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Guanidine is a chemically stable nitrogen compound that is excreted in human urine and is widely used in manufacturing of plastics, as a flame retardant and as a component of propellants, and is well known as a protein denaturant in biochemistry1-3. Guanidine occurs widely in nature and is used by several microorganisms as a nitrogen source, but microorganisms growing on guanidine as the only substrate have not yet been identified. Here we show that the complete ammonia oxidizer (comammox) Nitrospira inopinata and probably most other comammox microorganisms can grow on guanidine as the sole source of energy, reductant and nitrogen. Proteomics, enzyme kinetics and the crystal structure of a N. inopinata guanidinase homologue demonstrated that it is a bona fide guanidinase. Incubation experiments with comammox-containing agricultural soil and wastewater treatment plant microbiomes suggested that guanidine serves as substrate for nitrification in the environment. The identification of guanidine as a growth substrate for comammox shows an unexpected niche of these globally important nitrifiers and offers opportunities for their isolation.
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Microbial activity in drylands tends to be confined to rare and short periods of rain. Rapid growth should be key to the maintenance of ecosystem processes in such narrow activity windows, if desiccation and rehydration cause widespread cell death due to osmotic stress. Here, simulating rain with 2H2O followed by single-cell NanoSIMS, we show that biocrust microbial communities in the Negev Desert are characterized by limited productivity, with median replication times of 6 to 19 days and restricted number of days allowing growth. Genome-resolved metatranscriptomics reveals that nearly all microbial populations resuscitate within minutes after simulated rain, independent of taxonomy, and invest their activity into repair and energy generation. Together, our data reveal a community that makes optimal use of short activity phases by fast and universal resuscitation enabling the maintenance of key ecosystem functions. We conclude that desert biocrust communities are highly adapted to surviving rapid changes in soil moisture and solute concentrations, resulting in high persistence that balances limited productivity.
Assuntos
Ecossistema , Microbiota , Clima Desértico , Microbiologia do Solo , Chuva , SoloRESUMO
In this contribution we report the synthesis, characterization and in vitro anticancer activity of novel cyclometalated 4-phenylthiazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) complexes. Formation and sufficient purity of the complexes were unambigiously confirmed by 1H-, 13C- and 2D-NMR techniques, X-ray diffractometry, HRMS and elemental analysis. The binding preferences of these cyclometalates to selected amino acids and to DNA models including G-quadruplex structures were analyzed. Additionally, their stability and behaviour in aqueous solutions was determined by UV-Vis spectroscopy. Their cellular accumulation, their ability of inducing apoptosis, as well as their interference in the cell cycle were studied in SW480 colon cancer cells. The anticancer potencies were investigated in three human cancer cell lines and revealed IC50 values in the low micromolar range, in contrast to the biologically inactive ligands.
Assuntos
Antineoplásicos , Complexos de Coordenação , Rutênio , Humanos , Estrutura Molecular , Modelos Moleculares , Linhagem Celular Tumoral , Antineoplásicos/química , Ciclo Celular , Rutênio/farmacologia , Rutênio/química , Complexos de Coordenação/químicaRESUMO
Combining therapeutic with diagnostic agents (theranostics) can revolutionize the course of malignant diseases. Chemotherapy, hyperthermia, or radiation are used together with diagnostic methods such as magnetic resonance imaging (MRI). In contrast to conventional contrast agents (CAs), which only enable non-specific visualization of tissues and organs, the theranostic probe offers targeted diagnostic imaging and therapy simultaneously. METHODS: Novel salinomycin (Sal)-based theranostic probes comprising two different paramagnetic metal ions, gadolinium(III) (Gd(III)) or manganese(II) (Mn(II)), as signal emitting motifs for MRI were synthesized and characterized by elemental analysis, infrared spectral analysis (IR), electroparamagnetic resonance (EPR), thermogravimetry (TG) differential scanning calorimetry (DSC) and electrospray ionization mass spectrometry (ESI-MS). To overcome the water insolubility of the two Sal-complexes, they were loaded into empty bacterial ghosts (BGs) cells as transport devices. The potential of the free and BGs-loaded metal complexes as theranostics was evaluated by in vitro relaxivity measurements in a high-field MR scanner and in cell culture studies. RESULTS: Both the free Sal-complexes (Gd(III) salinomycinate (Sal-Gd(III) and Mn(II) salinomycinate (Sal-Mn(II)) and loaded into BGs demonstrated enhanced cytotoxic efficacy against three human tumor cell lines (A549, SW480, CH1/PA-1) relative to the free salinomycinic acid (Sal-H) and its sodium complex (Sal-Na) applied as controls with IC50 in a submicromolar concentration range. Moreover, Sal-H, Sal-Gd(III), and Sal-Mn(II) were able to induce perturbations in the cell cycle of treated colorectal and breast human cancer cell lines (SW480 and MCF-7, respectively). The relaxivity (r1) values of both complexes as well as of the loaded BGs, were higher or comparable to the relaxivity values of the clinically applied contrast agents gadopentetate dimeglumine and gadoteridol. CONCLUSION: This research is the first assessment that demonstrates the potential of Gd(III) and Mn(II) complexes of Sal as theranostic agents for MRI. Due to the remarkable selectivity and mode of action of Sal as part of the compounds, they could revolutionize cancer therapy and allow for early diagnosis and monitoring of therapeutic follow-up.
