Synthesis, structures and cytotoxic effects in vitro of cis- and trans-[PtIVCl4(NHC)2] complexes and their PtII precursors

Rehm, Tobias; Rothemund, Matthias; Dietel, Thomas; Kempe, Rhett; Schobert, Rainer

doi:10.1039/c9dt02438g

Cited by 18 publications

(13 citation statements)

References 31 publications

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“…Second, the inhibitory effects of different platinum complexes did not correlate with their DNA-binding capability, or cancer cell toxicity. For example, the platinum(IV) complex TR425, which is distinctly less toxic to cancer cells than cisplatin, and binds only weakly to linear DNA (Rehm et al, 2019), had a similar inhibitory potency as cisplatin in our translocation assay. Third, complexes that are considered non-functional in terms of DNA-binding and anticancer activity, such as transplatin, still showed type IV secretion inhibition to a higher extent than cisplatin dissolved in DMF.…”

Section: Discussionmentioning

confidence: 77%

“…However, when we tested complexes in which the DMSO ligand was replaced by a second NHC ligand in cis configuration (Rehm et al, 2016), we found some with clear antibacterial effects toward H. pylori (data not shown), but also others which had similar properties as cisplatin or the DMSOcontaining complexes ( Figure 4C). Finally, we analyzed the effect of an analogous platinum(IV) complex with two NHC ligands, which exhibits reduced DNA-binding properties and only moderate cytotoxicity (Rehm et al, 2019). Here, we also observed a substantial inhibitory potential with respect to CagA type IV secretion for compound TR425, while H. pylori growth was not strongly affected ( Figure 4D).…”

Section: Effects Of Other Platinum Complexes On Type IV Secretion Inhmentioning

confidence: 77%

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Inhibition of Type IV Secretion Activity and Growth of Helicobacter pylori by Cisplatin and Other Platinum Complexes

Lettl

Schindele

Testolin

et al. 2020

Front. Cell. Infect. Microbiol.

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Type IV secretion systems are protein secretion machineries that are frequently used by pathogenic bacteria to inject their virulence factors into target cells of their respective hosts. In the case of the human gastric pathogen Helicobacter pylori, the cytotoxin-associated gene (Cag) type IV secretion system is considered a major cause for severe disease, such as gastric cancer, and thus constitutes an attractive target for specific treatment options against H. pylori infections. Here, we have used a Cag type IV secretion reporter assay for screening a repurposing compound library for inhibitors targeting this system. We found that the antitumor agent cisplatin, a platinum coordination complex that kills target cells by formation of DNA crosslinks, is a potent inhibitor of the Cag type IV secretion system. Strikingly, we found that this inhibitory activity of cisplatin depends on a ligand exchange reaction which incorporates a solvent molecule (dimethylsulfoxide) into the complex, a modification which is known to be deleterious for DNA crosslinking, and for its anticancer activity. We extended our analysis to several analogous platinum complexes containing N-heterocyclic carbene, as well as DMSO or other ligands, and found varying inhibitory activities toward the Cag system which were not congruent with their DNA-binding properties, suggesting that protein interactions may cause the inhibitory effect. Inhibition experiments under varying conditions revealed effects on adherence and bacterial viability as well, and showed that the type IV secretion-inhibitory capacity of platinum complexes can be inactivated by sulfur-containing reagents and in complex bacterial growth media. Taken together, our results demonstrate DNA binding-independent inhibitory effects of cisplatin and other platinum complexes against different H. pylori processes including type IV secretion.

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Section: Discussionmentioning

confidence: 77%

Section: Effects Of Other Platinum Complexes On Type IV Secretion Inhmentioning

confidence: 77%

Inhibition of Type IV Secretion Activity and Growth of Helicobacter pylori by Cisplatin and Other Platinum Complexes

Lettl

Schindele

Testolin

et al. 2020

Front. Cell. Infect. Microbiol.

