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Design and optimization of 20-O-linked camptothecin glycoconjugates as anticancer agents
H G Lerchen1, J Baumgarten, K von dem Bruch
1Bayer AG, Central Research, Life Sciences, 51368 Leverkusen, Germany. hans-georg.lerchen.hl@bayer-ag.de
Abstract:
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.
Insights
Novel camptothecin glycoconjugates demonstrate enhanced tumor selectivity and potent antitumor activity. Glycoconjugate 19 shows promising results in preclinical models and is selected for clinical trials.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- 20(S)-camptothecin exhibits potent anticancer activity but suffers from poor solubility and stability.
- Developing camptothecin derivatives with improved biological profiles is crucial for effective cancer therapy.
Purpose of the Study:
- To design and synthesize novel 20-O-linked camptothecin glycoconjugates for enhanced tumor cell uptake.
- To optimize these glycoconjugates for improved solubility, stability, and tumor selectivity.
- To evaluate the in vitro and in vivo antitumor activity and toxicity of these novel compounds.
Main Methods:
- Synthesis of 20-O-linked camptothecin glycoconjugates with varying peptide spacers.
- In vitro cytotoxicity assays against tumor cell lines (e.g., HT29).
- Cellular uptake studies using fluorescence microscopy and flow cytometry.
- In vivo efficacy studies in a breast cancer xenograft model (MX-1).
- Toxicity assessment in hematopoietic stem cells and hepatocytes.
Main Results:
- Glycoconjugates with valine residues (17-22) showed good in vitro antitumor activity and stability.
- Glycoconjugates, particularly compound 19, were actively transported into HT29 tumor cells via lysosomal compartments.
- Compounds 19 and 21 demonstrated significant in vivo antitumor activity (>96% tumor growth inhibition) in the MX-1 model.
- Glycoconjugate 19 exhibited a favorable toxicity profile compared to topotecan and compound 21.
Conclusions:
- The peptide spacer significantly impacts the stability and activity of camptothecin glycoconjugates.
- Novel glycoconjugates demonstrate targeted cellular uptake and potent antitumor efficacy.
- Glycoconjugate 19 shows a promising therapeutic profile, warranting its advancement to clinical trials.