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Oxaliplatin is a very potent platinum(ii) drug which is frequently used in poly-chemotherapy schemes against advanced colorectal cancer. However, its benefit is limited by severe adverse effects as well as resistance development. Based on their higher tolerability, platinum(iv) prodrugs came into focus of interest. However, comparable to their platinum(ii) counterparts they lack tumor specificity and are frequently prematurely activated in the blood circulation. With the aim to exploit the enhanced albumin consumption and accumulation in the malignant tissue, we have recently developed a new albumin-targeted prodrug, which supposed to release oxaliplatin in a highly tumor-specific manner. In more detail, we designed a platinum(iv) complex containing two maleimide moieties in the axial position (KP2156), which allows selective binding to the cysteine 34. In the present study, diverse cell biological and analytical tools such as laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS), isotope labeling, and nano-scale secondary ion mass spectrometry (NanoSIMS) were employed to better understand the in vivo distribution and activation process of KP2156 (in comparison to free oxaliplatin and a non-albumin-binding succinimide analogue). KP2156 forms very stable albumin adducts in the bloodstream resulting in a superior pharmacological profile, such as distinctly prolonged terminal excretion half-life and enhanced effective platinum dose (measured by ICP-MS). The albumin-bound drug is accumulating in the malignant tissue, where it enters the cancer cells via clathrin- and caveolin-dependent endocytosis, and is activated by reduction to release oxaliplatin. This results in profound, long-lasting anticancer activity of KP2156 against CT26 colon cancer tumors in vivo based on cell cycle arrest and apoptotic cell death. Summarizing, albumin-binding of platinum(iv) complexes potently enhances the efficacy of oxaliplatin therapy and should be further developed towards clinical phase I trials.
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Oxaliplatin shows a superior clinical activity in colorectal cancer compared to cisplatin. Nevertheless, the knowledge about its cellular distribution and the mechanisms responsible for the different range of oxaliplatin-responsive tumors is far from complete. In this study, we combined highly sensitive element specific and isotope selective imaging by nanometer-scale secondary ion mass spectrometry (NanoSIMS) with transmission electron microscopy to investigate the subcellular accumulation of oxaliplatin in three human colon cancer cell lines (SW480, HCT116 wt, HCT116 OxR). Oxaliplatin bearing dual stable isotope labeled moieties, i.e. 2H-labeled diaminocyclohexane (DACH) and 13C-labeled oxalate, were applied for comparative analysis of the subcellular distribution patterns of the central metal and the ligands. In all the investigated cell lines, oxaliplatin was found to have a pronounced tendency for cytoplasmic aggregation in single membrane bound organelles, presumably related to various stages of the endocytic pathway. Moreover, nuclear structures, heterochromatin and in particular nucleoli, were affected by platinum-drug exposure. In order to explore the consequences of oxaliplatin resistance, subcellular drug distribution patterns were investigated in a pair of isogenic malignant cell lines with distinct levels of drug sensitivity (HCT116 wt and HCT116 OxR, the latter with acquired resistance to oxaliplatin). The subcellular platinum distribution was found to be similar in both cell lines, with only slightly higher accumulation in the sensitive HCT116 wt cells which is inconsistent with the resistance factor of more than 20-fold. Instead, the isotopic analysis revealed a disproportionally high accumulation of the oxalate ligand in the resistant cell line.