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“…Similar results have been previously observed for the reactions of K 2 [PtCl 4 ] with other silver carbenes. 53 − 57 …”

Section: Resultsmentioning

confidence: 99%

Phosphorescent Tris-cyclometalated Pt(IV) Complexes with Mesoionic N-Heterocyclic Carbene and 2-Arylpyridine Ligands

2022

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The synthesis, structure, photophysical properties, and electrochemistry of the first series of Pt(IV) tris-chelates bearing cyclometalated aryl-NHC ligands are reported. The complexes have the general formula [Pt(trz) 2 (C∧N)] + , combining two units of the cyclometalated, mesoionic aryl-NHC ligand 4-butyl-3-methyl-1-phenyl-1 H -1,2,3-triazol-5-ylidene (trz) with a cyclometalated 2-arylpyridine [C∧N = 2-(2,4-difluorophenyl)pyridine (dfppy), 2-phenylpyridine (ppy), 2-( p -tolyl)pyridine (tpy), 2-(2-thienyl)pyridine (thpy), 2-(9,9-dimethylfluoren-2-yl)pyridine (flpy)], and presenting a mer arrangement or metalated aryls. They exhibit a significant photostability under UV irradiation and long-lived phosphorescence in the blue to yellow color range, arising from 3 LC excited states involving the C∧N ligands, with quantum yields of up to 0.34 in fluid solution and 0.77 in the rigid matrix at 298 K. The time-dependent density functional theory (TD-DFT) calculations reveal that nonemissive, deactivating excited states of ligand-to-metal charge-transfer (LMCT) character are pushed to high energies as a consequence of the strong σ-donating ability of the carbenic moieties, making the Pt(trz) 2 subunit an essential structural component that enables efficient emissions from the chromophoric C∧N ligands, with potential application for the development of different Pt(IV) emitters with tunable properties.

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“…On the other hand, two elementary reactions, oxidative addition and reductive elimination, are very important because of their major role in many catalytic processes. − These reactions have been the subject of many studies, and organoplatinum(II) and -(IV) complexes have been used to investigate their chemistry in detail. − Most organoplatinum complexes used in this regard include N-donor (such as 2,2′-bipyridine) or cyclometalated (such as 2-phenylpyridinate) chelate ligands. − These organoplatinum(II) complexes having N^N or C^N ligands are highly reactive toward oxidative addition reactions, which typically proceed by an S N 2 mechanism, as has been confirmed experimentally − and computationally. − In contrast to many reports on the oxidative addition and reductive elimination of organoplatinum complexes bearing N^N or C^N chelate ligands, few studies have been reported on the reactivity of bis-NHC platinum complexes. ,− Bis-NHC chelate complexes of dimethylplatinum are rare. Jamali and co-workers prepared the complex [PtMe 2 (bis-NHC)] by the reaction of [PtMe 2 (μ-SMe 2 )] 2 with 1,1′-methylene-3,3′-bis[( N -( tert -butyl)imidazol-2-diylidene] in the presence of Ag 2 O .…”

Section: Introductionmentioning

confidence: 99%

Selectivity in Competitive C_sp²–C_sp³ versus C_sp³–C_sp³ Reductive Eliminations at Pt(IV) Complexes: Experimental and Computational Approaches

