Inhibition of mitosis by glycopeptide dendrimer conjugates of colchicine.
Glycopeptide dendrimers have been prepared bearing four or eight identical glycoside moieties at their surface (beta-glucose, alpha-galactose, alpha-N-acetyl-galactose, or lactose), natural amino acids within the branches (Ser, Thr, His, Asp, Glu, Leu, Val, Phe), 2,3-diaminopropionic acid as the branching unit, and a cysteine residue at the core. These dendrimers have been used as drug-delivery devices for colchicine. Colchicine was attached to the dendrimers at the cysteine thiol group through a disulfide or thioether linkage. The biological activities of the glycopeptide dendrimer conjugates were evaluated in HeLa tumor cells and non-transformed mouse embryonic fibroblasts (MEFs). The concentrations of glycopeptide dendrimer drug conjugates required to achieve inhibition of cell proliferation by interference with the tubulin system were found to be higher (IC50 > 1 microM) compared to the required colchicine concentration. On the other hand, the glycopeptide dendrimer conjugates inhibited the proliferation of HeLa cells 20-100 times more effectively than the proliferation of MEFs. In comparison, non-glycosylated dendrimers and colchicine itself showed a selectivity of 10-fold or less for HeLa cells.
Lagnoux
David
D
Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.
Darbre
Tamis
T
Schmitz
M Lienhard
ML
Reymond
Jean-Louis
JL
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003078:Colchicine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects*; D006020:Glycopeptides / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D008954:Models, Biological; D015394:Molecular Structure
D000970:Antineoplastic Agents; D050091:Dendrimers; D006020:Glycopeptides; D003078:Colchicine