The effect of binding of cis-diamminedichloroplatinum(II), its trans isomer and diethylenetriaminechloroplatinum(II) chloride to DNA on the splicing effectiveness of BamHI, EcoRI and SalI restriction endonucleases has been determined by means of gel electrophoresis. All three platinum complexes inhibit the cleavage of linearized plasmid DNA. In addition, the three platinum complexes bound to DNA constitute a barrier across which the linear diffusion of EcoRI on DNA is difficult. We interpret these findings to mean that the splicing effectiveness of restriction enzymes is influenced by bifunctional and monofunctional DNA adducts of platinum via both steric interference and DNA conformational distortions. Whereas the platinum adducts in the restriction sites or in their very close proximity inhibit the cleavage, the lesions occurring a greater distance from the restriction site can slow down the process of the localization of recognition sequences.

• MeSH
• cisplatina farmakologie   MeSH
• deoxyribonukleasa BamHI metabolismus   MeSH
• deoxyribonukleasa EcoRI metabolismus   MeSH
• DNA metabolismus   MeSH
• elektroforéza v agarovém gelu MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• plazmidy účinky léků   MeSH
• restrikční endonukleasy typu II metabolismus   MeSH
• stereoizomerie MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• cisplatina MeSH
• deoxyribonukleasa BamHI MeSH
• deoxyribonukleasa EcoRI MeSH
• DNA MeSH
• GTCGAC-specific type II deoxyribonucleases MeSH Prohlížeč
• organoplatinové sloučeniny MeSH
• restrikční endonukleasy typu II MeSH

BACKGROUND: We studied the interaction of oxaliplatin derivatives involving cytotoxic adenine-based cyclin-dependent kinase inhibitors, with human liver microsomal cytochrome P450. METHODS AND RESULTS: The activities of 9 human liver microsomal CYP forms (CYPs 1A2, 7-ethoxyresorufin O-deethylation; 2A6, coumarin 7-hydroxylation; 2B6, 7-ethoxy-4-(trifluoromethyl) coumarin O-deethylation; 2C8, luciferin-6´ methyl ether demethylation; 2C9, diclofenac 4´-hydroxylation, 6´-deoxyluciferin hydroxylation; 2C19, (S)-mephenytoin 4´-hydroxylation; 2D6, bufuralol 1´-hydroxylation, 2E1, chlorzoxazone 6-hydroxylation; 3A4, testosterone 6β-hydroxylation, luciferin-6´ benzyl ether debenzylation) were tested using HPLC, fluorescence and luminescence product detection. At 100 µM platinum(II) oxalato complex concentration, CYP inhibition was in general 25%-50%, except for the CYP3A4 form which showed roughly twice the inhibition (72%-95%). At low complex concentration (10 µM), the difference in inhibition of CYP3A4 and other forms was even more pronounced. Dixon and Lineweaver-Burk plots indicated a partially noncompetitive mechanism of CYP3A4 inhibition. CONCLUSIONS: The tested complexes significantly inhibit human liver microsomal CYP3A4 activity even at clinically relevant concentrations. This could be a serious drawback for the use of these compounds in clinical practice.

• Klíčová slova
• CDK inhibition, cytochrome P450, platinum(II) complexes, roscovitine derivatives,
• MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• hydroxylace MeSH
• jaterní mikrozomy metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• oxidace-redukce MeSH
• sloučeniny platiny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytochrom P-450 CYP3A MeSH
• ligandy MeSH
• sloučeniny platiny MeSH

