Conjugates
of Modified Cryptophycins and RGD-Peptides
Enter Target Cells by Endocytosis
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Abstract
Tumor
targeting anticancer drug conjugates that contain a tumor
recognition motif (homing device) are of high current relevance. Cryptophycins,
naturally occurring cytotoxic <i>cyclo</i>-depsipeptides,
have been modified by total synthesis to provide analogues suitable
for conjugation to peptide-based homing devices. An array of functionalized
β<sup>2</sup>-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