Doxorubicin (DOX) is a valuable drug for the treatment of breast cancer, liver cancer and soft-tissue sarcomas. However, its clinical application is limited by its dose-related, toxic side effects, such as cumulative cardiotoxicity. Efforts have therefore been made to create less toxic derivatives of DOX. The aim of this study was to develop a platform technology for the integrated chemical synthesis and cell-based screening of DOX derivatives. Relatively harsh conditions are often required to liberate a target molecule from the solid support which is problematic for complex natural products like DOX. In order to circumvent these issues, and to provide a biocompatible release platform, the present technology relies on the application of novel photolabile linkers.The primary amine and primary alcohol are two obvious sites for structural modification of DOX. Along these lines, we successfully developed strategies for the selective synthesis (and release) of otherwise quite sensitive DOX-peptide conjugates at both the N- and O-positions. In this way, pharmacologically promising DOX-derivatives could be synthesized in good purities applicable to biological screening assays.

Solid-phase synthesis of doxorubicin derivatives: Toward cell-based on-bead screening

248th National Meeting (2014)

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