Conjugates of Modified Cryptophycins and RGD-Peptides Enter Target Cells by Endocytosis
| Autor: | Benedikt Sammet, Christine Weiß, Jens Conradi, Soledad Royo Gracia, Markus Nahrwold, Norbert Sewald, Ralf Palmisano, Felix Mertink, Thomas Preuße, Tobias Bogner |
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| Rok vydání: | 2013 |
| Předmět: |
Protein Conformation
media_common.quotation_subject Peptide Molecular Dynamics Simulation Endocytosis Inhibitory Concentration 50 Cell Line Tumor Depsipeptides Drug Discovery Humans Cytotoxicity Internalization Nuclear Magnetic Resonance Biomolecular media_common chemistry.chemical_classification Microscopy Confocal Prodrug Drug Resistance Multiple chemistry Biochemistry Drug Resistance Neoplasm Cryptophycin Molecular Medicine Female Oligopeptides Cryptophycins Homing (hematopoietic) |
| Zdroj: | Journal of Medicinal Chemistry. 56:1853-1864 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm301346z |
| Popis: | Tumor targeting anticancer drug conjugates that contain a tumor recognition motif (homing device) are of high current relevance. Cryptophycins, naturally occurring cytotoxic cyclo-depsipeptides, have been modified by total synthesis to provide analogues suitable for conjugation to peptide-based homing devices. An array of functionalized β(2)-amino acids was synthesized and incorporated into cryptophycins. All analogues proved to be highly active in the cytotoxicity assay using the human cervix carcinoma cell line KB-3-1 and its multidrug-resistant subclone KB-V1. Conformational analysis of cryptophycin-52 and two synthetic analogues was performed by NMR and MD methods to obtain information on the influence of the unit C configuration on the overall conformation. An azide-functionalized cryptophycin was connected by CuAAC to an alkyne-containing fluorescently labeled cyclic RGD-peptide as the homing device for internalization studies. Confocal fluorescence microscopy proved integrin-mediated internalization by endocytosis and final lysosomal localization of the cryptophycin prodrug. |
| Databáze: | OpenAIRE |
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