ecole Nationale Supérieure de Chimie de Montpellier , 8 Rue de l'Ecole Normale, 34296 Montpellier cedex 5, France.
⁶ Core Research Laboratory, Istituto Toscano Tumori , viale Pieraccini, 6, 50139 Firenze, Italy.
⁷ Department of Chemical and Pharmaceutical Sciences, University of Trieste , via L. Giorgieri 1, 34127 Trieste, Italy.
⁸ Department of Chemistry "Ugo Schiff″, University of Florence, via della Lastruccia, 13 50019 Sesto F.no (FI), Italy; FiorGen, Polo Scientifico e Tecnologico, via Sacconi, 6 50019 Sesto F.no (FI), Italy.

Abstract

Two tetravalent architectures, the glycocalix 7 and the RAFT 9, presenting four residues of a GM-3 ganglioside lactone mimetic, target the host compartment of melanoma and significantly abrogate the effect induced by cancer-associated fibroblasts (CAFs) contact + hypoxia in the motility and invasiveness of tumor cells. The data reported support the involvement of glycosphingolipids (GSLs) in hypoxia and show an interesting role played by compound 9 in targeting melanoma cells thereby interfering with melanoma progression. The unprecedented findings reported for the glycocluster 9 may contribute to the understanding of the critical and complex interactions between tumor cells and their local environment paving the way for new therapeutic agents.

Keywords: Glycosides; mimetics; tumor antigen; tumor microenvironment.