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The ruthenium-based anticancer agent BOLD-100/KP1339 has shown promising results in several in vitro and in vivo tumour models as well as in early clinical trials. However, its mode of action remains to be fully elucidated. Recent evidence identified stress induction in the endoplasmic reticulum (ER) and concomitant down-modulation of HSPA5 (GRP78) as key drug effects. By exploiting the naturally formed adduct between BOLD-100 and human serum albumin as an immobilization strategy, we were able to perform target-profiling experiments that revealed the ribosomal proteins RPL10, RPL24, and the transcription factor GTF2I as potential interactors of this ruthenium(III) anticancer agent. Integrating these findings with proteomic profiling and transcriptomic experiments supported ribosomal disturbance and concomitant induction of ER stress. The formation of polyribosomes and ER swelling of treated cancer cells revealed by TEM validated this finding. Thus, the direct interaction of BOLD-100 with ribosomal proteins seems to accompany ER stress-induction and modulation of GRP78 in cancer cells.
Assuntos
Antineoplásicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Proteína Ribossômica L10/metabolismo , Proteínas Ribossômicas/metabolismo , Antineoplásicos/química , Retículo Endoplasmático/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Células HCT116 , Humanos , Compostos Organometálicos/química , Polirribossomos/metabolismo , Rutênio/química , Fatores de Transcrição TFII/metabolismo , TranscriptomaRESUMO
A series of 16 dinuclear thiopyridone-based organometallics with excellent water solubility, increased stability and remarkable cytotoxicity were synthesized and characterized. The complexes of this work formed dimeric species featuring a double positive charge in polar protic solvents, accounting for their outstanding solubility in aqueous solution. Most of them displayed higher antiproliferative activity than their parental thiomaltol complex, with unexpected cytotoxicity trends depending on the employed metal center, ligand modification, and cell line. Insights into their behavior in biological systems were gathered by means of amino-acid interaction studies, cytotoxicity tests in 3D spheroid models, laser ablation, cellular accumulation measurements, as well as cell cycle experiments.
Assuntos
Complexos de Coordenação/síntese química , Piranos/síntese química , Tionas/síntese química , Ciclo Celular , Linhagem Celular Tumoral , Complexos de Coordenação/química , Biblioteca Gênica , Humanos , Ligantes , Piranos/química , Solubilidade , Tionas/químicaRESUMO
Multicellular tumor spheroid models serve as an important three-dimensional in vitro cell model system as they mimic the complex tumor microenvironment and thus have contributed to valuable assays in drug discovery studies. In this study, we present a state-of-the-art laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) setup for high spatial resolution elemental imaging of multicellular tumor spheroids and an approach to account for variations in cell density. A low dispersion LA-ICPMS setup was employed, providing accelerated throughput and high sensitivity and permitting a lateral image resolution down to â¼2.5 µm for phosphorus and platinum in HCT116 colon cancer spheroids upon treatment with the clinically used anticancer drug oxaliplatin. Phosphorus was introduced as scalar to compensate for differences in cell density and tissue thickness and the Pt/P ratios together with the high resolution adopted in our approach allows the differentiation of platinum accumulation within each part of the morphology of the tumor spheroids (layers of proliferating, quiescent, and necrotic cells).
