To improve the biological profile of 20(S)-camptothecin, a novel class of 20-O-linked camptothecin glycoconjugates has been designed for preferential cellular uptake into tumor cells by an active transport mechanism. Such conjugates have been optimized for enhanced solubility, stabilization of the camptothecin lactone ring, sufficient hydrolytic and proteolytic stability, and for an overall improvement in tumor selectivity. The constitution of the peptide spacer has a major impact on stability and biological activity of the conjugates both in vitro and in vivo. Glycoconjugates 17-22 with valine residues at the linkage position to camptothecin are sufficiently stable and show good antitumor activity in vitro against HT29 and other tumor cell lines. Fluorescence microscopy and flow cytometry experiments indicate that glycoconjugates such as 19 are taken up into lysosomal compartments of the tumor cell line HT29 by an active transport mechanism. The steric configuration of the particular amino acid residues linked to the camptothecin moiety has a major impact on the in vivo activity of the corresponding glycoconjugates in the breast cancer xenograft MX-1 model. Inhibiting tumor growth by >96%, the glycoconjugates 19 and 21 show the best activity in this particular model and have been investigated more extensively. The glycoconjugate 19 compares favorably to topotecan 4 and glycoconjugate 21 with respect to toxicity against hematopoietic stem cells and hepatocytes. Based on its profile, 19 has been selected for clinical trials.

The circumvention of efficient "carbohydrate traps" in the liver is required for targeting glycoconjugates on tumor cells. As shown in the model system of bovine serum albumin (BSA) conjugates, the nature of R(1)-R(3) of the fucose epitope plays an important role in the discrimination of cellular uptake between tumor and liver cells as well as in the cytotoxic activity.

Die Umgehung der effizienten „Kohlenhydratfallen”︁ in der Leber ist für die Adressierung von Glycokonjugaten an Tumorzellen von entscheidender Bedeutung. Wie am Modellsystem der abgebildeten Rinderserumalbumin(BSA)‐Glycokonjugate gezeigt wird, spielt die Art der Substituenten R1–R3 am Fucose‐Epitop eine wichtige Rolle für die Diskriminierung zwischen der zellulären Aufnahme in Tumor‐ oder Leberzellen sowie für die Cytotoxizität.

Die Umgehung der effizienten „Kohlenhydratfallen”︁ in der Leber ist für die Adressierung von Glycokonjugaten an Tumorzellen von entscheidender Bedeutung. Wie am Modellsystem der abgebildeten Rinderserumalbumin(BSA)‐Glycokonjugate gezeigt wird, spielt die Art der Substituenten R1–R3 am Fucose‐Epitop eine wichtige Rolle für die Diskriminierung zwischen der zellulären Aufnahme in Tumor‐ oder Leberzellen sowie für die Cytotoxizität.