14096-51-6Relevant articles and documents
The Influence of the Axial Ligands of a Series of Platinum(IV) Anti-Cancer Complexes on their Reduction to Platinum(II) and Reaction with DNA
Ellis, Leanne T.,Er, Hui Meng,Hambley, Trevor W.
, p. 793 - 806 (1995)
The electrochemical reduction and DNA binding have been studied for a series of platinum(IV) complexes with Cl(-), OH(-), and carboxylate anions as the axial ligands; , , and , R = CH3, CH2CH3, CH2CH2CH3.Cathodic reduction potentials vary by more than 650 mV with the tetrachloro complex reduced most readily and the dihydroxo least readily.The binding of the complexes correlates with the reduction potentials with the more readily reduced complexes binding more readily to DNA.The influence of the reducing agent glutathione on platinum binding to DNA was found to depend on whether it was added before or after Pt/DNA incubation.The results are consistent with octahedral platinum(IV) binding monofunctionally to DNA, and molecular modelling studies have been used to confirm that this is sterically feasible.The crystal structure of has been determined by X-ray diffraction methods and refined to R = 0.028 (977 F).The crystals are monoclinic, space group C 2/c, a 15.569(6), b 8.104(1), c 13.188(1) Angstroem, β 136.38(2) deg.
Influence of equatorial and axial carboxylato ligands on the kinetic inertness of platinum(IV) complexes in the presence of ascorbate and cysteine and within dld-1 cancer cells
Chen, Catherine K. J.,Zhang, Jenny Z.,Aitken, Jade B.,Hambley, Trevor W.
, p. 8757 - 8764 (2013)
The rapid and premature reduction of platinum(IV) complexes in vivo is a significant impediment to these complexes being successfully employed as anticancer prodrugs. This study investigates the influence of the platinum(IV) coordination sphere on the ease of reduction of the platinum center in various biological contexts. In the presence of the biological reductants, ascorbate and cysteine, platinum(IV) complexes with dicarboxylato equatorial ligands were observed to exhibit lower reduction potentials and slower reduction rates than analogous platinum(IV) complexes with dichlorido equatorial ligands. Diaminetetracarboxylatoplatinum(IV) complexes exhibited unusually long half-lives in the presence of excess reductants; however, the complexes exhibited moderate potency in vitro, indicative of rapid reduction within the intracellular environment. By use of XANES spectroscopy, trans-[Pt(OAc) 2(ox)(en)] and trans-[PtCl2(OAc)2(en)] were observed to be reduced at a similar rate within DLD-1 cancer cells. This large variability in kinetic inertness of diaminetetracarboxylatoplatinum(IV) complexes in different biological contexts has significant implications for the design of platinum(IV) prodrugs.
Trend in cytotoxic activity of a series of cis-[APtCl2] (A = ethylenediamine methylated at different positions) complexes
Milanesio, Marco,Monti, Elena,Gariboldi, Marzia Bruna,Gabano, Elisabetta,Ravera, Mauro,Osella, Domenico
, p. 2803 - 2814 (2008)
The study of a series of cis-[APtCl2] complexes (A = ethylenediamine, en, methylated at different positions) was carried out to evaluate the effect of different methyl substitutions on the cytotoxic properties of the resulting derivatives. As expected, differentially methylated complexes were found to differ widely in their cytotoxic effects on human cultured ovarian carcinoma cells (A2780). Molecular mechanics (MM) calculations have been performed to assess the relationship between differential diamine methylation and the repulsive energy of the corresponding complexes when interacting with DNA. Compounds that bind DNA at high energetic cost relative to cisplatin, due to the steric hindrance of additional methyl groups, have shown high values for IC50 (concentration inhibiting tumour cell growth by 50%). Semi-quantitative analyses with a DNA electrochemical biosensor confirm that the interaction between cis-[APtCl2] complexes and ds-DNA deposed onto the electrode is stronger for the non-methylated derivative with respect to the fully methylated congener. In addition, MM calculations were used to investigate the interactions between DNA and cis-[(P-L-A)PtCl2] complexes [A = en group linked to an antiestrogen-like pharmacophore, P, via a -(CH2)n- spacer (n = 2, 4, 6, 8 and 10), L].
Synthesis of different pyrazine-bridged platinum(II) complexes and 1H NMR study of their catalytic abilities in the hydrolysis of the N-acetylated l-methionylglycine
Rajkovi?, Sne?ana,A?anin, Darko P.,?ivkovi?, Marija D.,Djuran, Milo? I.
