Q39927102 Dotaz Zobrazit nápovědu
In this overview, a short history and current state of the art regarding selected anticancer effective transition metal complexes are briefly described. In view of the fact that this text represents a part of experimental work for which Assoc. Prof. Pavel Štarha, Ph.D. was awarded the Alfred Bader Prize for Bioinorganic and Bioorganic chemistry by the Czech Chemical Society in 2017, the report is focused on the results realized mostly at the Division of Biologically Active Complexes and Molecular Magnets of the Regional Centre of Advanced Technologies and Materials of Palacký University in Olomouc. Some examples of highly cytotoxic complexes of platinum, gold, ruthenium, iridium and palladium are put into a broader context of their relative activities as compared to the generally accepted standard, i.e. cisplatin. Some of the presented compounds can be considered as pharmacologically prospective ones, which deserve to be further deeply evaluated in direction of future possible preclinical and clinical studies. Novelty and potential applicability of some of the developed complexes have been also supported by granting of several national and European patents.
- MeSH
- cisplatina farmakokinetika chemie škodlivé účinky MeSH
- cytokininy farmakologie chemie MeSH
- iridium MeSH
- komplexní sloučeniny * farmakologie chemie MeSH
- protinádorové látky * farmakologie chemie MeSH
- sloučeniny platiny dějiny farmakologie chemie klasifikace účinky záření MeSH
- Publikační typ
- práce podpořená grantem 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.
The gold(I) complexes of the general formula [Au(L(n))(PPh(3))]·xH(2)O (1-8; n = 1-8 and x = 0-1.5), where L(n) stands for a deprotonated form of the benzyl-substituted derivatives of 6-benzylaminopurine, were prepared, thoroughly characterized (elemental analyses, FT-IR, Raman and multinuclear NMR spectroscopy, ESI+ mass spectrometry, conductivity, DFT calculations), and studied for their in vitro cytotoxicity and in vitro and in vivo anti-inflammatory effects on LPS-activated macrophages (derived from THP-1 cell line) and using the carrageenan-induced hind paw edema model on rats. The obtained results indicate that the representative complexes (1, 3, 6) exhibit a strong ability to reduce the production of pro-inflammatory cytokines TNF-α, IL-1β and HMGB1 without influence on the secretion of anti-inflammatory cytokine IL-1RA in the LPS-activated macrophages. The complexes also significantly influence the formation of edema, caused by the intraplantar application of polysaccharide λ-carrageenan to rats in vivo. All the tested complexes showed similar or better biological effects as compared with Auranofin, but contrary to Auranofin they were found to be less cytotoxic in vitro. The obtained results clearly indicate that the gold(I) complexes behave as very effective anti-inflammatory agents and could prove to be useful for the treatment of difficult to treat inflammatory diseases such as rheumatoid arthritis.
