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The first Fe(III) complexes 1-6 with cyclin-dependent kinase (CDK) inhibitors of the type [Fe(L(n))Cl(3)].nH(2)O (n=0 for 1, 1 for 2, 2 for 3-6; L(1)-L(6)=C2- and phenyl-substituted CDK inhibitors derived from 6-benzylamino-9-isopropylpurine), have been synthesized and characterized by elemental analysis, IR, (57)Fe Mössbauer, (1)H and (13)C NMR, and ES+ mass spectroscopies, conductivity and magnetic susceptibility measurements, and thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The study revealed that the compounds are mononuclear, tetrahedral high-spin (S=5/2) Fe(III) complexes with an admixture of an S=3/2 spin state originating probably from five-coordinated Fe(III) ions either connecting with a bidentate coordination mode of the CDK inhibitor ligand or relating to the possibility that one crystal water molecule enters the coordination sphere of the central atom in a portion of molecules of the appropriate complex. Nearly spin-only value of the effective magnetic moment (5.82micro(eff)/micro(B)) was determined for compound 1 due to absence of crystal water molecule(s) in the structure of the complex. Based on NMR data and DFT calculations, we assume that the appropriate organic ligand is coordinated to the Fe(III) ion through the N7 atom of a purine moiety. The cytotoxicity of the complexes was tested in vitro against selected human cancer cell lines (G-361, HOS, K-562 and MCF-7) along with the ability to inhibit the CDK2/cyclinE kinase. The best cytotoxicity (IC(50): 4-23muM) and inhibition activity (IC(50): 0.02-0.09microM) results have been achieved in the case of complexes 2-4, and complexes 3, 4 and 6, respectively. In addition, the X-ray structure of 2-chloro-6-benzylamino-9-isopropylpurine, i.e. a precursor for the preparation of L(1), L(4) and L(5), is also described.

MeSH
antitumorózní látky chemická syntéza chemie farmakologie MeSH
elektrochemické techniky metody MeSH
inhibiční proteiny cyklin-dependentních kinas chemie metabolismus MeSH
léky antitumorózní - screeningové testy MeSH
lidé MeSH
molekulární modely MeSH
molekulární struktura MeSH
nádorové buněčné linie MeSH
puriny chemie MeSH
spektrální analýza metody MeSH
železo chemie MeSH
zvířata MeSH
Check Tag
lidé MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

Synthesis, characterization and in vitro cytotoxicity of the first palladium (II) oxalato complexes involving adenine-based ligands

Journal of inorganic biochemistry. 2009 ; 103 (7) : 978-988.

J Inorg Biochem
Medvik
Zdroj

The first [Pd(L(n))(2)(ox)] xH(2)O oxalato(ox) complexes involving 2-chloro-N6-(benzyl)-9-isopropyladenine (L(1); complex 1), 2-chloro-N6-(4-methoxybenzyl)-9-isopropyladenine (L(2); 2), 2-chloro-N6-(2,3-dimethoxybenzyl)-9-isopropyladenine (L(3); 3), 2-chloro-N6-(2,4-dimethoxybenzyl)-9-isopropyladenine (L(4); 4), and 2-chloro-N6-(4-methylbenzyl)-9-isopropyladenine (L(5); 5) have been synthesized by the reactions of potassium bis(oxalato)palladate(II) dihydrate, [K(2)Pd(ox)(2)].2H(2)O, with the mentioned organic compounds (H(2)ox=oxalic acid; x=0 for 1-3 and 5 or 2 for 4). Elemental analyses (C, H, N), FTIR, Raman and NMR ((1)H, (13)C, (15)N) spectroscopies, conductivity measurements and thermal studies (thermogravimetric and differential thermal analyses, TG/DTA) have been used to characterize the prepared complexes. The molecular structures of [Pd(L(2))(2)(ox)] (2) and [Pd(L(5))(2)(ox)].L(5).Me(2)CO (5.L(5).Me(2)CO) have been determined by a single crystal X-ray analysis. The geometry of these complexes is slightly distorted square-planar with two appropriate L(n) (n=2 or 5) molecules mutually arranged in the head-to-head (2) or head-to-tail (5) orientation. The L(n) ligands are coordinated to the central Pd(II) ion via the N7 atoms. The same conclusions regarding the binding properties of L(1)-L(5) ligands can be made based on multinuclear NMR spectra. In vitro cytotoxicity of the complexes 1-5 has been evaluated against human chronic myelogenous leukaemia (K562) and human breast adenocarcinoma (MCF7) cancer cell lines. Significant cytotoxicity has been determined for the complexes 3 (IC(50)=6.2 microM) and 5 (IC(50)=6.8 microM) on the MCF7 cell line, which is even better than that found for the well-known and widely-used platinum-bearing antineoplastic drugs, i.e. oxaliplatin and cisplatin.