Assuntos
Antineoplásicos/metabolismo , Neoplasias do Colo/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Oxaliplatina/metabolismo , Esferoides Celulares/metabolismo , Células HCT116 , Humanos , Fósforo/metabolismo , Platina/metabolismoRESUMO
The reaction of [Ru(CO)6Cl2], 1, with N[combining low line]3-methylbenzimidazole (MBI) and 5,6-dimethylbenzimidazole (DMBI) afforded two new complexes with the general formula fac-[RuII(CO)3Cl2L], L = MBI (2) or DMBI (4). Crystals of cis,trans-[RuII(CO)2Cl2(N[combining low line]3-MBI)2], 3, were also obtained from the mother liquor that produced 2. In the presence of water, the dissociation of Ru-N, Ru-Cl and Ru-CO bonds occurred as a function of time, water content and pH. Density functional theory structure simulations/optimizations were carried out at the Becke3LYP level of theory for evaluating the relative stability of possible conformers. ESI-MS studies revealed the ability of the complexes to link model proteins, such as lysozyme, bovine pancreatic ribonuclease and cytochrome c, with the partial release of the heteroaromatic base, chlorido and carbonyl ligands. X-ray diffraction studies on crystals grown from a solution of HEWL and 2 showed the partial removal of chloride and CO. Cytotoxicity tests yielded two-digit micromolar IC50 values in CH1/PA-1 and SW480 cancer cells. In contrast to CORM-3 and 2, a significantly reduced tumor growth was observed with 4 in the murine colon cancer CT-26 model in vivo.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rutênio/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Técnicas de Química Sintética , Cristalografia por Raios X , Humanos , Ligantes , Camundongos , Modelos Moleculares , Muramidase/química , Muramidase/metabolismo , Compostos Organometálicos/síntese química , Compostos Organometálicos/metabolismo , Conformação Proteica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of novel symmetrically and unsymmetrically coordinated platinum(IV) complexes with monodentate carboxylato ligands was synthesized. The compounds exhibit a general coordination sphere of [Pt(en)(OCOR)2(OCOR')(OCORâ³)], where the carboxylato ligands are represented by acetato and succinic acid monoester ligands. Dicarboxylatoplatinum(II) complexes were synthesized and oxidized symmetrically or unsymmetrically to obtain platinum(IV) complexes, which were subsequently carboxylated with noncyclic anhydrides. The compounds were investigated in detail by elemental analysis, mass spectrometry, infrared and multinuclear ((1)H, (13)C, (15)N, (195)Pt) NMR spectroscopy as well as by X-ray diffraction in some cases. The reduction behavior was followed by NMR spectroscopy, while stability and lipophilicity were examined by analytical reversed phase HPLC measurements. Cytotoxic properties were studied in three human cancer cell lines derived from cisplatin sensitive ovarian teratocarcinoma (CH1/PA-1), cisplatin insensitive colon carcinoma (SW480) and non-small cell lung cancer (A549). Thereby, the most lipophilic (yet water soluble) platinum(IV) complexes showed promising IC50 values in the low micromolar and even nanomolar range, demonstrating the significant advantage of using equatorially coordinated monodentate carboxylato ligands.
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Antineoplásicos/síntese química , Compostos Organoplatínicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Compostos Organoplatínicos/química , Compostos Organoplatínicos/toxicidade , Oxirredução , Pró-Fármacos/químicaRESUMO
The clinical development of anticancer metallodrugs is often hindered by the elusive nature of their molecular targets. To identify the molecular targets of an antimetastatic ruthenium organometallic complex based on 1,3,5-triaza-7-phosphaadamantane (RAPTA), we employed a chemical proteomic approach. The approach combines the design of an affinity probe featuring the pharmacophore with mass-spectrometry-based analysis of interacting proteins found in cancer cell lysates. The comparison of data sets obtained for cell lysates from cancer cells before and after treatment with a competitive binder suggests that RAPTA interacts with a number of cancer-related proteins, which may be responsible for the antiangiogenic and antimetastatic activity of RAPTA complexes. Notably, the proteins identified include the cytokines midkine, pleiotrophin and fibroblast growth factor-binding protein 3. We also detected guanine nucleotide-binding protein-like 3 and FAM32A, which is in line with the hypothesis that the antiproliferative activity of RAPTA compounds is due to induction of a G2/M arrest and histone proteins identified earlier as potential targets.
