Chlorambucil conjugates of dinuclear p-cymene ruthenium trithiolato complexes: synthesis, characterization and cytotoxicity study in vitro and in vivo
Language English Country Germany Media print-electronic
Document type Journal Article
PubMed
27040952
DOI
10.1007/s00775-016-1353-z
PII: 10.1007/s00775-016-1353-z
Knihovny.cz E-resources
- Keywords
- Anticancer activity, Arene ruthenium, Chlorambucil, Dinuclear complexes, In vivo study,
- MeSH
- Chlorambucil chemistry MeSH
- Cymenes MeSH
- Neoplasms, Experimental drug therapy pathology MeSH
- Humans MeSH
- Molecular Conformation MeSH
- Monoterpenes chemistry MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Organometallic Compounds chemical synthesis chemistry pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Ruthenium chemistry MeSH
- Drug Screening Assays, Antitumor MeSH
- Sulfhydryl Compounds chemistry MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 4-cymene MeSH Browser
- Chlorambucil MeSH
- Cymenes MeSH
- Monoterpenes MeSH
- Organometallic Compounds MeSH
- Antineoplastic Agents MeSH
- Ruthenium MeSH
- Sulfhydryl Compounds MeSH
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.
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