title: Protein ruthenation and DNA alkylation: chlorambucil-functionalized RAPTA complexes and their anticancer activity.
abstract: 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.
authors.affiliation: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), CH-1015, Lausanne, Switzerland. paul.dyson@epfl.ch.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Nazarov
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Meier
authors.forename: Olivier
authors.initials: O
authors.lastname: Zava
authors.forename: Yulia N
authors.initials: YN
authors.lastname: Nosova
authors.forename: Elena R
authors.initials: ER
authors.lastname: Milaeva
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hartinger
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
mesh_terms: D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000737:chemistry* / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000081007:Cymenes; D004247:DNA / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D061986:MCF-7 Cells; D009942:Organometallic Compounds / Q000737:chemistry; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D056831:Coordination Complexes; D000081007:Cymenes; D009942:Organometallic Compounds; D011506:Proteins; C534678:RAPTA-T; D025801:Ubiquitin; C530402:dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II); D002699:Chlorambucil; D004247:DNA