Structural properties of plasmid DNA and model lipid membrane treated with newly synthesized platinum(II) complex cis-[PtCl2{P(CH2CH2COOH)3}2] (cis-DTCEP for short) were studied and compared with effects of anticancer drug cisplatin, cis-[Pt(NH3)2Cl2] (cis-DDP for short). Time Correlated Single Photon Counting Fluorescence Correlation Spectroscopy (TCSPC-FCS) was employed to study interactions between those platinum complexes and DNA. The TCSPC-FCS results suggest that bonding of cis-DTCEP derivative to DNA leads to plasmid strain realignment towards much more compact structure than in the case of cis-DDP. Application of both differential scanning calorimetry and infrared spectroscopy to platinum complexes/DPPC showed that cis-DTCEP slightly increases the phospholipid's main phase transition temperature resulting in decreased fluidity of the model membrane. The newly investigated compound-similarly to cis-DDP-interacts mainly with the DPPC head group however not only by the means of electrostatic forces: this compound probably enters into hydrophilic region of the lipid bilayer and forms hydrogen bonds with COO groups of glycerol and PO2- group of DPPC.

• Klíčová slova
• DNA, DPPC bilayer, DSC, IR spectroscopy, Platinum(II) complex, TCSPC-FCS,
• MeSH
• chemické modely * MeSH
• DNA chemie   MeSH
• fluidita membrány MeSH
• fluorescenční spektrometrie MeSH
• fosfiny chemie   MeSH
• komplexní sloučeniny chemie   MeSH
• lipidové dvojvrstvy chemie   MeSH
• platina chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• fosfiny MeSH
• komplexní sloučeniny MeSH
• lipidové dvojvrstvy MeSH
• platina MeSH

The platinum(II) malonato (Mal) and decanoato (Dec) complexes of the general formulas [Pt(Mal)(naza)2] (1-3) and cis-[Pt(Dec)2(naza)2] (4-7) were prepared, characterized and tested for their in vitro cytotoxicity against cisplatin-sensitive (A2780) and cisplatin-resistant (A2780R) human ovarian carcinoma cell lines and non-cancerous human lung fibroblasts (MRC-5); naza=halogeno-derivatives of 7-azaindole. Complexes 1-7 effectively overcome the acquired resistance of ovarian carcinoma cells to cisplatin. Complexes 2 (IC50=26.6±8.9μM against A2780 and 28.9±6.7μM against A2780R), 4 (IC50=14.5±0.6μM against A2780 and 14.5±3.8μM against A2780R) and 5 (IC50=13.0±1.1μM against A2780 and 13.6±4.9μM against A2780R) indicated decreased toxicity against healthy MRC-5 cells (IC50>50.0μM for 2 and >25.0μM for 4 and 5). The representative complexes 2 and 4 showed mutually different effect on the A2780 cell cycle at IC50 concentrations after 24h exposure. Concretely, the complex 2 caused cell cycle arrest at G0/G1 phase, while 4 induced cell death by apoptosis with high population of cells in sub-G1 cell cycle phase. The hydrolysis and interactions of the selected complexes with biomolecules (glutathione (GSH) and guanosine monophosphate (GMP)) were also studied by means of 1H NMR and ESI+ mass spectra.

• Klíčová slova
• 7-Azaindole derivatives, Antitumour activity, Cell cycle, Decanoato, Malonato, Platinum(II) complexes,
• MeSH
• buněčné linie MeSH
• chemorezistence účinky léků   MeSH
• cisplatina chemie   MeSH
• epitelové buňky účinky léků   patologie   MeSH
• fibroblasty cytologie   účinky léků   MeSH
• glutathion chemie   MeSH
• indoly chemie   MeSH
• inhibiční koncentrace 50 MeSH
• komplexní sloučeniny chemická syntéza   farmakologie   MeSH
• kontrolní body fáze G1 buněčného cyklu účinky léků   MeSH
• kyselina 5'-guanylová chemie   MeSH
• kyseliny karboxylové chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemická syntéza   farmakologie   MeSH
• protinádorové látky chemická syntéza   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-azaindole dimer MeSH Prohlížeč
• cisplatina MeSH
• glutathion MeSH
• indoly MeSH
• komplexní sloučeniny MeSH
• kyselina 5'-guanylová MeSH
• kyseliny karboxylové MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH

