title: Glycopeptide dendrimer colchicine conjugates targeting cancer cells.
abstract: Screening of a 65,536-member one-bead-one-compound (OBOC) combinatorial library of glycopeptide dendrimers of structure ((betaGal)(n)(+1)X(8)X(7)X(6)X(5))(2)DapX(4)X(3)X(2)X(1)(beta-Gal)(m) (betaGal=beta-galactosyl-thiopropionic acid, X(8-1)=variable amino acids, Dap=l-2,3-diaminopropionic acid, n, m=0, or 1 if X(8)=Lys resp. X(1)=Lys) for binding of Jurkat cells to the library beads in cell culture, resynthesis and testing lead to the identification of dendrimer J1 (betaGal-Gly-Arg-His-Ala)(2)Dap-Thr-Arg-His-Asp-CysNH(2) and related analogues as delivery vehicles. Cell targeting is evidenced by FACS with fluorescein conjugates such as J1F. The colchicine conjugate J1C is cytotoxic with LD(50)=1.5 microM. The beta-galactoside groups are necessary for activity, as evidenced by the absence of cell-binding and cytotoxicity in the non-galactosylated, acetylated analogue AcJ1F and AcJ1C, respectively. The pentagalactosylated dendrimer J4 betaGal(4)(Lys-Arg-His-Leu)(2)Dap-Thr-Tyr-His-Lys(betaGal)-Cys) selectively labels Jurkat cell as the fluorescein derivative J4F, but its colchicine conjugate J4C lacks cytotoxicity. Tubulin binding assays show that the colchicine dendrimer conjugates do not bind to tubulin, implying intracellular degradation of the dendrimers releasing the active drug.
authors.affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, CH-3012 Berne, Switzerland.
authors.forename: Emma M V
authors.initials: EM
authors.lastname: Johansson
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.forename: Tamis
authors.initials: T
authors.lastname: Darbre
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003078:Colchicine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D050091:Dendrimers / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006020:Glycopeptides / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008954:Models, Biological; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D006020:Glycopeptides; D003078:Colchicine