Download MendeleyHighly 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, A.E., Sewald, N.(2024) Angew Chem Int Ed Engl 63: e202416210-e202416210
- PubMed: 39324938
- DOI: https://doi.org/10.1002/anie.202416210
- Primary Citation of Related Structures:
9FYD - PubMed Abstract:
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.
Organizational Affiliation:
Bielefeld University, Chemistry, GERMANY.
