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Platinum(II) complexes containing iminoethers: a trans platinum antitumour agent
M Coluccia1, A Boccarelli, M A Mariggiò
1Dipartimento di Scienze Biomediche e Oncologia Umana, Sez. Patologia Generale e Oncologia Sperimentale, Policlinico, Bari, Italy.
Chemico-Biological Interactions
|December 22, 1995
Summary
A novel trans platinum complex with iminoether ligands demonstrates significant antitumor activity against leukemia and solid tumors in mice. This compound exhibits a unique mechanism of action, differing from traditional platinum-based drugs like cisplatin.
Area of Science:
- Inorganic Chemistry
- Medicinal Chemistry
- Cancer Research
Background:
- Platinum-based drugs, particularly cisplatin, are mainstays in cancer chemotherapy.
- The antitumor activity of platinum complexes is often associated with their cis geometry.
- Trans platinum complexes have historically shown limited therapeutic potential.
Purpose of the Study:
- To investigate the biological activity of cis and trans platinum complexes with iminoether ligands.
- To explore the potential of a trans platinum complex with EE iminoether configuration as an anticancer agent.
- To elucidate the mechanism of action of this novel trans platinum complex.
Main Methods:
- Synthesis and characterization of cis and trans platinum complexes with iminoether ligands (EE, EZ, ZZ isomers).
- In vivo studies using P388 leukemia and Lewis lung carcinoma models in mice.
- In vitro assays including cytotoxicity, DNA synthesis inhibition, mutagenic activity, DNA binding, and DNA interstrand cross-linking.
Main Results:
- The trans-EE iminoether platinum complex exhibited potent antitumor activity in both P388 leukemia and Lewis lung carcinoma models.
- This trans-EE complex showed comparable efficacy to cisplatin in reducing tumor mass and lung metastases.
- Cytotoxicity, DNA synthesis inhibition, and mutagenic activity were greater for the trans-isomer in iminoether compounds, unlike amine complexes.
- DNA binding was slower but comparable after 24 hours for iminoether complexes versus amine complexes.
- The trans-EE complex did not induce DNA conformational alterations typical of cis platinum drugs but showed reduced DNA interstrand cross-linking ability.
Conclusions:
- A novel trans platinum complex with iminoether ligands possesses significant antitumor activity.
- This complex represents a promising trans platinum anticancer agent with a distinct mechanism of action compared to cis-DDP.
- The findings challenge the traditional paradigm that only cis platinum complexes are therapeutically effective.