- In vitro and in vivoactivity of series of cationic dinuclearPt(II) complexes
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The antitumour potential of nine dinuclear platinum(II) complexes of the type [{Pt(L)Cl}2(μ-X)]2+(where L represents two NH3 or different bidentantly coordinated diamine ligand - ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2-dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd; (±)-1,3-pentanediamine,1,3-pnd, and X is a bridging pyrazine (pz) or pyridazine (pydz) ligand) were determined by in vitro and in vivo assays using the CT26 cell line and a murine model of heterotopic colon cancer tumour induced in immunocompetent BALB/c mice. This study concludes that complexes Pt1, Pt2 and Pt7 possess significant in vitro cytotoxic activity against mouse colon carcinoma CT26 cells, while all these complexes show moderate apoptotic effect. Complexes Pt1 and Pt7 arrested CT26 cells in G2/M phase of cell cycle, while, evaluated by detection of Ki67 expressing cells, complexes Pt5 and Pt6 exerted the highest antiproliferative effect. Complexes Pt1 and Pt2 exerted significant in vivo antitumour effects. These complexes reduced the growth of primary tumour and the incidence of lung and liver metastases without causing the significant hepato- and nephro- toxicity. Our data indicate considerable antitumour activity of platinum(II) complexes against CT26 cells in vitro and in vivo and imply possible further investigations on their role as potential chemotherapeutic agents.
- Vasi?, Ivana,Rajkovi?, Sne?ana,Arsenijevi?, Aleksandar,Milovanovi?, Marija,Arsenijevi?, Neboj?a,Milovanovi?, Jelena,?ivkovi?, Marija D.
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- One-Pot Synthesis of New Organometallic Compounds with Platinum-Carbon Bond
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Organometallic compounds of platinum containing ortho metalated para-nitro-benzamidate or 1-naphthalene-methylamine have been prepared by one-pot synthesis. The para-nitro-benzamidate [Pt{K2C,N-pNO2-C6H4C(O)NH}(R,R-DACH)] (compound 2) was obtained starting from [PtCl2(R,R-DACH)] and para-nitro-benzonitrile, which, in the reaction conditions, hydrolyzes to the corresponding amide and forms the dinuclear intermediate [Pt2{μ-N,O-pNO2-C6H4C(O)NH}2(R,R-DACH)2]SO4 (compound 1·SO4) with HH or HT arrangement of the two bridging amidato ligands. Compound 1·SO4, kept at 90 °C for few hours, transforms into 2. The ortho-metalated PtII derivative with 1-naphthalene-methylamine [PtCl{K2C,N-C10H6CH2NH2}(DMSO)] (3) was obtained by direct reaction of [PtCl2(DMSO)2] with the amine. Unlike compound 2 that has no labile ligands, compound 3 has Cl and DMSO ligands that can be released, allowing the formation of cross-links with DNA. Oxidation of 3 to the PtIV counterpart was performed with PhICl2 (compound 4). Unexpectedly, although six-coordinate complexes of PtIV are considered to be inert, 4 underwent spontaneous isomerization from the mer to the fac isomer. All compounds have been fully characterized by multinuclear NMR spectroscopy, which has enabled complete assignment of all proton resonances. In the case of compound 2, a single-crystal X-ray investigation was also performed, showing, with the only exception of the puckered cyclohexane ring, a complete planarity of the complex frame, which could favor an intercalative interaction with DNA.
