Details

Autor(en) / Beteiligte

• Nazarov, Alexey A
• Meier, Samuel M
• Zava, Olivier
• Nosova, Yulia N
• Milaeva, Elena R
• Hartinger, Christian G
• Dyson, Paul J

Titel

Protein ruthenation and DNA alkylation: chlorambucil-functionalized RAPTA complexes and their anticancer activity

Ist Teil von

• Dalton transactions : an international journal of inorganic chemistry, 2015-02, Vol.44 (8), p.3614-3623

Ort / Verlag

England

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• Chemotherapeutics for the treatment of tumorigenic conditions that feature novel modes of action are highly sought after to overcome the limitations of current chemotherapies. Herein, we report the conjugation of the alkylating agent chlorambucil to the RAPTA scaffold, a well-established pharmacophore. While chlorambucil is known to alkylate DNA, the RAPTA complexes are known to coordinate to amino acid side chains of proteins. Therefore, such a molecule combines DNA and protein targeting properties in a single molecule. Several chlorambucil-tethered RAPTA derivatives were prepared and tested for their cytotoxicity, stability in water and reactivity to protein and DNA substrates. The anticancer activity of the complexes is widely driven by the cytotoxicity of the chlorambucil moiety. However, especially in the cisplatin-resistant A2780R cells, the chlorambucil-functionalized RAPTA derivatives are in general more cytotoxic than chlorambucil and also a mixture of chlorambucil and the parent organoruthenium RAPTA compound. In a proof-of-principle experiment, the cross-linking of DNA and protein fragments by a chlorambucil-RAPTA derivative was observed. The conjugation of chlorambucil to the RAPTA scaffold results in an anticancer active agent capable of cross-linking DNA and proteins.