Design and optimization of 20-O-linked camptothecin glycoconjugates as anticancer agents

To improve the biological profile of 20(S)-camptothecin, a novel class of 2 0-O-linked camptothecin glycoconjugates has been designed for preferential cellular uptake into tumor cells by an active transport mechanism. Such con jugates have been optimized for enhanced solubility, stabilization of the c amptothecin lactone ring, sufficient hydrolytic and proteolytic stability, and for an overall improvement in tumor selectivity. The constitution of th e peptide spacer has a major impact on stability and biological activity of the conjugates both in vitro and in vivo, Glycoconjugates 17-22 with valin e 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 tha t glycoconjugates such as 19 are taken up into lysosomal compartments of th e tumor cell line HT29 by an active transport mechanism. The steric configu ration of the particular amino acid residues linked to the camptothecin moi ety has a major impact on the in vivo activity of the corresponding glycoco njugates in the breast cancer xenograft MX-1 model. Inhibiting tumor growth by > 96%, the glycoconjugates 19 and 21 show the best activity in this par ticular model and have been investigated more extensively. The glycoconjuga te 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.