Abstract
New platinum(II) complexes [PtCl(O,O′-acac)(L)] (1) and [Pt(O,O′-acac)(γ-acac)(L)] (2) (L = DMSO, a; DMS, b) containing a single chelated (O,O′-acac) (1), or one chelated and one σ-bonded (γ-acac) acetylacetonate (2) have been synthesized. The new Pt(II) complexes exhibited high in vitro cytotoxicity on cisplatin sensitive and resistant cell lines and showed negligible reactivity with nucleobases (Guo and 5′-GMP) but selective substitution of DMSO/DMS with soft biological nucleophiles, such as L-methionine. In order to assess the ability of the new complexes with respect to cisplatin to induce apoptosis by interaction with nongenomic targets, the Ames' test, a standard reverse mutation assay, was carried out on two Salmonella typhimurium strains (TA98 and TA100). Interestingly, the new complexes did not show the well-known mutagenic activity exhibited by cisplatin and are, therefore, able to activate apoptotic pathways without interacting with DNA.
Highlights
After more than 30 years since its first clinical use, cisplatin is still one of the most widely used drugs in anticancer chemotherapy [1]
We reported the 1H NMR investigations on reactivity of the new compounds with hard and soft biological nucleophiles, such as nucleobases and sulfur amino acids, confirming selective reaction with the latter [23]
The new complexes coordinate, instead of the mono- and bidentate amine ligands of the classical cisplatin analogues, O,O -acetylacetonate chelate as carrier ligand and DMS or DMSO ligands. Due to their ability to induce apoptosis in endometrial cancer cells (HeLa) and in cisplatin-resistant breast cancer cell lines (MCF-7) with different pathways with respect to cisplatin, further investigations were performed on the reactivity of novel compounds with biological targets and on the mutagenic capability
Summary
After more than 30 years since its first clinical use, cisplatin is still one of the most widely used drugs in anticancer chemotherapy [1]. The action mechanism of cisplatin has been explained in its essential aspects, relatively to its interaction with DNA. Some essential chemical processes, related to what happens before the cisplatin reaches the DNA, generally considered its final target, are still to be identified. Among these processes, the best known is the formation of aquospecies, the main reaction of activation of the drug [2, 3] which occurs in the cytoplasmic compartment by hydrolysis of the chloride ligands. In the last years several Pt(II) and Pt(IV) complexes have been synthesised, but only a few compounds, such as carboplatin and oxaliplatin [1, 11], are used in clinical therapy
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