Details

Autor(en) / Beteiligte

• Lagnoux, David
• Darbre, Tamis
• Schmitz, M. Lienhard
• Reymond, Jean-Louis

Titel

Inhibition of Mitosis by Glycopeptide Dendrimer Conjugates of Colchicine

Ist Teil von

• Chemistry : a European journal, 2005-06, Vol.11 (13), p.3941-3950

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• Glycopeptide dendrimers have been prepared bearing four or eight identical glycoside moieties at their surface (β‐glucose, α‐galactose, α‐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 μM) 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. Attaching the cytotoxic natural product colchicine to a glycopeptide dendrimer allows delivery of this anti‐mitotic agent to cancer cells. The glycopeptide dendrimer conjugates have been prepared by solid‐phase synthesis of the dendritic peptide, followed by surface glycosylation and coupling of the colchicine at the core. The conjugates show a greater than 100‐fold selectivity for cancer cells over healthy cells. This new drug‐selective delivery strategy might allow some of the limitations of non‐selective cytotoxic natural products to be overcome.