et al. 2021

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Three classes of Pt(II) complexes of the types [PtMe 2 (NHC)] (NHC = 1,1′-dimethyl-3,3′-methylenediimidazolin-2,2′-diylidene), [PtMe 2 (N^N)] (N^N = 2,2′-bipyridine, 1,10phenanthroline), and [PtMe(C^N)(SMe 2 )] (C^N = 2-phenylpyridinate, benzo[h]quinolinate), with a systematic variation in the chelating ligand, were chosen to investigate the oxidative addition of Pt(II) complexes with acetyl halides and the ensuing C−C reductive elimination from the corresponding Pt(IV) complexes.In accordance with the nature of the chelating ligand, the following conclusions can be ascertained: (i) in the reaction of [PtMe 2 (NHC)] complex 1a with acetyl halides, the order of the energy barriers (kcal/mol) for C−X bond activation is computed as Cl (24.4) ≈ Br (23.7) ≈ I (23.6), which are in a narrow range, showing no significant halide effect; (ii) while the energy barriers for oxidative addition of acetyl halides to complex 1a are almost the same, the C sp 3 −C sp 2 (CH 3 −COMe) reductive elimination barriers from [PtMe 2 (NHC)(MeCO)X] for X = Cl, Br, I are 23.5, 16.3, and 10.3 kcal/mol, respectively (lower than the acetyl halide oxidative addition to [PtMe 2 (NHC)]), suggesting that, when X = I, the Pt(IV) complex is more prone to undergo reductive elimination in comparison to the related Cl and Br analogues; (iii) the NHC Pt(IV) complexes selectively form C sp 3 −C sp 2 bonds instead of C sp 3 −C sp 3 bonds in reductive elimination; (iv) while NHC Pt(IV) complexes undergo a C−C reductive elimination process, the C−C coupling reaction is quite difficult for [PtCl(COMe)Me 2 (N^N)] complexes because of the high energy barrier found for C−C bond formation versus C−Cl oxidative addition; (v) similarly to NHC Pt(IV) complexes, the cycloplatinated (IV) complexes [PtCl(COMe)Me(C^N)(SMe 2 )] readily undergo C−C bond formation with reductive elimination.

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Synthesis, structures and cytotoxic effects in vitro of cis- and trans-[Pt^IVCl₄(NHC)₂] complexes and their Pt^II precursors

Abstract: PhICl2 oxidises cis-/trans-[PtIICl2(NHC)2] complexes to stable, cancer-selective, cytotoxic cis-/trans-[PtIVCl4(NHC)2] complexes while H2O2 or NaOCl give [PtIVCl4−n(OH)n(NHC)2] complexes that decompose.

Cited by 18 publications

References 31 publications

Inhibition of Type IV Secretion Activity and Growth of Helicobacter pylori by Cisplatin and Other Platinum Complexes

Inhibition of Type IV Secretion Activity and Growth of Helicobacter pylori by Cisplatin and Other Platinum Complexes

Phosphorescent Tris-cyclometalated Pt(IV) Complexes with Mesoionic N-Heterocyclic Carbene and 2-Arylpyridine Ligands

Selectivity in Competitive C_sp²–C_sp³ versus C_sp³–C_sp³ Reductive Eliminations at Pt(IV) Complexes: Experimental and Computational Approaches

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Synthesis, structures and cytotoxic effects in vitro of cis- and trans-[PtIVCl4(NHC)2] complexes and their PtII precursors

Abstract: PhICl2 oxidises cis-/trans-[PtIICl2(NHC)2] complexes to stable, cancer-selective, cytotoxic cis-/trans-[PtIVCl4(NHC)2] complexes while H2O2 or NaOCl give [PtIVCl4−n(OH)n(NHC)2] complexes that decompose.

Cited by 18 publications

References 31 publications

Inhibition of Type IV Secretion Activity and Growth of Helicobacter pylori by Cisplatin and Other Platinum Complexes

Inhibition of Type IV Secretion Activity and Growth of Helicobacter pylori by Cisplatin and Other Platinum Complexes

Phosphorescent Tris-cyclometalated Pt(IV) Complexes with Mesoionic N-Heterocyclic Carbene and 2-Arylpyridine Ligands

Selectivity in Competitive Csp2–Csp3 versus Csp3–Csp3 Reductive Eliminations at Pt(IV) Complexes: Experimental and Computational Approaches

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Synthesis, structures and cytotoxic effects in vitro of cis- and trans-[Pt^IVCl₄(NHC)₂] complexes and their Pt^II precursors

Selectivity in Competitive C_sp²–C_sp³ versus C_sp³–C_sp³ Reductive Eliminations at Pt(IV) Complexes: Experimental and Computational Approaches