title: Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis.
abstract: 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.
authors: Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany.
authors: Markus
authors: M
authors: Nahrwold
authors: Christine
authors: C
authors: Weiß
authors: Tobias
authors: T
authors: Bogner
authors: Felix
authors: F
authors: Mertink
authors: Jens
authors: J
authors: Conradi
authors: Benedikt
authors: B
authors: Sammet
authors: Ralf
authors: R
authors: Palmisano
authors: Soledad
authors: S
authors: Royo Gracia
authors: Thomas
authors: T
authors: Preuße
authors: Norbert
authors: N
authors: Sewald
mesh_terms: D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004705:Endocytosis; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D018613:Microscopy, Confocal; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D047630:Depsipeptides; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid