Platinum(II) complexes with tris(2-carboxyethyl)phosphine, X-ray structure and reactions with polar solvents and glutathione

Pruchnik, Hanna; Lis, Tadeusz; Pruchnik, Florian P.

doi:10.1016/j.jorganchem.2015.05.050

Cited by 14 publications

(19 citation statements)

References 31 publications

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“…Furthermore, the TCEP phosphine has been shown to increase the binding of cisplatin to a Sp1 zinc finger protein (34). We speculate that the phosphine facilitates substitution of the ammine ligand in the trans position (35) and binding of Pt(II) to ⌬⌬Ihh-SIC (supplemental Fig. S4).…”

Section: Discussionmentioning

confidence: 91%

Exploring Intein Inhibition by Platinum Compounds as an Antimicrobial Strategy

Chan

Pearson

Green

et al. 2016

Journal of Biological Chemistry

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Inteins, self-splicing protein elements, interrupt genes and proteins in many microbes, including the human pathogen Mycobacterium tuberculosis. Using conserved catalytic nucleophiles at their N-and C-terminal splice junctions, inteins are able to excise out of precursor polypeptides. The splicing of the intein in the mycobacterial recombinase RecA is specifically inhibited by the widely used cancer therapeutic cisplatin, cis-[Pt(NH 3 ) 2 Cl 2 ], and this compound inhibits mycobacterial growth. Mass spectrometric and crystallographic studies of Pt(II) binding to the RecA intein revealed a complex in which two platinum atoms bind at N-and C-terminal catalytic cysteine residues. Kinetic analyses of NMR spectroscopic data support a two-step binding mechanism in which a Pt(II) first rapidly interacts reversibly at the N terminus followed by a slower, first order irreversible binding event involving both the N and C termini. Notably, the ligands of Pt(II) compounds that are required for chemotherapeutic efficacy and toxicity are no longer bound to the metal atom in the intein adduct. The lack of ammine ligands and need for phosphine represent a springboard for future design of platinum-based compounds targeting inteins. Because the intein splicing mechanism is conserved across a range of pathogenic microbes, developing these drugs could lead to novel, broad range antimicrobial agents.Inteins, self-splicing protein elements that invade a host gene, have been of great interest to the field of biotechnology. The unique ability of an intein to break and form peptide linkages has led to their use in applications (1, 2) ranging from sensors of small molecules (3, 4) and environmental conditions (5) to single step protein purification platforms (6, 7). However, there are still underexplored reactions involving native inteins, notably their susceptibility as targets for antimicrobial drugs (8). In nature, inteins reside in key host proteins across several bacterial and fungal pathogens, including Mycobacterium tuberculosis, Mycobacterium leprae, and Cryptococcus neoformans (9).These splicing elements divide the host protein into two parts, termed N-and C-exteins on the corresponding ends of the intein. In the precursor form, the host protein is usually non-functional because of the tendency of an intein to insert into highly conserved functional regions of the protein. In M. tuberculosis, inteins occur in three genes, recA, sufB, and dnaB (9). The functionality of these proteins is key to the survival of the bacterium and relies upon the splicing of the intein from the respective host proteins. Because inteins do not occur in multicellular organisms, prevention of protein splicing provides a promising strategy for the development of novel antimicrobial therapeutics.Canonical intein splicing occurs by a multistep process (10). First, a nucleophilic attack is initiated by the N-terminal cysteine residue (C1) of the intein on the preceding peptide bond, resulting in thioester formation (Fig. 1A, step 1). A second nucleophilic a...

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Section: Discussionmentioning

confidence: 91%

Exploring Intein Inhibition by Platinum Compounds as an Antimicrobial Strategy

Chan

Pearson

Green

et al. 2016

Journal of Biological Chemistry

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“…This effort seems to be worth making due to high anticancer potential of this class of drugs and the resistance and strong side-effects of existing platinum-based agents. Recently, a new platinum-based compounds containing a phosphine ligand tris(2-carboxyethyl)phosphine [P(CH 2 CH 2 COOH) 3 ] (TCEP) instead of ammonia group and two chlorine atoms in cis and in trans conformation with potential anticancer activity has been introduced (16). TCEP is a fast and strong sulphhydryl reducing agent cleaving disulfide linkage in proteins, peptides and other compounds containing S-S bond (16,17).…”

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confidence: 99%

“…Recently, a new platinum-based compounds containing a phosphine ligand tris(2-carboxyethyl)phosphine [P(CH 2 CH 2 COOH) 3 ] (TCEP) instead of ammonia group and two chlorine atoms in cis and in trans conformation with potential anticancer activity has been introduced (16). TCEP is a fast and strong sulphhydryl reducing agent cleaving disulfide linkage in proteins, peptides and other compounds containing S-S bond (16,17). Since 1991, when a direct and convenient method of TCEP synthesis was manufactured (17), it has been commercially available and widely used in biochemistry as a reducing agent to mimic natural, reducing environment, so that sulphhydryl groups of proteins, including enzymes, could remain in their reduced form and preserve their activity in solutions (18).…”

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confidence: 99%

Complex of Platinum(II) with Tris(2-carboxyethyl)phosphine Induces Apoptosis in Canine Lymphoma/Leukemia Cell Lines

Henklewska

Pawlak

Pruchnik

et al. 2017

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“…The Pt‐TCEP ( cis ‐[PtCl 2 (TCEP) 2 ]) was prepared at the Faculty of Chemistry at the University of Wroclaw . CDDP ( cis ‐[PtCl 2 (NH 3 ) 2 ]), FBS, l ‐glutamine, penicillin and streptomycin solution, 0.25% trypsin‐EDTA, trypan blue, poly‐ l ‐lysine, ribonuclease A, propidium iodide (PI), RIPA buffer, SigmaFAST Protease Inhibitor Cocktail and TBST buffer were purchased from Sigma‐Aldrich (Steinheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Nevertheless, none of them have been tested against cancers commonly occurring in dogs. A new platinum‐based compound containing a phosphine ligand‐tris(2‐carboxyethyl)phosphine (P[CH 2 CH 2 COOH] 3 ) (Pt‐TCEP) was shown to have structural properties and biochemical reactivity, suggesting that it can have anticancer activity . Also, studies on the interaction of Pt‐TCEP with plasmid DNA revealed that it has a stronger folding effect than cisplatin.…”

Section: Introductionmentioning

confidence: 99%

In vitro effects of the activity of novel platinum (II) complex in canine and human cell lines

Henklewska

Pawlak

Kutkowska

et al. 2019

Vet Comparative Oncology

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The anticancer activity of novel platinum derivative, a complex of platinum with tris (2-carboxyethyl)phosphine (Pt-TCEP), has been evaluated in canine (D-17) and human osteosarcoma (U2-OS) cell lines. Viability of cells after incubation for 24 or 72 hours with increasing concentrations (0.625, 1.25, 2.50, 5, 10 and 20 μM) of Pt-TCEP was tested in an MTT assay and compared to effect of cisplatin. Longer-term effect of Pt-TCEP was evaluated in the colony-forming unit assay after 24 hours exposure to the Pt-TCEP (2 and 3 μM) and subsequent incubation for 2 weeks. The influence of the compound on the cell cycle was measured after 24 hours treatment with Pt-TCEP (3 μM). Its pro-apoptotic activity was examined after 24 hours treatment with Pt-TCEP (1.25, 2.50, 5, 10 and 20 μM) using flow cytometry. Expression of main proteins involved in apoptosis was measured after exposure for 24 hours to 3 or 5 μM Pt-TCEP in Western Blot. The compound much more effectively decreased cell viability than cisplatin in case of both cell lines. IC 50 of Pt-TCEP was 5.93 ± 0.12 in D-17 and 3.45 ± 0.14 in U2-OS cell lines after 24 hours, and 1.77 ± 0.14 in D-17 and 1.53 ± 0.11 in U2-OS after 72 hours (P < .05). The compound arrested cells in the G2/M phase and inhibited the ability of cells to form colonies. Pt-TCEP induced caspase-dependent apoptosis. The expression of the anti-apoptotic Bcl-X L protein was decreased after Pt-TCEP treatment in both cell lines. The results confirmed anticancer activity of Pt-TCEP against canine and human osteosarcoma cell lines. K E Y W O R D S anticancer activity, comparative oncology, osteosarcoma cell lines, platinum complex

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Platinum(II) complexes with tris(2-carboxyethyl)phosphine, X-ray structure and reactions with polar solvents and glutathione

Cited by 14 publications

References 31 publications

Exploring Intein Inhibition by Platinum Compounds as an Antimicrobial Strategy

Exploring Intein Inhibition by Platinum Compounds as an Antimicrobial Strategy

Complex of Platinum(II) with Tris(2-carboxyethyl)phosphine Induces Apoptosis in Canine Lymphoma/Leukemia Cell Lines

In vitro effects of the activity of novel platinum (II) complex in canine and human cell lines

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