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Metal (Au, Pt, Pd, Ni) Bis(dithiolene) complexes as dual-action agents combating cancer and trypanosomatid infections
Hadi Hachem1, Yann Le Gal1, Olivier Jeannin1
1Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) - UMR 6226, F-35000 Rennes, France.
Abstract:
Cancer and infection diseases pose severe threats to public health worldwide stressing the need for more effective and efficient treatments. Thus, the search for broad-spectrum activity drugs seems justifiable and urgent. Herein, we investigate the anticancer and antitrypanosomatid (anti-Trypanosoma cruzi) activities of eight monoanionic metal bis(dithiolene) complexes, [Ph4P][M(R-thiazdt)2] with Mn+ = Au3+, Pt2+, Pd2+, Ni2+, containing N-alkyl-1,3-thiazoline-2-thione dithiolene ligands (R-thiazdt) with different alkyl groups (R = Et, tBu). Compared to auranofin (AF) and cisplatin (CP), two reference drugs in clinical use, all complexes showed high anticancer activities against A2780 ovarian cancer cells (IC50 values of 0.6-3.8 μM) some also being able to overcome CP resistance in A2780cisR cells. The selectivity index (SI), the IC50 values on normal cells (HDF) vs. A2780 cells, indicated good anticancer specificity (SI > 3) for most of the complexes but with clinical relevance for [Ph4P][Pd(tBu-thiazdt)2] (SI = 10). All complexes showed relevant antitrypanosomatid activities (IC50 values of 2.6-5.8 μM) some even exhibiting lower IC50 values than the reference drug nifurtimox (NFX). The mechanism of cell death seemed to be mediated mainly by the formation of reactive oxygen species (ROS), although to lesser extent for the gold complexes but superior to AF. Although ROS play a role in the main apoptotic pathways, cell death by apoptosis was not evident as shown by the caspase-3/7 assay and the morphological cell features studies by electron microscopy (SEM). Results obtained evidenced that [Ph4P][Pt(tBu-thiazdt)2] and [Ph4P][Pd(tBu-thiazdt)2] complexes might have potential as novel anticancer and antitrypanosomatid agents as alternatives to current therapeutics.
Insights
New metal bis(dithiolene) complexes show potent anticancer and anti-Trypanosoma cruzi activities. These compounds, including platinum and palladium variants, demonstrate broad-spectrum efficacy and potential as novel therapeutic agents against cancer and parasitic infections.
Area of Science:
- Medicinal Chemistry
- Inorganic Chemistry
- Parasitology
Background:
- Cancer and infectious diseases are major global health threats requiring novel broad-spectrum treatments.
- Metal bis(dithiolene) complexes offer a promising avenue for developing new therapeutic agents due to their diverse chemical properties.
Purpose of the Study:
- To investigate the anticancer and antitrypanosomatid (anti-Trypanosoma cruzi) activities of eight novel monoanionic metal bis(dithiolene) complexes.
- To evaluate the selectivity and potential mechanisms of action of these complexes compared to established drugs.
Main Methods:
- Synthesis and characterization of eight [Ph4P][M(R-thiazdt)2] complexes (M = Au, Pt, Pd, Ni; R = Et, tBu).
- In vitro evaluation of anticancer activity against A2780 ovarian cancer cells and A2780cisR cells.
- Assessment of antitrypanosomatid activity against Trypanosoma cruzi.
- Determination of selectivity index (SI) using normal human dermal fibroblasts (HDF).
- Investigation of cell death mechanisms, including reactive oxygen species (ROS) generation and apoptosis assays.
Main Results:
- All complexes exhibited significant anticancer activity (IC50: 0.6-3.8 μM) against A2780 cells, with some overcoming cisplatin resistance.
- [Ph4P][Pd(tBu-thiazdt)2] showed a promising selectivity index (SI=10).
- All complexes demonstrated potent antitrypanosomatid activity (IC50: 2.6-5.8 μM), with some outperforming nifurtimox.
- Cell death was primarily mediated by ROS generation, though apoptosis was not clearly evident.
- Gold complexes showed lower ROS generation compared to other metals but were still superior to auranofin.
Conclusions:
- The synthesized metal bis(dithiolene) complexes possess significant anticancer and antitrypanosomatid activities.
- [Ph4P][Pt(tBu-thiazdt)2] and [Ph4P][Pd(tBu-thiazdt)2] show particular promise as novel therapeutic agents.
- These complexes represent potential alternatives to current treatments for cancer and Chagas disease, warranting further investigation.
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