- Barbanente, Alessandra,Intini, Francesco P.,Margiotta, Nicola,Natile, Giovanni,Pacifico, Concetta
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- Synthesis, cytotoxic activity and DNA interaction studies of new dinuclear platinum(ii) complexes with an aromatic 1,5-naphthyridine bridging ligand: DNA binding mode of polynuclear platinum(ii) complexes in relation to the complex structure
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The synthesis, spectroscopic characterization, cytotoxic activity and DNA binding evaluation of seven new dinuclear platinum(ii) complexes Pt1-Pt7, with the general formula [{Pt(L)Cl}2(μ-1,5-nphe)](ClO4)2 (1,5-nphe is 1,5-naphthyridine; while L is two ammines (Pt1) or one bidentate coordinated diamine: ethylenediamine (Pt2), (±)-1,2-propylenediamine (Pt3), trans-(±)-1,2-diaminocyclohexane (Pt4), 1,3-propylenediamine (Pt5), 2,2-dimethyl-1,3-propylenediamine (Pt6), and 1,3-pentanediamine (Pt7)), were reported. In vitro cytotoxic activity of these complexes was evaluated against three tumor cell lines, murine colon carcinoma (CT26), murine mammary carcinoma (4T1) and murine lung cancer (LLC1) and two normal cell lines, murine mesenchymal stem cells (MSC) and human fibroblast (MRC-5) cells. The results of the MTT assay indicate that all investigated complexes have almost no cytotoxic effects on 4T1 and very low cytotoxicity toward LLC1 cell lines. In contrast to the effects on LLC1 and 4T1 cells, complexes Pt1 and Pt2 had significant cytotoxic activity toward CT26 cells. Complex Pt1 had a much lower IC50 value for activity on CT26 cells compared with cisplatin. In comparison with cisplatin, all dinuclear Pt1-Pt7 complexes showed lower cytotoxicity toward normal MSC and MRC-5 cells. In order to measure the amount of platinum(ii) complexes taken up by the cells, we quantified the cellular platinum content using inductively coupled plasma mass spectrometry (ICP-QMS). Molecular docking studies performed to evaluate the potential binding mode of dinuclear platinum(ii) complexes Pt1-Pt7 and their aqua derivatives W1-W7, respectively, at the double stranded DNA showed that groove spanning and backbone tracking are the most stable binding modes.
- Konovalov, Bata,?ivkovi?, Marija D.,Milovanovi?, Jelena Z.,Djordjevi?, Dragana B.,Arsenijevi?, Aleksandar N.,Vasi?, Ivana R.,Janji?, Goran V.,Franich, Andjela,Manojlovi?, Dragan,Skrivanj, Sandra,Milovanovi?, Marija Z.,Djuran, Milo? I.,Rajkovi?, Sne?ana
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p. 15091 - 15102
(2018/11/10)
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- Chlorido and bromido oxaliplatin analogues as potential agents for CRC treatment: Solution behavior, protein binding and cytotoxicity evaluation
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Despite the widespread use of platinum drugs in the treatment of colorectal cancer (CRC), due to the heavy side effects and to intrinsic or acquired Pt resistance, new and more efficient drugs are urgently needed. Starting from the encouraging results obt
- Marzo, Tiziano,Pratesi, Alessandro,Cirri, Damiano,Pillozzi, Serena,Petroni, Giulia,Guerri, Annalisa,Arcangeli, Annarosa,Messori, Luigi,Gabbiani, Chiara
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p. 318 - 324
(2017/09/30)
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- Synthetic method of oxaliplatin
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The invention discloses a synthetic method of oxaliplatin. The synthetic method comprises the following steps: firstly, taking potassium chloroplatinite and (1R,2R)-1,2-cyclohexanediamine, putting the substances into water, keeping a mixed solution in dark place and reacting the mixed solution under the conditions that the temperature is 35 to 45 DEG C and microwave is 200 to 500W to obtain cis-dichloro(1R,2R)-1,2-cyclohexanediamineplatinum; secondly, dissolving a product obtained in the first step into water, adding silver sulfate, keeping a mixed solution in the dark place, stirring the mixed solution under the conditions that the temperature is 35 to 50 DEG C and microwave is 200 to 400W and then filtering; thirdly, taking filtrate in the second step, adding tetraethylammonium lodide and activated carbon, stirring and filtering; fourthly, taking filtrate in the third step, first adding oxalic acid and Ba(OH)2.8H2O in the stirring process, stirring for 2 to 3 hours under the condition of keeping in the dark place, filtering, and evaporating and refining the filtrate to obtain the oxaliplatin. By using microwave reaction conditions, the efficiency is improved, reaction time is shortened, production period is shortened, and the production cost is reduced; the purity and the yield of a product are higher.