, p. 42 - 47 (2013)
Four binuclear {[Pt(L)Cl]2(μ-pz)}Cl2-type complexes have been synthesized and characterized by elemental microanalyses and NMR (1H and 13C) spectroscopy (L is ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach and pz is bridging pyrazine ligand). The chlorido complexes were converted into the corresponding aqua species, {[Pt(L)(H2O)]2(μ-pz)}4+, and 1H NMR spectroscopy was applied to study their reactions with the N-acetylated l-methionylglycine, Ac-L-Met-Gly. The {[Pt(L)(H2O)] 2(μ-pz)}4+ complex and dipeptide were reacted in 1:1 and 1:2 M ratios, respectively, and all reactions were performed in the pH range 2.0-2.5 and at 37 C. In the reactions with equimolar amounts of the reactants all Pt(II) aqua complexes bind to the methionine side chain of Ac-L-Met-Gly dipeptide and promote the cleavage of the amide bond involving the carboxylic group of methionine. It was found that the amount of hydrolyzed dipeptide strongly depends from the steric bulk of bidentate coordinated diamine ligand L in {[Pt(L)(H2O)]2(μ-pz)}4+ complex (en > 1,2-pn > ibn > dach). However, in the reaction with an excess of dipeptide the influence of the nature of diamine ligand L on this hydrolytic process could not be observed due to the fact that slow decomposition of {[Pt(L)(H 2O)]2(μ-pz)}4+ complex was occured.
Selective Co-Encapsulation Inside an M6L4Cage
Leenders, Stefan H. A. M.,Becker, René,Kumpulainen, Tatu,de Bruin, Bas,Sawada, Tomohisa,Kato, Taito,Fujita, Makoto,Reek, Joost N. H.
, p. 15468 - 15474 (2016)
There is broad interest in molecular encapsulation as such systems can be utilized to stabilize guests, facilitate reactions inside a cavity, or give rise to energy-transfer processes in a confined space. Detailed understanding of encapsulation events is required to facilitate functional molecular encapsulation. In this contribution, it is demonstrated that Ir and Rh-Cp-type metal complexes can be encapsulated inside a self-assembled M6L4metallocage only in the presence of an aromatic compound as a second guest. The individual guests are not encapsulated, suggesting that only the pair of guests can fill the void of the cage. Hence, selective co-encapsulation is observed. This principle is demonstrated by co-encapsulation of a variety of combinations of metal complexes and aromatic guests, leading to several ternary complexes. These experiments demonstrate that the efficiency of formation of the ternary complexes depends on the individual components. Moreover, selective exchange of the components is possible, leading to formation of the most favorable complex. Besides the obvious size effect, a charge-transfer interaction may also contribute to this effect. Charge-transfer bands are clearly observed by UV/Vis spectrophotometry. A change in the oxidation potential of the encapsulated electron donor also leads to a shift in the charge-transfer energy bands. As expected, metal complexes with a higher oxidation potential give rise to a higher charge-transfer energy and a larger hypsochromic shift in the UV/Vis spectrum. These subtle energy differences may potentially be used to control the binding and reactivity of the complexes bound in a confined space.
Nucleolar Stress Induction by Oxaliplatin and Derivatives
Sutton, Emily C.,Mcdevitt, Christine E.,Prochnau, Jack Y.,Yglesias, Matthew V.,Mroz, Austin M.,Yang, Min Chieh,Cunningham, Rachael M.,Hendon, Christopher H.,Derose, Victoria J.
, p. 18411 - 18415 (2019)
Platinum(II) compounds are a critical class of chemotherapeutic agents. Recent studies have highlighted the ability of a subset of Pt(II) compounds, including oxaliplatin but not cisplatin, to induce cytotoxicity via nucleolar stress rather than a canonical DNA damage response. In this study, influential properties of Pt(II) compounds were investigated using redistribution of nucleophosmin (NPM1) as a marker of nucleolar stress. NPM1 assays were coupled to calculated and measured properties such as compound size and hydrophobicity. The oxalate leaving group of oxaliplatin is not required for NPM1 redistribution. Interestingly, although changes in diaminocyclohexane (DACH) ligand ring size and aromaticity can be tolerated, ring orientation appears important for stress induction. The specificity of ligand requirements provides insight into the striking ability of only certain Pt(II) compounds to activate nucleolar processes.
Synthesis, characterization, cytotoxic activity, and 19F NMR spectroscopic investigations of (OC-6-33)-diacetato(ethane-1,2-diamine)bis(3,3,3-trifluoropropanoato)platinum(IV) and its platinum(II) counterpart
H?fer, Doris,Cseh, Klaudia,Hejl, Michaela,Roller, Alexander,Jakupec, Michael A.,Galanski, Markus,Keppler, Bernhard K.
