Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation
Dessin C, Schachtsiek T, Voss J, Abel A-C, Neumann B, Stammler H-G, Prota AE, Sewald N (2024)
Angewandte Chemie International Edition.
Zeitschriftenaufsatz
| E-Veröff. vor dem Druck | Englisch
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Autor*in
Dessin, CedricUniBi;
Schachtsiek, ThomasUniBi;
Voss, JonaUniBi ;
Abel, Anne-Catherine;
Neumann, BeateUniBi;
Stammler, Hans-GeorgUniBi;
Prota, Andrea E.;
Sewald, NorbertUniBi
Einrichtung
Abstract / Bemerkung
Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging. The unit D, natively 2-hydroxyisocaproic acid (leucic acid), was envisaged as a promising attachment site based on structural information from X-ray analysis. A versatile, scalable and efficient synthetic route towards conjugable cryptophycins with modification in unit D was developed and an array of new cryptophycin analogues was synthesized. Several derivatives, especially those containing lipophilic groups with low steric demand such as alkylated amino groups, exhibit low picomolar cytotoxicity often combined with efficacy against multidrug-resistant tumor cells. The newly established cryptophycin analogues comprise a broad range of relevant functional groups used as conjugation handles, among them amino, hydroxy, carboxy, as well as sulfur-containing derivatives. X-ray crystallographic analysis of a tubulin-bound cryptophycin together with quantitative structure activity relationship manifested rationales for the synthesis of most potent cryptophycin derivatives and further confirmed the suitability of modifications in unit D. © 2024 Wiley‐VCH GmbH.
Erscheinungsjahr
2024
Zeitschriftentitel
Angewandte Chemie International Edition
eISSN
1521-3773
Page URI
https://pub.uni-bielefeld.de/record/2993281
Zitieren
Dessin C, Schachtsiek T, Voss J, et al. Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation. Angewandte Chemie International Edition. 2024.
Dessin, C., Schachtsiek, T., Voss, J., Abel, A. - C., Neumann, B., Stammler, H. - G., Prota, A. E., et al. (2024). Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.202416210
Dessin, Cedric, Schachtsiek, Thomas, Voss, Jona, Abel, Anne-Catherine, Neumann, Beate, Stammler, Hans-Georg, Prota, Andrea E., and Sewald, Norbert. 2024. “Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation”. Angewandte Chemie International Edition.
Dessin, C., Schachtsiek, T., Voss, J., Abel, A. - C., Neumann, B., Stammler, H. - G., Prota, A. E., and Sewald, N. (2024). Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation. Angewandte Chemie International Edition.
Dessin, C., et al., 2024. Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation. Angewandte Chemie International Edition.
C. Dessin, et al., “Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation”, Angewandte Chemie International Edition, 2024.
Dessin, C., Schachtsiek, T., Voss, J., Abel, A.-C., Neumann, B., Stammler, H.-G., Prota, A.E., Sewald, N.: Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation. Angewandte Chemie International Edition. (2024).
Dessin, Cedric, Schachtsiek, Thomas, Voss, Jona, Abel, Anne-Catherine, Neumann, Beate, Stammler, Hans-Georg, Prota, Andrea E., and Sewald, Norbert. “Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation”. Angewandte Chemie International Edition (2024).
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