Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis

Nahrwold M, Weiß C, Bogner T, Mertink F, Conradi J, Sammet B, Palmisano R, Royo Gracia S, Preuße T, Sewald N (2013)
Journal of medicinal chemistry 56(5): 1853-1864.

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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 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.
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Nahrwold M, Weiß C, Bogner T, et al. Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis. Journal of medicinal chemistry. 2013;56(5):1853-1864.
Nahrwold, M., Weiß, C., Bogner, T., Mertink, F., Conradi, J., Sammet, B., Palmisano, R., et al. (2013). Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis. Journal of medicinal chemistry, 56(5), 1853-1864.
Nahrwold, M., Weiß, C., Bogner, T., Mertink, F., Conradi, J., Sammet, B., Palmisano, R., Royo Gracia, S., Preuße, T., and Sewald, N. (2013). Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis. Journal of medicinal chemistry 56, 1853-1864.
Nahrwold, M., et al., 2013. Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis. Journal of medicinal chemistry, 56(5), p 1853-1864.
M. Nahrwold, et al., “Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis”, Journal of medicinal chemistry, vol. 56, 2013, pp. 1853-1864.
Nahrwold, M., Weiß, C., Bogner, T., Mertink, F., Conradi, J., Sammet, B., Palmisano, R., Royo Gracia, S., Preuße, T., Sewald, N.: Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis. Journal of medicinal chemistry. 56, 1853-1864 (2013).
Nahrwold, Markus, Weiß, Christine, Bogner, Tobias, Mertink, Felix, Conradi, Jens, Sammet, Benedikt, Palmisano, Ralf, Royo Gracia, Soledad, Preuße, Thomas, and Sewald, Norbert. “Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis”. Journal of medicinal chemistry 56.5 (2013): 1853-1864.
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Dal Corso A, Caruso M, Belvisi L, Arosio D, Piarulli U, Albanese C, Gasparri F, Marsiglio A, Sola F, Troiani S, Valsasina B, Pignataro L, Donati D, Gennari C., Chemistry 21(18), 2015
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The cryptophycins as potent payloads for antibody drug conjugates.
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PMID: 25613677
Recent approaches for the synthesis of modified cryptophycins.
Weiss C, Sammet B, Sewald N., Nat Prod Rep 30(7), 2013
PMID: 23732943

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