The thiocyanate complexes of Pd(II), Pt(II) and Pt(IV) were studied by capillary zone electrophoresis. Pd(II) can be detected in the form of the thiocyanate complex at 305 nm with higher sensitivity than in the form of its chloro complex (absorption maximum 214 nm). A detection limit equal to 5 ppb for Pd has been finally achieved. The possibility of simultaneous determination of Pd(II) and Pt(IV) in the form of thiocyanate complexes has also been demonstrated. When the method optimized for the determination of Pt(II) was applied to the drugs Cykloplatin and Ribocarbo (containing carboplatin) and Platidiam (containing cisplatin), good agreement of the platinum content with the declared value was obtained. Samples of vehicle exhaust particulates (National Institute for Environmental Studies, Japan, No. 8 reference material) were also analyzed.

• MeSH
• cisplatina analýza   MeSH
• elektroforéza kapilární * MeSH
• karboplatina analýza   MeSH
• palladium analýza   MeSH
• platina analýza   MeSH
• protinádorové látky analýza   MeSH
• spektrofotometrie MeSH
• thiokyanatany analýza   MeSH
• výfukové emise vozidel analýza   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina MeSH
• karboplatina MeSH
• palladium MeSH
• platina MeSH
• protinádorové látky MeSH
• thiokyanatany MeSH
• výfukové emise vozidel MeSH

Mechanistic studies are presented of a novel class of aminophosphine platinum(II) complexes as potential anticancer agents. These new agents, which have demonstrated activity against murine and human tumor cells including those resistant to cisplatin are cis-[PtCl2(Me2N(CH2)3PPh2-P)2] (Com1) and cis-[PtCl(C6H11NH(CH2)2PPh2-N,P)(C6H11NH(CH2) 2PPh2-P)] (Com2). We studied modifications of natural and synthetic DNAs in cell-free media by Com1 and Com2 by various biomedical and biophysical methods and compared the results with those obtained when DNA was modified by cisplatin. The results indicated that Com1 and Com2 coordinated to DNA faster than cisplatin. Bifunctional Com1 formed DNA adducts coordinating to single adenine or guanine residues or by forming cross-links between these residues. In comparison with cisplatin, Com1 formed the adducts more frequently at adenine residues and also formed fewer bidentate lesions. The monofunctional Com2 only formed DNA monodentate adducts at guanine residues. In addition, Com1 terminated DNA synthesis in vitro more efficiently than cisplatin whereas Com2 blocked DNA synthesis only slightly. DNA unwinding studies, measurements of circular dichroism spectra, immunochemical analysis, and studies of the B-Z transition in DNA revealed conformational alterations induced by the adducts of Com1, which were distinctly different from those induced by cisplatin. Com2 had little influence on DNA conformation. It is suggested that the activity profile of aminophosphine platinum(II) complexes, which is different from that of cisplatin and related analogs, might be associated with the specific DNA binding properties of this new class of platinum(II) compounds.

• MeSH
• adukty DNA metabolismus   MeSH
• cirkulární dichroismus MeSH
• cisplatina farmakologie   MeSH
• DNA chemie   účinky léků   metabolismus   MeSH
• ethidium MeSH
• imunochemie MeSH
• konformace nukleové kyseliny MeSH
• molekulární sekvence - údaje MeSH
• protinádorové látky farmakologie   MeSH
• reagencia zkříženě vázaná farmakologie   MeSH
• sekvence nukleotidů MeSH
• sekvenční seřazení MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• cisplatina MeSH
• DNA MeSH
• ethidium MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH

In vitro antitumour activity of the [Pt(ox)(L(n))(2)] (1-7) and [Pd(ox)(L(n))(2)] (8-14) oxalato (ox) complexes involving N6-benzyl-9-isopropyladenine-based N-donor carrier ligands (L(n)) against ovarian carcinoma (A2780), cisplatin resistant ovarian carcinoma (A2780cis), malignant melanoma (G-361), lung carcinoma (A549), cervix epitheloid carcinoma (HeLa), breast adenocarcinoma (MCF7) and osteosarcoma (HOS) human cancer cell lines was studied. Some of the tested complexes were even several times more cytotoxic as compared with cisplatin employed as a positive control. The improved cytotoxic effect was demonstrated for the platinum(II) complexes 3 (IC(50)=3.2+/-1.0 microM and 3.2+/-0.6 microM) and 5 (IC(50)=4.0+/-1.0 microM and 4.1+/-1.4 microM) against A2780 and A2780cis, as compared with 11.5+/-1.6 microM, and 30.3+/-6.1 microM determined for cisplatin, respectively. The significant in vitro cytotoxicity against MCF7 (IC(50)=8.2+/-3.8 microM for 12) and A2780 (IC(50)=5.4+/-1.2 microM for 14) was evaluated for the palladium(II) oxalato complexes, which again exceeded cisplatin, whose IC(50) equalled 19.6+/-4.3 microM against the MCF7 cells. Selected complexes were also screened for their in vitro cytotoxic effect in primary cultures of human hepatocytes and they were found to be non-hepatotoxic.

• MeSH
• adenin analogy a deriváty   chemie   MeSH
• cisplatina farmakologie   MeSH
• HeLa buňky MeSH
• hepatocyty cytologie   účinky léků   MeSH
• inhibiční koncentrace 50 MeSH
• karboplatina farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• organokovové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• oxaliplatin MeSH
• palladium chemie   MeSH
• platina chemie   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• cisplatina MeSH
• karboplatina MeSH
• organokovové sloučeniny MeSH
• organoplatinové sloučeniny MeSH
• oxaliplatin MeSH
• palladium MeSH
• platina MeSH
• protinádorové látky MeSH

The mechanism of substitution water exchange reactions in square planar trans-Pt[(NH(3))(2)T(H(2)O)](n+) complexes is studied (T = H(2)O, NH(3), OH(-), F(-), Cl(-), Br(-), H(2)S, CH(3)S(-), SCN(-), CN(-), PH(3), CO, CH(3)(-), H(-), C(2)H(4)). The trans effect is explained in terms of sigma-donation and pi-back-donation whose relative strengths are quantified by the changes of electron occupations of 5d platinum atomic orbitals. The sigma-donation strength is linearly correlated with the Pt-H(2)O (leaving ligand) bond length (trans influence). The kinetic trans effect strength correlates proportionally with the sigma-donation ability of the trans-ligand except the ligands with strong pi-back-donation ability that stabilizes transition state structure. The sigma-donation ability of the ligand is dependent on the sigma-donation strength of the ligand in the trans position. Therefore the trans effect caused by sigma-donation can be understood as a competition between the trans-ligands for the opportunity to donate electron density to the central Pt(II) atom. The influence of the trans effect on the reaction mechanism is also shown. For ligands with a very strong sigma-donation (e.g. CH(3)(-) and H(-)), the substitution proceeds by a dissociative interchange (I(d)) mechanism. Ligands with strong pi-back donation ability (e.g. C(2)H(4)) stabilize the pentacoordinated intermediate and the substitution proceeds by a two step associative mechanism. For ligands with weak sigma-donation and pi-back-donation abilities, the highest activation barriers have to be overcome and substitutions can be described by an associative interchange (I(a)) mechanism. The results are supported by the energy decomposition and the natural orbital analysis.

• MeSH
• chemické modely * MeSH
• kinetika MeSH
• kvantová teorie MeSH
• ligandy MeSH
• platina chemie   MeSH
• sloučeniny platiny chemie   MeSH
• voda chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ligandy MeSH
• platina MeSH
• sloučeniny platiny MeSH
• voda MeSH