MeSH
adenin chemie MeSH
antitumorózní látky chemická syntéza chemie toxicita MeSH
krystalografie rentgenová MeSH
lidé MeSH
ligandy MeSH
molekulární struktura MeSH
nádorové buněčné linie MeSH
organokovové sloučeniny chemická syntéza chemie toxicita MeSH
oxaláty chemie toxicita MeSH
palladium chemie toxicita MeSH
Check Tag
lidé MeSH
Publikační typ
práce podpořená grantem MeSH

Článek

Interactions of olomoucine II with human liver microsomal cytochromes P450

Drug metabolism and disposition. 2009 ; 37 (6) : 1198-1202.

Drug Metab Dispos
Medvik
Zdroj

Olomoucine II is a cyclin-dependent kinase inhibitor and a potential antineoplastic agent because it can arrest animal cell cycles. This study examines its interactions with human liver microsomal cytochrome P450 (P450) enzymes. Spectroscopic and high-performance liquid chromatography (HPLC) methods were used to estimate the degree of olomoucine II-mediated inhibition of enzymatic activities of eight drug-metabolizing P450s in vitro. In addition, mass spectrometry coupled with HPLC was used to identify an olomoucine II metabolite (2,5-dihydroxyroscovitine) formed in the reaction mixtures, and CYP3A4 was found to be responsible for the hydroxylation of the N(6)-benzyl ring at position 5, leading to this compound. Olomoucine II significantly inhibited the enzymatic activities of CYP1A2, CYP2C9, and (to a lesser degree) CYP3A4. The results indicate that use of olomoucine II as a drug could affect the activities of CYP3A4, CYP1A2, and CYP2C9 in vivo. Hence, the clinical relevance of these interactions should be carefully evaluated.

Článek

Dinuclear copper(II) complexes containing 6-(benzylamino)purines as bridging ligands : synthesis, characterization, and in vitro and in vivo antioxidant activities

Journal of inorganic biochemistry. 2009 ; 103 (3) : 432-440.

J Inorg Biochem
Medvik
Zdroj

A series of dinuclear copper(II) complexes involving 6-(benzylamino)purine derivatives, (HL(n)), as bridging ligands were synthesized, characterized and tested for both their in vitro and in vivo antioxidant activities. Based on results of elemental analyses, temperature dependence of magnetic susceptibility measurements, UV-vis, FTIR, EPR, NMR and MALDI-TOF mass spectroscopy, conductivity measurements and thermal analyses, the complexes with general compositions of [Cu(2)(mu-HL(n))(4)Cl(2)]Cl(2).2H(2)O (1-4) and [Cu(2)(mu-HL(n))(2)(mu-Cl)(2)Cl(2)] (5-7) were prepared {where n=1-4; HL(1)=6-[(2-methoxybenzyl)amino]purine, HL(2)=6-[(4-methoxybenzyl)amino]purine, HL(3)=6-[(2,3-dimethoxybenzyl)amino]purine and HL(4)=6-[(3,4-dimethoxybenzyl)amino]purine}. In the case of complexes 2, 3, 5 and 7, the antioxidant activities were studied by both in vitro {superoxide dismutase-mimic (SOD-mimic) activity} and in vivo {cytoprotective effect against the alloxan-induced diabetes (antidiabetic activity)} methods. The obtained IC(50) value of the SOD-mimic activity for the complex 5 (IC(50)=0.253 microM) was shown to be even better than that of the native bovine Cu,Zn-SOD enzyme (IC(50)=0.480 microM), used as a standard. As for the antidiabetic activity, the pretreatment of mice with complexes 3 and 7 led to the complete elimination of cytotoxic attack of alloxan and its free radical metabolites, used as a diabetogenic agent. The cytoprotective effect of these compounds was proved by the preservation of the initial blood glucose levels of the pretreated animals, as against the untreated control group.

