title: Chlorambucil conjugates of dinuclear p-cymene ruthenium trithiolato complexes: synthesis, characterization and cytotoxicity study in vitro and in vivo.
abstract: Four diruthenium trithiolato chlorambucil conjugates have been prepared via Steglich esterification from chlorambucil and the corresponding trithiolato precursors. All conjugates are highly cytotoxic towards human ovarian A2780 and A2780cisR cancer cell lines with IC50 values in the nanomolar range. The conjugates exhibit selectivity towards A2780 cells as compared to non-cancerous HEK293 cells, while being only slightly selective for RF24 and A2780cisR cells. In vivo, the conjugate [10]BF4 suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival. The reactivity of the chlorambucil conjugates with glutathione, a potential target of the dinuclear ruthenium motive, and with the 2-deoxyguanosine 5'-monophosphate (dGMP-a model target of chlorambucil) was studied by mass spectrometry and NMR spectroscopy. The conjugates did not show catalytic activity for the oxidation of glutathione nor binding to nucleotides, indicating that glutathione oxidation and DNA alkylation are not key mechanisms of action. Four highly cytotoxic diruthenium trithiolato chlorambucil conjugates have been prepared. All conjugates exhibit selectivity towards A2780 cells as compared to HEK293 cells, while being only slightly active in RF24 and A2780cisR cells. In vivo, the best candidate suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival.
authors.affiliation: Institut de Chimie, Université de Neuchâtel, Neuchâtel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Stíbal
authors.affiliation: Institut de Chimie, Université de Neuchâtel, Neuchâtel, Switzerland. bruno.therrien@unine.ch.
authors.forename: Bruno
authors.initials: B
authors.lastname: Therrien
authors.affiliation: Institut de Chimie, Université de Neuchâtel, Neuchâtel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Süss-Fink
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Nowak-Sliwinska
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.affiliation: Faculty of Medicine in Hradec Králové, Computer Technology Center, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Čermáková
authors.affiliation: Faculty of Medicine in Hradec Králové, Department of Medical Biochemistry, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Řezáčová
authors.affiliation: Faculty of Medicine in Hradec Králové, Department of Medical Biochemistry, Charles University in Prague, Hradec Králové, Czech Republic. TomsikP@lfhk.cuni.cz.
authors.forename: Pavel
authors.initials: P
authors.lastname: Tomšík
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000737:chemistry*; D000081007:Cymenes; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D039821:Monoterpenes / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D000081007:Cymenes; D039821:Monoterpenes; D009942:Organometallic Compounds; D013438:Sulfhydryl Compounds; D002699:Chlorambucil; C007210:4-cymene; D012428:Ruthenium
keywords: Anticancer activity; Arene ruthenium; Chlorambucil; Dinuclear complexes; In vivo study