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In vitro anticancer active cis-Pt(II)-diiodido complexes containing 4-azaindoles
Pavel Štarha1, Zdeněk Trávníček2, Ján Vančo1
1Biologically Active Complexes and Molecular Magnets, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University in Olomouc, Šlechtitelů 27, 783 71, Olomouc, Czech Republic.
Summary
New platinum(II) complexes with 4-azaindole ligands show potent anticancer activity against ovarian and colon cancer cells. N1-alkylation of 4-azaindole (ip4aza) enhances cytotoxicity and overcomes cisplatin resistance, with low toxicity to human hepatocytes.
Area of Science:
- Coordination Chemistry
- Medicinal Chemistry
- Cancer Research
Background:
- Platinum(II) complexes are vital chemotherapeutic agents, but acquired resistance limits their efficacy.
- 4-Azaindole (4aza) and its derivatives offer novel ligand scaffolds for platinum-based drugs.
- N1-alkylation of 4-azaindole may modulate the biological activity and resistance profile of platinum complexes.
Purpose of the Study:
- To synthesize and characterize novel cis-diiodido-platinum(II) complexes incorporating 4-azaindole (4aza) and N1-isopropyl-4-azaindole (ip4aza) ligands.
- To evaluate the in vitro cytotoxicity of these complexes against human ovarian and colon cancer cell lines, including cisplatin-resistant variants.
- To assess the potential of these complexes to overcome cisplatin resistance and their toxicity in primary human hepatocytes.
Main Methods:
- Synthesis of four cis-diiodido-platinum(II) complexes: cis-[Pt(4aza)2I2] (1), cis-[PtI2(ip4aza)2] (2), cis-[Pt(4aza)I2(NH3)] (3), and cis-[PtI2(ip4aza)(NH3)] (4).
- Characterization using multinuclear NMR spectroscopy and ESI mass spectrometry.
- In vitro cytotoxicity assays on A2780 (ovarian), A2780R (cisplatin-resistant ovarian), and HT-29 (colon) cancer cell lines.
- Hepatocyte toxicity assessment using primary human hepatocytes.
- Cell cycle analysis via flow cytometry.
Main Results:
- Complexes 1-4 exhibited significant in vitro cytotoxicity against tested cancer cell lines, with some showing higher activity than cisplatin.
- N1-alkylation (ip4aza) in complexes 2 and 4 led to significantly higher cytotoxicity compared to their 4aza counterparts (1 and 3) in A2780 and A2780R cells.
- Resistance factors (0.8-1.4) indicated that complexes 1-4 could overcome acquired cisplatin resistance in A2780R cells.
- Complexes 1 and 2 demonstrated low toxicity against primary human hepatocytes.
- Flow cytometry revealed that complexes 1-4 induce distinct cell cycle perturbations compared to cisplatin, suggesting alternative mechanisms of action.
Conclusions:
- N1-isopropyl-4-azaindole platinum(II) complexes represent promising anticancer agents with potent activity and the ability to overcome cisplatin resistance.
- The observed low hepatotoxicity and distinct mechanism of action warrant further investigation for clinical development.
- These findings highlight the therapeutic potential of modified azaindole ligands in platinum-based chemotherapy.
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