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The novel guanidine compounds trans-[Pt(NH2Me)2{NH=C(NHMe)NR}2](Cl)2 (R=NEt2 [7], NC5H10 [8]) (trans-7,8) were synthesized by the nucleophilic addition of methylamine to dialkylcyanamide ligands of the push-pull nitrile complexes trans-[PtCl2(RCN)2] (R=NEt2, NC5H10). In vitro cytotoxicity tests conducted for the entire series of the guanidine complexes, i.e. trans-7,8, the neutral cis- or trans-[PtCl2{NH=C(NH2)R}2] (cis-1-3 and trans-1-3) and the cationic cis- or trans-[Pt(NH3)2{NH=C(NH2)R}2](Cl)2 (cis-4-6 and trans-4-6) (R=NMe2 [1,4], NEt2 [2,5], NC5H10 [3,6]) in two human cancer cell lines, CH1 (ovarian carcinoma) and SW480 (colon cancer), confirmed that the cytotoxicity of several trans-configured (trans-3,6) complexes is higher than that of cis-congeners (cis-3,6). Cellular platinum levels were analyzed by inductively coupled plasma mass spectrometry upon treatment of SW480 cells, revealing a dependence of cellular accumulation on the geometrical isomerism and the steric hindrance of the variable substituent R on the guanidine ligand. DNA interactions of selected guanidine complexes were studied in order to find hints for the possible reasons for their different activities. Changes induced to the electrophoretic mobility of a dsDNA plasmid confirmed the potency of the guanidine complexes (e.g. trans-1,3,5,6 and cis-1,3,4) to significantly alter DNA secondary structure, indicating DNA as a possible critical target of these compounds.
Assuntos
Antineoplásicos/síntese química , DNA/efeitos dos fármacos , Guanidina/síntese química , Compostos Organoplatínicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Guanidina/química , Guanidina/farmacologia , Humanos , Ligantes , Estrutura Molecular , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Platina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Multi-elemental, isotope selective nano-scale secondary ion mass spectrometry (NanoSIMS) combined with confocal laser-scanning microscopy was used to characterize the subcellular distribution of 15N-labeled cisplatin in human colon cancer cells. These analyses indicated predominant cisplatin colocalisation with sulfur-rich structures in both the nucleus and cytoplasm. Furthermore, colocalisation of platinum with phosphorus-rich chromatin regions was observed, which is consistent with its binding affinity to DNA as the generally accepted crucial target of the drug. Application of 15N-labeled cisplatin and subsequent measurement of the nitrogen isotopic composition and determination of the relative intensities of platinum and nitrogen associated secondary ion signals in different cellular compartments with NanoSIMS suggested partial dissociation of Pt-N bonds during the accumulation process, in particular within nucleoli at elevated cisplatin concentrations. This finding raises the question as to whether the observed intracellular dissociation of the drug has implications for the mechanism of action of cisplatin. Within the cytoplasm, platinum mainly accumulated in acidic organelles, as demonstrated by a direct combination of specific fluorescent staining, confocal laser scanning microscopy and NanoSIMS. Different processing of platinum drugs in acidic organelles might be relevant for their detoxification, as well as for their mode of action.
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With the aim of systematically studying fundamental structure-activity relationships as a basis for the development of Ru(II) arene complexes (arene = p-cymene or biphenyl) bearing mono-, bi-, or tridentate am(m)ine ligands as anticancer agents, a series of ammine, ethylenediamine, and diethylenetriamine complexes were prepared by different synthetic routes. Especially the synthesis of mono-, di-, and triammine complexes was found to be highly dependent on the reaction conditions, such as stoichiometry, temperature, and time. Hydrolysis and protein-binding studies were performed to determine the reactivity of the compounds, and only those containing chlorido ligands undergo aquation or form protein adducts. These properties correlate well with in vitro tumor-inhibiting potency of the compounds. The complexes were found to be active in anticancer assays when meeting the following criteria: stability in aqueous solution and low rates of hydrolysis and binding to proteins. Therefore, the complexes least reactive to proteins were found to be the most cytotoxic in cancer cells. In general, complexes with biphenyl as arene ligand inhibited the growth of tumor cells more effectively than the cymene analogues, consistent with the increase in lipophilicity. This study highlights the importance of finding a proper balance between reactivity and stability in the development of organometallic anticancer agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Rutênio/química , Rutênio/farmacologia , Antineoplásicos/química , Cisplatino/farmacologia , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Etilenodiaminas/química , Etilenodiaminas/farmacologia , Feminino , Humanos , Ligantes , Estrutura Molecular , Compostos Organometálicos/química , Relação Estrutura-AtividadeRESUMO
The synthesis and in vitro cytotoxicity of a series of Ru(II)(arene) complexes with carbohydrate-derived phosphite ligands and various arene co-ligands is described. The arene ligand has a strong influence on the in vitro anticancer activity of this series of compounds, which correlates fairly well with cellular accumulation. The most lipophilic compound bearing a biphenyl moiety and a cyclohexylidene-protected carbohydrate is the most cytotoxic with unprecedented IC50 values for the compound class in three human cancer cell lines. This compound shows reactivity to the DNA model nucleobase 9-ethylguanine, but does not alter the secondary structure of plasmid DNA, indicating that other biological targets are responsible for its cytotoxic effect.