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Paragraph 0011; 0017; 0022; 0027
(2017/08/31)
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- Analysis of montmorillonite clay as a vehicle in platinum anticancer drug delivery
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As a proof-of-concept study, the platinum anticancer complex [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]chloride, PHENSS, was loaded into montmorillonite (MMT) clay to evaluate its utility as a drug delivery vehicle. Loading is complete within one hour and the total amount of PHENSS that can be loaded into the clay is based on the PHENSS solution concentration in which the MMT is suspended. From a PHENSS solution concentration of 30 mM, a maximum loading of 0.257 mmol per gram of MMT can be achieved. The pH of the solution also has an effect with a solution pH of 6 giving maximum loading of PHENSS. Metal complex release from the MMT was examined using the dialysis bag and dispersion methods. PHENSS is incompletely released from MMT; after 4 h just 47% has been released from the clay using the dialysis method and 30% using the dispersion method. The release is also very fast with a half-life of just 10-16 min. The MMT was shown to have a negative effect on the in vitro cytotoxicity of PHENSS in the human breast cancer cell lines MCF-7 and MDA-MB-231, presumably due to the incomplete release of the metal complex from the clay. Overall the results demonstrate that MMT is not a suitable slow release vehicle for PHENSS, although it may still be of use to other platinum complexes and drugs.
- Apps, Michael G.,Ammit, Alaina J.,Gu, Alice,Wheate, Nial J.
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p. 513 - 518
(2014/08/18)
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- Design, synthesis and in-vitro cytotoxicity of novel platinum (II) complexes with phthalate as the leaving group
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Three platinum (II) complexes (6-8) with phthalate as the leaving group were synthesized and characterized by FTIR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis. In-vitro cytotoxicity of all three complexes was evaluated using COLO 205 (human colon cancer cell line) against the parent drug "oxaliplatin". The compound 4-amino-(transcyclohexane-1,2-diamine) platinum(II) (8) showed potent cytotoxicity with IC50 = 0.12 μM as compared to oxaliplatin (IC50 = 0.19 μM) and its aqueous solubility was found to be 16 mg/mL which is higher than oxaliplatin (8 mg/mL). The acute toxicity showed that the platinum complex (8) was less toxic than oxaliplatin. Molecular oxaliplatin-DNA complex structure indicates that the diaminocyclohexane (DACH) and Pt (II) showed interactions with N7 and O6 of GG base pairs of DNA helix. In this present study, it is interesting to note that all three platinum based anticancer agents with phthalate as the leaving group exhibited great cytotoxicity, less toxicity, good lipophilicity as well as better aqueous solubility. 2013 Bentham Science Publishers.
- Sharma, Rajiv,Rawal, Ravindra K.,Malhotra, Manav,Gaba, Tripti,Sharma,Bhardwaj
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p. 872 - 878
(2013/12/04)
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- Reduction of some Pt(iv) complexes with biologically important sulfur-donor ligands
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The reduction of the Pt(iv) complexes [PtCl4(bipy)], [PtCl 4(dach)] and [PtCl4(en)] by glutathione (GSH), l-cysteine (l-Cys) and l-methionine (l-Met) was investigated by stopped-flow spectrophotometry at pH 2.0 (in 0.01 M perchloric acid) and at pH 7.2 (in 25 mM Hepes buffer). Kinetic measurements were performed under pseudo-first order conditions with an excess of the reducing agent. The order of the reactivity of the studied complexes was [PtCl4(bipy)] > [PtCl4(dach)] > [PtCl4(en)], and reactivity of investigated reducing agents followed the order GSH > l-Cys > l-Met. All the reactions between the selected Pt(iv) complexes and the sulfur donor biomolecules proceeded by a reductive elimination process that included nucleophilic attack by the reducing agent on one of the mutually trans-coordinated chloride ligands, which led to a two-electron transfer process. The final products of the redox reactions were the corresponding reduced Pt(ii) complexes and the oxidized form of the reducing agents.
- Jovanovi?, Sne?ana,Petrovi?, Biljana,Bugar?i?, ?ivadin D.,Van Eldik, Rudi
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supporting information
p. 8890 - 8896
(2013/07/27)
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- Thermal degradation characteristics of selected organoplatinum antitumor agents
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The thermal decomposition characteristics of representatives of three classes of organoplatinum compounds have been examined by thermogravimetry. Substituted salicylato (1, 2-diaminocyclohexane)platinum(II) compounds undergo thermal decomposition by sequential loss of first the salicylato ligand and then the amine ligand to afford a residue corresponding to the platinum content of the compound. The thermal decomposition of N-arylsalicylaldimino(1,2-diaminocyclohexane)platinum(II) nitrate is more complex, but is also characterized by two major weight losses. Thermal decomposition of bis-(2-thiophenecarboxylato)platinum(II) is characterized by ligand fragmentation to generate a residual mass corresponding to the platinum content of the compound.