[Pt(L)(2)(ox)] (1), [Pt(2-OMeL)(2)(ox)] (2), [Pt(3-OMeL)(2)(ox)] (3), [Pt(2,3-diOMeL)(2)(ox)] (4), [Pt(2,4-diOMeL)(2)(ox)] (5), [Pt(3,4-diOMeL)(2)(ox)] (6) and [Pt(3,5-diOMeL)(2)(ox)].4H(2)O (7) platinum(II) oxalato (ox) complexes were synthesized using the reaction of potassium bis(oxalato)platinate(II) dihydrate with 2-chloro-N6-(benzyl)-9-isopropyladenine or its benzyl-substituted analogues (nL). The complexes 1-7, which represent the first platinum(II) oxalato complexes involving adenine-based ligands, were fully characterized by various physical methods including multinuclear and two dimensional NMR spectroscopy. A single-crystal X-ray analysis of [Pt(2,4-diOMeL)(2)(ox)].2DMF (5.2DMF; DMF=N,N'-dimethylformamide), proved the slightly distorted square-planar geometry in the vicinity of the Pt(II) ion with one bidentate-coordinated oxalate dianion and two adenine derivatives (nL) coordinated to the Pt(II) centre through the N7 atom of an adenine moiety, thereby giving a PtN(2)O(2) donor set. In vitro cytotoxicity of the prepared complexes was tested by an MTT assay against osteosarcoma (HOS) and breast adenocarcinoma (MCF7) human cancer cell lines. The best results were achieved for the complexes 2 and 5 in the case of both cell lines, whose IC(50) values equalled 3.6+/-1.0, and 4.3+/-2.1microM (for 2), and 5.4+/-3.8, and 3.6+/-2.1microM (for 5), respectively. The IC(50) equals 9.2+/-1.5microM against MCF7 cells in the case of 1. The in vitro cytotoxicity of the mentioned complexes significantly exceeded commercially used platinum-based anticancer drugs cisplatin (34.2+/-6.4microM and 19.6+/-4.3microM) and oxaliplatin (>50.0microM for both cancer cell lines).

• MeSH
• adenin chemie   MeSH
• cisplatina farmakologie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• oxaliplatin MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• cisplatina MeSH
• organoplatinové sloučeniny MeSH
• oxaliplatin MeSH
• protinádorové látky MeSH

This work presents a deeper pharmacological evaluation of two formerly prepared and characterized, and highly in vitro cytotoxic platinum(II) oxalato complexes [Pt(ox)(L1)2] (1) and [Pt(ox)(L2)2] (2), containing the derivatives of cyclin-dependent kinase inhibitor (CDKi) seliciclib ((R)-roscovitine, CYC202) coordinating as N-donor carrier ligands, i.e., 2-(1-ethyl-2-hydroxyethylamino)-N6-(4-methoxybenzyl)-9-isopropyladenine (L1) and 2-chloro-N6-(2,4-dimethoxybenzyl)-9-isopropyladenine (L2). The positive results of in vitro cytotoxicity screening on human cancer cell lines (HeLa, HOS, A2780, A2780R, G361 and MCF7 with IC50 at low micromolar levels) published previously, motivated us to perform extended preclinical in vitro experiments to reveal the mechanisms associated with the induction of cancer cell death. In addition, the in vivo antitumor activity was evaluated using the mouse lymphocytic leukaemia L1210 model. The obtained results revealed that complex 1 exceeds the antitumor effect of cisplatin (as for the extension of life-span of mice) and shows far less adverse effects as compared to reference drug cisplatin. The in vitro and ex vivo studies of cellular effects and molecular mechanisms of cell death induction showed that the mechanism of action of complex 1 is essentially different from that of cisplatin. The obtained results showed a possible way how to obtain antitumor active platinum(II) oxalato complexes with better therapeutic profile than contemporary used platinum-based therapeutics.

• Klíčová slova
• Antitumor activity, Ex vivo, In vivo, Platinum(II) complexes, Seliciclib derivatives,
• MeSH
• apoptóza účinky léků   MeSH
• cisplatina škodlivé účinky   MeSH
• lidé MeSH
• lymfom patologie   MeSH
• myši inbrední DBA MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemie   MeSH
• oxaláty chemie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• roskovitin chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina MeSH
• organoplatinové sloučeniny MeSH
• oxaláty MeSH
• protinádorové látky MeSH
• roskovitin MeSH