, p. 190 - 199 (2019)
Tetracarboxylatoplatinum(IV) complexes are interesting representatives of potential anticancer active platinum(IV) drugs. Revealing higher kinetic inertness in comparison to their cytotoxic platinum(II) counterparts, they offer an opportunity to reduce toxic and deactivating side reactions. Platinum(IV) complexes are generally considered as prodrugs, which have to be reduced in order to exert their anticancer activity. Two model complexes, a platinum(II) and platinum(IV) complex featuring two equatorial 3,3,3-trifluoropropanoato (tfpa) and in the case of the latter two axial acetato ligands, were synthesized and characterized in detail by multinuclear (1H, 13C, 15N, 19F, 195Pt) one- and two-dimensional NMR spectroscopy, high-resolution electrospray ionization mass spectrometry, elemental analysis and X-ray diffraction analysis. Cytotoxicity was evaluated in three human cancer cell lines (A549, SW480 and CH1/PA-1) by the MTT colorimetric assay, exhibiting IC50 values down to the low micromolar range. The fluorinated ligands in equatorial positions allowed detailed and highly sensitive 19F NMR spectroscopic investigations. Besides reaction studies in the presence of small molecules, e.g. ascorbic acid and 5′-GMP, the reduction of the platinum(IV) complex was additionally investigated in two cancer cell extracts deriving from the cell lines SW480 and CH1/PA-1 in order to estimate the intracellular reduction behavior. A significant increase in the rate of reduction in cell extracts (depending on the chosen cell line) compared to the reduction with ascorbic acid could be demonstrated.
pH and thermo dual stimulus-responsive liposome nanoparticles for targeted delivery of platinum-acridine hybrid agent
Zhou, Qian,You, Chaoqun,Ling, Yang,Wu, Hongshuai,Sun, Baiwang
, p. 41 - 48 (2019)
The complexes of the type [PtCl(L2)(ACRAMTU)](NO3)2 (ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) were synthesized: PT-ACRAMTU (1), L2 = ethane-1,2-diamine (en); PT(dach)-ACRAMTU (2), L2 = (1R,2R)-1,2-diaminocyclohexane (dach); PT(pda-OH)-ACRAMTU (3), L2 = 2-hydroxy-1,3-propanediamine (pda-OH). The complexes containing diverse diamines exhibit different DNA binding capacity and cytotoxicity. Complex 3 shows excellent capability not only on the strongest non-cisplatin-type DNA damage, but also superior anticancer activity in NCI-H460 cells (IC50 = 0.23 ± 0.05 μM). For overcoming water insolubly and side effects, we encapsulated complex 3 into liposomes. PT@NPs were characterized in terms of particle size, morphology, drug loading capacity (DLC), encapsulation efficiency (EE) and stability. In vitro triggered release showed that the release of the platinum drug was steerable and the release rate was fast under low pH ( Tm = 41 °C). PT@NPs showed significant inhibitory effect in NCI-H460 cells. Flow cytometry analysis indicates G0/G1 phase arrest of cells treated with complex 3, whereas cells treated with cisplatin progress to G2/M of the cell cycle. The mechanistic differences validate that complex 3 is a potent anticancer agent superior than current clinical platinum-based therapies. PT@NPs have the potential in drug delivery systems (DDS) for non-small cell lung cancer (NSCLC) therapy.
Diaminehalogenoplatinum(II) complex reactions with DMSO
Josephsen, Jens
, p. 54 - 58 (2018)
The platinum(II) complexes [Pt(N-N)X2] (X = Cl, Br, and I; (N-N) = 1,2-ethanediamine (en) and 1,3-propanediamine (tn)) have been synthesised; their reactions with DMSO in DMSO to substitute halogenide were followed using changing integrals of NMR-spectroscopic signals. The rate constant for [PtenCl2] was found to be 1.0*10?4 s?1 at 300 K and from kinetic runs at different temperatures the energy of activation was estimated as 82 kJ*mol?1 in this case. The rate constant depends on the size of halogenide and was found to be forty times larger for [PtenI2] than for its dichloro-analogue. In the tn-series reactions were a little faster than in the en-series. For all six [Pt(N-N)X2] complexes the solvolysis stopped at the coordination of one DMSO and the six new [Pt(N-N)DMSOX]X were isolated and characterised. Further the [PtenDMSOCl]+ was isolated as its nitrate and perchlorate. DMSO exchange reactions (in DMSO) of [PtenDMSOX]+ were found to be slightly slower than the solvolysis reactions, iodide again giving rise to the most labile system. Ion pair formation in DMSO was found to be modest to almost negligible with a formation constant of 30 M?1 in the case of [PtenDMSOCl]Cl as the largest.
Distribution of Halogen Atoms in Mixed-Valence Linear-Chain Complexes of Platinum: A Solid-State (15)N NMR Study
Austin, Elliot J. W.,Barrie, Patrick J.,Clark, Robin J. H.
, p. 3859 - 3863 (1995)
High-resolution solid-state (15)N NMR spectroscopy is used to demonstrate unambiguously the presence of Cl-Pt(IV)-Br units in [Pt(en)2][Pt(en)2Cl(2-2x)Br2x](ClO4)4 complexes (0 a measure of the bromine concentration in the chain to be made.It is demonstrated that the halogen distribution is fairly close, but not identical, to random about this site. This suggests that the overall distribution of halogen atoms throughout the mixed-valence chain can be treated as being virtually random.
