Cytotoxicity, hydrophobicity, uptake, and distribution of osmium(II) anticancer complexes in ovarian cancer cells
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Sabine H van Rijt1, Arindam Mukherjee, Ana M Pizarro
1Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
Abstract:
The cytotoxicity, hydrophobicity (log P), cellular uptake, aqueous reactivity, and extent of DNA adduct formation in the A2780 ovarian carcinoma cells for four osmium(II) arene complexes [(eta(6)-arene)Os(4-methyl-picolinate)Cl] that differ only in their arene ligands as benzene (1), p-cymene (2), biphenyl (3), or tetrahydroanthracene (4) are reported. There is a correlation between hydrophobicity (log P), cellular uptake, nucleus uptake, and cytotoxicity of the complexes, following the order 3 approximately 4 > 2 > 1, suggesting that the arene plays an important role in the biological activity of these types of compounds. Cell distribution studies using fractionation showed that all four compounds distribute similarly within cells. DNA binding of osmium did not correlate with cytotoxicity, indicating that the nature of the DNA lesion may also be crucial to activity. TEM images of ovarian cells treated with 3 revealed morphological changes associated with apoptosis with possible involvement of mitochondria.
Insights
Four osmium(II) arene complexes showed varying cytotoxicity against ovarian cancer cells. Increased hydrophobicity correlated with higher cellular uptake and cytotoxicity, but not DNA binding, suggesting arene ligands are key to biological activity.
Area of Science:
- Organometallic Chemistry
- Cancer Biology
- Pharmacology
Background:
- Osmium(II) complexes are investigated for anticancer properties.
- The influence of arene ligands on complex activity is not fully understood.
Purpose of the Study:
- To evaluate the biological activity of four osmium(II) arene complexes.
- To correlate physicochemical properties with cytotoxicity in ovarian carcinoma cells.
Main Methods:
- Synthesis and characterization of four osmium(II) arene complexes.
- Assessment of cytotoxicity, hydrophobicity (log P), cellular uptake, and DNA adduct formation in A2780 cells.
- Transmission electron microscopy (TEM) for cellular morphology analysis.
Main Results:
- Cytotoxicity, cellular uptake, and nucleus uptake correlated with hydrophobicity (log P) in the order: biphenyl (3) ≈ tetrahydroanthracene (4) > p-cymene (2) > benzene (1).
- Osmium-DNA binding did not correlate with cytotoxicity.
- Complex 3 induced morphological changes indicative of apoptosis, potentially involving mitochondria.
Conclusions:
- The arene ligand significantly influences the biological activity of osmium(II) complexes.
- Hydrophobicity is a critical factor for cellular uptake and cytotoxicity.
- Mechanisms beyond direct DNA binding, such as apoptosis induction, contribute to osmium complex anticancer activity.
