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Mutagenic Tests Confirm That New Acetylacetonate Pt(II) Complexes Induce Apoptosis in Cancer Cells Interacting with Nongenomic Biological Targets.

De Pascali SA, Lugoli F, De Donno A, Fanizzi FP - Met Based Drugs (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Prov. le Lecce/Monteroni, 73100 Lecce, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

1H NMR spectra in D2O (400.13 MHz, standard TSP) of 1a with excess of L-methionine and 5′-GMP at different reaction times. Rapid reaction with L-methionine (decreasing coordinated (#) and increasing free DMS (∗) signals) and negligible or very slow reaction with 5′-GMP were observed.
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fig1: 1H NMR spectra in D2O (400.13 MHz, standard TSP) of 1a with excess of L-methionine and 5′-GMP at different reaction times. Rapid reaction with L-methionine (decreasing coordinated (#) and increasing free DMS (∗) signals) and negligible or very slow reaction with 5′-GMP were observed.

Mentions: By 1H NMR the reactivity of water soluble complexes (1a, 2a, and 2b) with biological nucleophiles (nucleobases and amino acids) was investigated. The poor water solubility of [PtCl(O,O′-acac)(DMS)] (1b) prevented further investigation on its reactivity and biological activities. The reactions with soft biological nucleophiles, such as L-methionine (L-met), rapidly gave the same selective substitution of DMSO or DMS, already seen for these complexes towards classical soft nucleophiles (DMS, PPh3, ethylene, carbon monoxide) [23]. Indeed, also in the presence of L-methionine excess both 1a and 2a complexes gave selective substitution reaction of DMSO affording, respectively, to the neutral species [PtCl(O,O′-acac)(L-met)] [Pt(O,O′-acac)(γ-acac)(L-met)]. Moreover, this substitution reaction not only was more selective but also was faster. In Figure 1 the 1H NMR time monitoring of reaction of 1a with L-met was reported. Adding L-met excess to a solution of 1a in D2O, after only 5 minutes (the time needed to record a 1H NMR spectra) the substitution of DMSO ligand and the coordination of L-Met were observed by the decreasing of the signal at 3.44 ppm, assigned to the coordinated DMSO ligand.


Mutagenic Tests Confirm That New Acetylacetonate Pt(II) Complexes Induce Apoptosis in Cancer Cells Interacting with Nongenomic Biological Targets.

De Pascali SA, Lugoli F, De Donno A, Fanizzi FP - Met Based Drugs (2011)

1H NMR spectra in D2O (400.13 MHz, standard TSP) of 1a with excess of L-methionine and 5′-GMP at different reaction times. Rapid reaction with L-methionine (decreasing coordinated (#) and increasing free DMS (∗) signals) and negligible or very slow reaction with 5′-GMP were observed.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3094815&req=5

fig1: 1H NMR spectra in D2O (400.13 MHz, standard TSP) of 1a with excess of L-methionine and 5′-GMP at different reaction times. Rapid reaction with L-methionine (decreasing coordinated (#) and increasing free DMS (∗) signals) and negligible or very slow reaction with 5′-GMP were observed.
Mentions: By 1H NMR the reactivity of water soluble complexes (1a, 2a, and 2b) with biological nucleophiles (nucleobases and amino acids) was investigated. The poor water solubility of [PtCl(O,O′-acac)(DMS)] (1b) prevented further investigation on its reactivity and biological activities. The reactions with soft biological nucleophiles, such as L-methionine (L-met), rapidly gave the same selective substitution of DMSO or DMS, already seen for these complexes towards classical soft nucleophiles (DMS, PPh3, ethylene, carbon monoxide) [23]. Indeed, also in the presence of L-methionine excess both 1a and 2a complexes gave selective substitution reaction of DMSO affording, respectively, to the neutral species [PtCl(O,O′-acac)(L-met)] [Pt(O,O′-acac)(γ-acac)(L-met)]. Moreover, this substitution reaction not only was more selective but also was faster. In Figure 1 the 1H NMR time monitoring of reaction of 1a with L-met was reported. Adding L-met excess to a solution of 1a in D2O, after only 5 minutes (the time needed to record a 1H NMR spectra) the substitution of DMSO ligand and the coordination of L-Met were observed by the decreasing of the signal at 3.44 ppm, assigned to the coordinated DMSO ligand.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Prov. le Lecce/Monteroni, 73100 Lecce, Italy.

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.

No MeSH data available.


Related in: MedlinePlus