MeSH
antioxidancia farmakologie chemická syntéza chemie MeSH
cytoprotekce MeSH
experimentální diabetes mellitus chemicky indukované MeSH
financování organizované MeSH
hypoglykemika farmakologie chemická syntéza chemie MeSH
kinetin farmakologie chemická syntéza chemie MeSH
měď chemie MeSH
myši MeSH
superoxiddismutasa metabolismus MeSH
zvířata MeSH
Check Tag
myši MeSH
zvířata MeSH

Článek

Synthesis, characterization and biological activity of ring-substituted 6-benzylamino-9-tetrahydropyran-2-yl and 9-tetrahydrofuran-2-ylpurine derivatives

Bioorganic & medicinal chemistry. 2009 ; 17 (5) : 1938-1947.

Bioorg Med Chem
Medvik
Zdroj

In an attempt to improve specific biological functions of cytokinins routinely used in plant micropropagation, 33 6-benzylamino-9-tetrahydropyran-2-ylpurine (THPP) and 9-tetrahydrofuran-2-ylpurine (THFP) derivatives, with variously positioned hydroxy and methoxy functional groups on the benzyl ring, were prepared. The new derivatives were prepared by condensation of 6-chloropurine with 3,4-dihydro-2H-pyran or 2,3-dihydrofuran and then by the condensation of these intermediates with the corresponding benzylamines. The prepared compounds were characterized by elemental analyses, TLC, HPLC, melting point determinations, CI+ MS and (1)H NMR spectroscopy. The cytokinin activity of all the prepared derivatives was assessed in three classical cytokinin bioassays (tobacco callus, wheat leaf senescence and Amaranthus bioassay). The derivatives 6-(3-hydroxybenzylamino)-9-tetrahydropyran-2-ylpurine (3) and 6-(3-hydroxybenzylamino)-9-tetrahydrofuran-2-ylpurine (23) were selected, because of the high affinity of their parent compound meta-topolin (mT, 6-(3-hydroxybenzylamino)purine) to cytokinin receptors, as model compounds for studying their perception by the receptors CRE1/AHK4 and AHK3 in a bacterial assay. Both receptors perceived these two derivatives less well than they perceived the parent compound. Subsequently, the susceptibility of several new derivatives to enzyme degradation by cytokinin oxidase/dehydrogenase was studied. Substitution of tetrahydropyran-2-yl (THP) at the N(9) position decreased the turnover rates of all new derivatives to some extent. To provide a practical perspective, the cytotoxicity of the prepared compounds against human diploid fibroblasts (BJ) and the human cancer cell lines K-562 and MCF-7 was also assayed in vitro. The prepared compounds showed none or marginal cytotoxicity compared to the corresponding N(9)-ribosides. Finally, the pH stability of the two model compounds was assessed in acidic and neutral water solutions (pH 3-7) by high-performance liquid chromatography (HPLC).

MeSH
cytokininy chemie metabolismus MeSH
fibroblasty účinky léků MeSH
financování organizované MeSH
furany chemická syntéza chemie toxicita MeSH
kinetika MeSH
koncentrace vodíkových iontů MeSH
lidé MeSH
nádorové buněčné linie MeSH
puriny chemická syntéza chemie toxicita MeSH
pyrany chemická syntéza chemie toxicita MeSH
stabilita léku MeSH
Check Tag
lidé MeSH

Abstrakt

Identifikace nových přírodních látek v Orobanche flava pomocí 1D a 2D NMR spektroskopie

Chemické listy. 2008 ; 102 (8) : 724.

ISSN 0009-2770
Medvik
Zdroj

Publikační typ
abstrakty MeSH

Článek

Novel iron complexes bearing N6-substituted adenosine derivatives: synthesis, magnetic, 57Fe Mossbauer, DFT, and in vitro cytotoxicity studies

Bioorganic & medicinal chemistry. 2008 ; 16 (18) : 8719-8728.