- MeSH
- akutní monocytární leukemie MeSH
- antiflogistika nesteroidní chemická syntéza chemie farmakologie MeSH
- cytokiny krev MeSH
- cytotoxiny chemická syntéza chemie farmakologie MeSH
- edém chemicky indukované farmakoterapie metabolismus patologie MeSH
- karagenan MeSH
- komplexní sloučeniny chemická syntéza chemie farmakologie MeSH
- krysa rodu rattus MeSH
- kvantová teorie MeSH
- lidé MeSH
- lipopolysacharidy farmakologie MeSH
- makrofágy účinky léků metabolismus MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- potkani Wistar MeSH
- puriny chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zlato MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
A series of seven platinum(II) cyclobutane-1,1-dicarboxylato (cbdc) complexes {[Pt(cbdc)(L(n))(2)], 1-7}, derived from carboplatin by a substitution of two NH(3) molecules for two 2,6,9-trisubstituted 6-benzylaminopurine-based N-donor ligands (L(n)), was studied by the MTT assay for their in vitro cytotoxic activity against seven human cancer cell lines, i.e. lung carcinoma (A549), cervix epithelioid carcinoma (HeLa), osteosarcoma (HOS), malignant melanoma (G361), breast adenocarcinoma (MCF7), ovarian carcinoma (A2780) and its cisplatin-resistant analogue (A2780cis), and against two primary cultures of human hepatocytes (LH31 and LH32). The prepared complexes were cytotoxic against several cancer cells, in some cases even more than cisplatin. The best results were achieved for complexes 1 (IC(50)=17.4 ± 2.0 μM) and 2 (IC(50)=14.8 ± 2.1 μΜ) against HOS cells, 1 (IC(50)=15.1 ± 6.8 μM), 2 (IC(50)=13.6 ± 5.2 μM) and 6 (IC(50)=19.0 ± 6.6 μM) against MCF7, 6 (IC(50)=6.4 ± 0.1 μM) against A2780, and 1-6 (IC(50)=15.6 ± 4.0, 12.9 ± 3.7, 15.8 ± 3.8, 16.6 ± 5.5, 22.1 ± 2.5, and 5.6 ± 1.7 μM, respectively) against A2780cis. Viability of human hepatocytes was not declined by the tested complexes up to the concentration of 50 μM (for 1, 3-7) and 20 μM (for 2; caused by lower solubility of this complex).
- MeSH
- cisplatina farmakologie MeSH
- dospělí MeSH
- hepatocyty účinky léků metabolismus patologie MeSH
- karboplatina analogy a deriváty chemie farmakologie MeSH
- kinetin chemie farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie metabolismus patologie MeSH
- organoplatinové sloučeniny chemická syntéza farmakologie MeSH
- protinádorové látky farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of dinuclear copper(II) complexes of the compositions [Cu(2)(micro-L(n))(2)(micro-Cl)(2)Cl(2)] (1, 2), [Cu(2)(micro-L(n))(4)Cl(2)]Cl(2).2H(2)O (3, 4) and [Cu(2)(micro-L(n))(4)(ClO(4))(2)](ClO(4))(2).xSolv (5, 6; xSolv=4MeOH for 5 and 2EtOH for 6), involving 6-(benzylamino)purine derivatives (L(n)), have been evaluated with the aim to determine their possible drug interactions and their capability to induce the expression of major drug-metabolizing cytochromes P450. The above-mentioned complexes have been chosen based on the fact that substantial both in vitro (cytotoxicity, SOD-mimic) and in vivo (antidiabetic) biological activity has been found for them. As models, primary cultures of human hepatocytes and human hepatoma cells HepG2 transiently transfected with a plasmid containing dioxin-responsive element fused to the luciferase reporter gene (DRE-LUC) have been chosen. It has been found that the tested complexes 1-6 did not significantly induce the expression of CYP1A2 and CYP3A4 mRNAs in the concentration range of 0.1-10.0microM, in three different primary human hepatocyte cultures after 24h of the treatment. On the other hand, the model inducers, i.e. 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and rifampicin, significantly increased the levels of CYP1A2 and CYP3A4 mRNAs in all cultures. In addition, compounds 1-6 did not transactivate DRE-LUC in transiently transfected HepG2, while TCDD strongly induced luciferase activity after 24h of incubation. Based on the obtained results, it may be concluded that the studied dinuclear copper(II) complexes 1-6 possess very low toxicological potential to cause drug interactions in terms of transcriptional activation of the major human cytochromes P450.
- MeSH
- benzylové sloučeniny chemie toxicita MeSH
- cytochrom P-450 CYP1A2 genetika metabolismus MeSH
- cytochrom P-450 CYP3A genetika metabolismus MeSH
- dospělí MeSH
- hepatocyty účinky léků metabolismus MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- měď chemie toxicita MeSH
- messenger RNA genetika metabolismus MeSH
- molekulární struktura MeSH
- puriny chemie toxicita MeSH
- receptory aromatických uhlovodíků metabolismus MeSH
- regulace genové exprese enzymů účinky léků MeSH
- senioři MeSH
- steroidní receptory metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
- 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