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Novel platinum complexes of trans geometry [PtCl(2){(Z)-R(H)CâNOH}(2)] [R = Me (1), Et (3)] and [PtCl(2){(E)-R(H)CâNOH}{(Z)-R(H)CâNOH}] [R = Me (2), Et (4)] as well as the classic trans-[PtCl(2)(R(2)CâNOH)(2)] [R = Me, Et] were reacted with an equivalent amount of silver acetate in acetone solution at ambient temperature, resulting in formation of unprecedented head-to-tail-oriented oximato-bridged dimers [PtCl{µ-(Z)-R(H)CâNO}{(Z)-R(H)CâNOH}](2) [R = Me (5), Et (7)], [PtCl{µ-(Z)-R(H)CâNO}{(E)-R(H)CâNOH}](2) [R = Me (6), Et (8)], and [PtCl(µ-R(2)CâNO)(R(2)CâNOH)](2) [R = Me (9), Et (10)], correspondingly. The dimeric species feature a unique six-membered diplatinacycle and represent the first example of oxime ligands coordinated to platinum via the oxygen atom. All complexes were characterized by elemental analyses, electrospray ionization mass spectrometry, IR and multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, as well as X-ray diffraction in the cases of dimers 6 and 9. Furthermore, the crystal and molecular structures of a trimeric oximato-bridged complex 11 comprising three platinum units connected in a chain way were established. The cytotoxicity of both dimers and the respective monomers was comparatively evaluated in three human cancer cell lines: cisplatin-sensitive CH1 cells as well as cisplatin-resistant SW480 and A549 cells, whereupon structure-activity relationships were drawn. Thus, it was found that dimerization results in a substantial (up to 7-fold) improvement of IC(50) values of (aldoxime)Pt(II) compounds, whereas for the analogous complexes featuring ketoxime ligands the reverse trend was observed. Remarkably, the novel dimers yielded no cross-resistance with cisplatin in SW480 cells, exhibiting up to 2-fold enhanced cytotoxicity in comparison with the CH1 cell line and thereby possessing a promising potential to overcome resistance toward platinum anticancer drugs. The latter point was also confirmed by investigating the potency of apoptosis induction in the case of one monomer as well as one dimer; the investigated complexes proved to be strong apoptotic agents which could induce cell death even in the cisplatin-resistant SW480 cell line.
Assuntos
Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Oximas/química , Platina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Ru(II)(arene) anticancer compounds with maleimide functionality were prepared to allow selective interaction with thiol-containing biomolecules and thereby enforcing the selective delivery of the compounds to the tumour.
Assuntos
Antineoplásicos/química , Maleimidas/química , Compostos Organometálicos/química , Rutênio/química , Compostos de Sulfidrila/química , Acetilcisteína/análogos & derivados , Acetilcisteína/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisteína/química , Relação Dose-Resposta a Droga , Glutationa/química , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of six novel bis(carboxylato)dichloridobis(ethylamine)platinum(IV) complexes was synthesized and characterized in detail by elemental analysis, FT-IR, ESI-MS, HPLC, multinuclear ((1)H, (13)C, (15)N, (195)Pt) NMR spectroscopy and in one case by X-ray diffraction. Cytotoxic properties of the complexes were evaluated in four human tumor cell lines originating from ovarian carcinoma (CH1 and SK-OV-3), colon carcinoma (SW480) and non-small cell lung cancer (A549) by means of the MTT colorimetrical assay. In addition, their octanol/water partition coefficients (log P values) were determined. Remarkably the most active (and also most lipophilic) compounds, having 4-propyloxy-4-oxobutanoato and 4-(2-propyloxy)-4-oxobutanoato axial ligands, showed IC(50) values down to the low nanomolar range.