title: Organometallic cobalamin anticancer derivatives for targeted prodrug delivery via transcobalamin-mediated uptake.
abstract: Herein we report the synthesis of new water-soluble vitamin B12prodrugs bearing metal complexes at the β-upper side of the cobalt center. A total of three derivatives with the general design {Co-C[triple bond, length as m-dash]C-bpy-M}, where M represents a cytotoxic metal complex, were prepared and tested for their cytotoxicity against MCF-7 breast cancer cells. The choice of the metal was oriented on the eminent Pt and promising Ru and Re species to demonstrate the general applicability of the approach. The recognition of the derivatives by transcobalamin was demonstrated by competitive displacement assays using rhodamine labeled B12. This compound further served to prepare a dual luminescent probe by orthogonal synthesis with M = ((HCCbpy)Ru(bpy)2)Cl2and to perform in vitro assays. Cellular imaging experiments allowed us to observe the different compartmentalization of both dyes and thus prove that the species follow the natural cobalamin uptake as well as the self-triggered release of the β-upper complex.
authors.affiliation: Department of Chemistry, University of Fribourg, Chemin du Musée 9, 1700 Fribourg, Switzerland. fabio.zobi@unifr.ch.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Rossier
authors.affiliation: Adolphe Merkle Institute, Chemin des Verdiers 4, 1700 Fribourg, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hauser
authors.affiliation: Department of Chemistry, University of Fribourg, Chemin du Musée 9, 1700 Fribourg, Switzerland. fabio.zobi@unifr.ch.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Kottelat
authors.affiliation: Adolphe Merkle Institute, Chemin des Verdiers 4, 1700 Fribourg, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rothen-Rutishauser
authors.affiliation: Department of Chemistry, University of Fribourg, Chemin du Musée 9, 1700 Fribourg, Switzerland. fabio.zobi@unifr.ch.
authors.forename: Fabio
authors.identifier: http://orcid.org/0000-0002-9077-7184
authors.initials: F
authors.lastname: Zobi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism*; D001692:Biological Transport; D003035:Cobalt / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism*; D014155:Transcobalamins / Q000378:metabolism*; D014805:Vitamin B 12 / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011355:Prodrugs; D014155:Transcobalamins; D003035:Cobalt; D014805:Vitamin B 12