Bioorg Med Chem
Medvik
Zdroj

Iron complexes (1-7) involving N6-benzyladenosine derivatives of the predominant composition [Fe(L(n))Cl(3)].H(2)O {where L(1)=N6-(2-fluorobenzyl)adenosine (1), L(2)=N6-(4-fluorobenzyl)adenosine (2), L(3)=N6-(2-trifluoromethylbenzyl)adenosine (3), L(4)=N6-(3-trifluoromethylbenzyl)adenosine (4), L(5)=N6-(4-trifluoromethylbenzyl)adenosine (5), L(6)=N6-(4-trifluoromethoxybenzyl)adenosine (6), and L(7)=N6-(4-chlorobenzyl)adenosine (7)} have been synthesized. The compounds have been characterized by elemental analysis, variable-temperature and in-field 57Fe Mossbauer, ES+ MS, FTIR, 1H and 13C NMR spectroscopies, magnetochemical and conductivity measurements, thermal (TGA/DSC/DTA) analyses, and DFT calculations. It has been found that the organic molecule is coordinated to iron via N7 atom of the appropriate adenosine derivative and the products are represented by mixtures of complexes with various iron oxidation (Fe(III)/Fe(II)) and spin states (S=5/2, 4/2, 3/2, 2/2) and geometries (tetrahedral or trigonal bipyramidal). It is caused by the fact that partial redox processes proceed during the reactions due to the presence of a ribose moiety, which is oxidized to the corresponding 5'-ribotic acid, and simultaneously, a portion of Fe(III) cations is reduced to Fe(II) ones. Moreover, a significant effect of crystal water molecules on stereochemistry, and hence, on magnetic and spectral properties of the prepared complexes has been found. The compounds have been tested for their in vitro cytotoxicity against the following human cancer cell lines: malignant melanoma (G-361), osteogenic sarcoma (HOS), chronic myelogenous leukemia (K-562), and breast adenocarcinoma (MCF-7). The most important results have been obtained for complex 2 with IC(50) values 8-16 microM against HOS, K-562, and MCF-7 cell lines, and for complex 6 with IC(50) value 4 microM against MCF-7 cell line.

Článek

Synthesis, characterization and assessment of the cytotoxic properties of cis and trans-[Pd(L)(2)Cl(2)] complexes involving 6-benzylamino-9-isopropylpurine derivatives

Journal of inorganic biochemistry. 2007 ; 101 (3) : 477-492.

ISSN 0162-0134
Medvik
Zdroj

A series of square-planar Pd(II) complexes of the composition cis-[Pd(L(n))(2)Cl(2)] {L(1)=2-chloro-6-benzylamino-9-isopropylpurine (1), L(2)=2-chloro-6-[(4-methoxybenzyl)amino]-9-isopropylpurine (2), L(3)=2-chloro-6-[(2-methoxybenzyl)amino]-9-isopropylpurine (3) and 2-[(chloropropyl)amino]-6-benzylamino-9-isopropylpurine (6)} has been synthesized by the reaction of PdCl(2) with L(n) in a 1:2 molar ratio. In contrast, the same reaction followed by recrystallization of the product from N,N'-dimethylformamide (DMF) leads to trans-[Pd(L(n))(2)Cl(2)] x nDMF {L(3), n=0 (4), n=1(4( *)DMF); L(4)=2-chloro-6-[(2,3-dimethoxybenzyl)-amino]-9-isopropylpurine, n=0 (5), n=1.5 (5( *)DMF). The compounds have been characterized by elemental analyses, conductivity measurements, electrospray mass spectra in the positive ion mode (ES+MS), FTIR, (1)H and (13)C NMR spectra, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Moreover, the complexes 2 and 6 have been also investigated by (15)N NMR spectroscopy. The molecular structures of L(5), {(H(2+)L(5))(Cl(-))(2)} x H(2)O, i.e. the protonated form of L(5), trans-[Pd(L(3))(2)Cl(2)] (4) and trans-[Pd(L(4))(2)Cl(2)] (5) have been determined by single crystal X-ray analysis. NMR data and X-ray structures revealed that the organic molecules are coordinated to Pd via N7 atom of a purine moiety. All the complexes and the corresponding ligands have been tested in vitro for their cytotoxicity against four human cancer cell lines: breast adenocarcinoma (MCF7), malignant melanoma (G361), chronic myelogenous leukaemia (K562) and osteogenic sarcoma (HOS). Promising in vitro cytotoxic effect has been found for cis-[Pd(L(2))(2)Cl(2)] (2), having the IC(50) values of 12, 10, 25, and 14 microM against MCF7, G361, K562, and HOS, respectively, and for trans-[Pd(L(3))(2)Cl(2)].DMF (4) with the IC(50) value of 15 microM against G361.

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