Terapia zhubných nádorových ochorení patrí medzi najstaršie a zároveň najperspektívnejšie oblasti aplikácie zlúčenín kovov v terapii. Druhá časť prehľadu o metalofarmakách sa zameriava na dejinný vývoj a súčasné využitie komplexných zlúčenín v terapii rakoviny. Najprv sa venuje najznámejšiemu a najúspešnejšiemu liečivu spomedzi metalofarmák – cisplatine. Po stručnom náčrte objavu antineoplastických vlastností tejto zlúčeniny sa zaoberá jej chemickými vlastnosťami, toxicitou, klinickými aplikáciami, mechanizmom účinku a vývojom rezistencie. V ďalšom sú diskutované tiež komplexy iných kovov ako potenciálne chemoterapeutiká, ako aj perspektívne smery výskumu v tejto oblasti. Tento stručný prehľad má za cieľ poskytnúť základnú orientáciu v tejto problematike pre farmaceutov i chemikov, ako aj ostatných záujemcov o danú oblasť z radov odbornej verejnosti.
Therapy of malignant tumors is among the oldest and at the same time the most promising application areas of therapeutic metal complexes. The second part of our survey on metallopharmaceuticals deals with historical development and current state of coordination compounds in cancer therapy. It starts with the most famous and most successful metallodrug – cisplatin. After a brief account of the discovery of the anticancer properties of this substance follows the discussion of its chemical properties, toxicity, clinical application and resistance. Hereafter, complexes of other metals along with innovative research directions are addressed. The aim of this brief survey is to provide basic overview of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public.
- MeSH
- Chemistry, Bioinorganic MeSH
- Cisplatin therapeutic use MeSH
- Drug Therapy methods MeSH
- Coordination Complexes therapeutic use MeSH
- Metals * therapeutic use MeSH
- Humans MeSH
- Neoplasms * drug therapy MeSH
- Platinum therapeutic use MeSH
- Ruthenium therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review 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
- Adenine chemistry MeSH
- Cisplatin pharmacology MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds chemical synthesis chemistry pharmacology MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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.
Twelve steroidal platinum(II) complexes were synthesized by reaction of potassium tetrachloroplatinate with steroidal esters of L-methionine and L-histidine. The steroidal esters coordinated as bidentate ligands via S and N donor atoms of L-methionine and via two N donor atoms of L-histidine. Cholesterol, cholestanol, diosgenine, pregnenolone, dehydroepiandrosterone, testosterone, estrone, and estradiol were used as the steroidal compounds. The esters and complexes prepared were characterized by infrared, mass, and (1)H NMR spectroscopy and elemental analysis. Platinum complexes were tested for in vitro cytotoxicity against several cancer cell lines: T-lymphoblastic leukemia CEM, breast carcinoma MCF-7, lung carcinoma A-549, multiple myeloma RPMI 8226, and one normal cell line human fibroblast BJ.
- MeSH
- Esters chemical synthesis chemistry toxicity MeSH
- Financing, Organized MeSH
- Histidine chemistry MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Methionine chemistry MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Platinum chemistry MeSH
- Steroids chemistry MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans 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
- Adenine analogs & derivatives chemistry MeSH
- Cisplatin pharmacology MeSH
- HeLa Cells MeSH
- Hepatocytes cytology drug effects MeSH
- Inhibitory Concentration 50 MeSH
- Carboplatin pharmacology MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Organometallic Compounds chemical synthesis chemistry pharmacology MeSH
- Organoplatinum Compounds pharmacology MeSH
- Palladium chemistry MeSH
- Platinum chemistry MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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 (1)H NMR and ESI+ mass spectra.
- MeSH
- Cell Line MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Cisplatin chemistry MeSH
- Epithelial Cells drug effects pathology MeSH
- Fibroblasts cytology drug effects MeSH
- Glutathione chemistry MeSH
- Indoles chemistry MeSH
- Inhibitory Concentration 50 MeSH
- Coordination Complexes chemical synthesis pharmacology MeSH
- G1 Phase Cell Cycle Checkpoints drug effects MeSH
- Guanosine Monophosphate chemistry MeSH
- Carboxylic Acids chemistry MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds chemical synthesis pharmacology MeSH
- Antineoplastic Agents chemical synthesis pharmacology MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Leukemia, Experimental MeSH
- Animal Experimentation MeSH
- Mice MeSH
- Platinum MeSH
- Polymers MeSH
- Antineoplastic Agents MeSH
- In Vitro Techniques MeSH
- Check Tag
- Mice MeSH
- Publication type
- Comparative Study MeSH
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
- Cisplatin pharmacokinetics chemistry adverse effects MeSH
- Cytokinins pharmacology chemistry MeSH
- Iridium MeSH
- Coordination Complexes * pharmacology chemistry MeSH
- Antineoplastic Agents * pharmacology chemistry MeSH
- Platinum Compounds history pharmacology chemistry classification radiation effects MeSH
- Publication type
- Research Support, Non-U.S. Gov't 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.
- MeSH
- Apoptosis drug effects MeSH
- Cisplatin adverse effects MeSH
- Humans MeSH
- Lymphoma pathology MeSH
- Mice, Inbred DBA MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds chemistry MeSH
- Oxalates chemistry MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Roscovitine chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