- Howell,Beholz,Sastry
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p. 395 - 403
(2008/10/08)
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- Chemical properties and antitumor activity of complexes of platinum containing substituted sulfoxides [PtCl(R′R″SO)(diamine)]NO3. Chirality and leaving group ability of sulfoxide affecting biological activity
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The preparation and antitumor activity in L1210 leukemia of a novel set of platinum complexes of formula [PtCl(R′R″SO)-(diam)]NO3 (diam = bidentate amine such as 1,2-diaminocyclohexane (dach) or 1,1-bis(aminomethyl)cyclohexane (damch) and R′R″SO = substituted sulfoxides such as dimethyl (Me2SO), methyl benzyl (MePhSO), methyl benzyl (MeBzSO), diphenyl (Ph2SO), and dibenzyl sulfoxide (Bz2SO)) is reported. The complexes are the first well-defined antitumor platinum complexes containing sulfur as ligand. The antitumor activity is dependent on both the nature of the amine and, especially the nature of the sulfoxide. In the case of asymmetric sulfoxides, such as methyl p-tolyl sulfoxide (MeTolSO), preparation of the optically pure forms shows a distinct effect of chirality of the sulfoxide ligand on the biological activity. The possible mechanisms of antitumor action are discussed. Studies on displacement of sulfoxide by Cl- and H2O show the order of lability to be Ph2SO > MePhSO > MeTolSO > Bz2SO > MeBzSO > Me2SO. The lability is also dependent on amine, with damch complexes being significantly more reactive than their dach analogues. The pseudo-first-order rate constants, which range over 2 orders of magnitude, preclude a simple loss of sulfoxide as a mechanism of antitumor activity. The complexes may act by binding to DNA with subsequent loss of sulfoxide ligand.
- Farrell, Nicholas,Kiley, Donna M.,Schmidt, Wendy,Hacker, Miles P.
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p. 397 - 403
(2008/10/08)
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- Platinum complexes of vitamin C: Reaction chemistry of carbon-bound cis-[(diamine)(ascorbato-C2,O5)platinum] chelates
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The reaction between a series of cis-[Pt(RNH2)2(ascorbato-C2,O5)] chelates, where (RNH2)2 is ethylenediamine (en), [1,2-15N]en, (15NH3)2, trans-(R,R)-, trans-(S,S)- or cis-(R,S)-diaminocyclohexane (dach), and various acids (HX = HNO3, HCl, CH3SO3H) were studied in an attempt to prepare monodentate ascorbate complexes of the form cis-[Pt(RNH2)2(ascorbato-C2)(L)]+/0 (1a), where L is an anionic or neutral ligand such as Cl-, ascorbate-O3, or S-Me2SO. 195Pt and 13C NMR studies of the reaction of the 15N-labeled ascorbate chelate [Pt(15en)(C2,O5-Asc)] (1) with aqueous acids show that, in the absence of a nucleophile, the protonated chelate [Pt(15en)(C2,O5-HAsc)]+ (2) is favored over the ring-opened complex [Pt(15en)(C2-HAsc)(H2O)]+ (3). Protonation occurs at the O5 site of the ascorbate ligand, and the pKa of the resulting complex is ～2.0 in water. While the protonated chelate 2 can be isolated from nonaqueous solvents, the complex decomposes to ascorbic acid and [Pt(15en)(H2O)2]2+ in aqueous solution. The ring-opened complex 3 was observed as an intermediate in the hydrolysis reaction of the protonated chelate 2. Similar behavior is observed with the dach and cis-diammine analogues. When the ascorbate chelates are protonated in the presence of a nucleophile in aprotic solvents, ring-opened complexes of the form 1a are obtained. In the two cases where these complexes were isolated (L = Cl- or S-Me2SO), both compounds were unstable in aqueous solutions; the chloro complex undergoes ring closure, re-forming the C2,O5 chelate, and the Me2SO complex isomerizes to the oxygen-bound ascorbate complex cis-[Pt(diamine)(O3-HAsc)(S-Me2SO)]+. Ring-opened complexes of form 1a, containing weak donors such as NO3-, SO42-, CH3CO2-, and O3-HAsc-, are also unstable when prepared from the C2,O5 chelate. In general, the monodentate C2-bound ascorbate complexes prefer the ring-closed structure when platinum is bound to the re face of the ascorbate ligand.
- Hollis, L. Steven,Stern, Eric W.
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p. 2826 - 2831
(2008/10/08)
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