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1.
Inorg Chem ; 63(2): 1296-1316, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38174357

RESUMO

Organometallic half-sandwich complexes [(η5-Cp)IrCl(L)]PF6 (1) and [(η5-Cp)RhCl(L)]PF6 (2) were prepared using pentamethylcyclopentadienyl chloride dimers of iridium(III) or rhodium(III) with the 4-amino-N-(2,2'-bipyridin-5-yl)benzenesulfonamide ligand (L) and ammonium hexafluorophosphate. The crystal structures of L, 1, and 2 were analyzed in detail. The coordination reactions of the ligand with the central ions were confirmed using various spectroscopic techniques. Additionally, the interactions between sulfaligand, Ir(III), and Rh(III) complexes with carbonic anhydrase (CA), human serum albumin (HSA), and CT-DNA were investigated. The iridium(III) complex (1) did not show any antiproliferative properties against four different cancer cell lines, i.e., nonsmall cell lung cancer A549, colon cancer HCT-116, breast cancer MCF7, lymphoblastic leukemia Nalm-6, and a nonmalignant human embryonic kidney cell line HEK293, due to high binding affinity to GSH. The sulfonamide ligand (L) and rhodium(III) complex (2) were further studied. L showed competitive inhibition toward CA, while complexes 1 and 2, uncompetitive. All compounds interacted with HSA, causing a conformational change in the protein's α-helical structure, suggesting the induction of a more open conformation in HSA, reducing its biological activity. Both L and 2 were found to induce cell death through a caspase-dependent pathway. These findings position L and 2 as potential starting compounds for pharmaceutical, therapeutic, or medicinal research.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Complexos de Coordenação , Neoplasias Pulmonares , Ródio , Humanos , Complexos de Coordenação/química , Ligantes , Irídio/farmacologia , Irídio/química , Ródio/farmacologia , Ródio/química , Células HEK293 , Antineoplásicos/química , Linhagem Celular Tumoral
2.
Int J Mol Sci ; 24(24)2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38139274

RESUMO

The new 5-substituted SN-38 derivatives, 5(R)-(N-pyrrolidinyl)methyl-7-ethyl-10-hydroxycamptothecin (1) and its diastereomer 5(S) (2), were investigated using a combination of nuclear magnetic resonance (NMR) spectroscopy and molecular modeling methods. The chemical stability, configuration stability, and propensity to aggregate as a function of concentration were determined using 1H NMR. The calculated self-association constants (Ka) were found to be 6.4 mM-1 and 2.9 mM-1 for 1 and 2, respectively. The NMR experiments were performed to elucidate the interaction of each diastereomer with a nicked decamer duplex, referred to as 3. The calculated binding constants were determined to be 76 mM-1 and 150 mM-1 for the 1-3 and 2-3 complexes, respectively. NMR studies revealed that the interaction between 1 or 2 and the nicked decamer duplex occurred at the site of the DNA strand break. To complement these findings, molecular modeling methods and calculation protocols were employed to establish the interaction mode and binding constants and to generate molecular models of the DNA/ligand complexes.


Assuntos
DNA , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Irinotecano , DNA/química
3.
Molecules ; 27(20)2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36296539

RESUMO

The understanding of the mechanism of Topo I inhibition by organic ligands is a crucial source of information that has led to the design of more effective and safe pharmaceuticals in oncological chemotherapy. The vast number of inhibitors that have been studied in this respect over the last decades have enabled the creation of a concept of an 'interfacial inhibitor', thereby describing the machinery of Topo I inhibition. The central module of action of this machinery is the interface of a Topo I/DNA/inhibitor ternary complex. Most of the 'interfacial inhibitors' are primarily kinetic inhibitors that form molecular complexes with an "on-off" rate timing; therefore, all of the contacts between the inhibitor and both the enzyme and the DNA are essential to keep the complex stable and reduce the "off rate". To test this hypothesis, we designed the compound using a C-9-(N-(2'-hydroxyethyl)amino)methyl substituent in an SN38 core, with a view that a flexible substituent may bind inside the nick of a model of the DNA and stabilize the complex, leading to a reduction in the "off rate" of a ligand in a potential ternary complex in vivo. Using docking analysis and molecular dynamics, free energy calculations on the level of the MM-PBSA and MM-GBSA model, here we presented the in silico-calculated structure of a ternary complex involving the studied compound 1. This confirmed our suggestion that compound 1 is situated in a groove of the nicked DNA model in a few conformations. The number of hydrogen bonds between the components of a ternary complex was established, which strengthens the complex and supports our view. The docking analysis and free energy calculations for the receptor structures which were obtained in the MD simulations of the ternary complex 1/DNA/Topo I show that the binding constant is stronger than it was for similar complexes with TPT, CPT, and SN38, which are commonly considered as strong Topo I inhibitors. The binary complex structure 1/DNA was calculated and compared with the experimental results of a complex that was in a solution. The analysis of the cross-peaks in NOESY spectra allowed us to assign the dipolar interactions between the given protons in the calculated structures. A DOSY experiment in the solution confirmed the strong binding of a ligand in a binary complex, having a Ka of 746 mM-1, which was compared with a Ka of 3.78 mM-1 for TPT. The MALDI-ToF MS showed the presence of the biohybrid, thus evidencing the occurrence of DNA alkylation by compound 1. Because of it having a strong molecular complex, alkylation is the most efficient way to reduce the "on-off" timing as it acts as a tool that causes the cog to brake in a working gear, and this is this activity we want to highlight in our contribution. Finally, the Topo I inhibition test showed a lower IC50 of the studied compound than it did for CPT and SN38.


Assuntos
Camptotecina , Prótons , Ligantes , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/química , DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase , DNA/metabolismo , Preparações Farmacêuticas
4.
Dalton Trans ; 51(22): 8804-8820, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35616922

RESUMO

Three sawhorse-type ruthenium(I) complexes containing purine analogs such as triazolopyrimidines of the general formula [Ru2(CO)4(µ-OOCCH3)2(L)2], where L is 1,2,4-triazolo[1,5-a]pyrimidine (tp for 1), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp for 2) and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp for 3), have been synthesized and characterized by elemental analysis, infrared analysis, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, 15N), and single-crystal X-ray diffraction (for 1 and 2). By assay with myoglobin, the photo-activated CO-releasing molecule (PhotoCORM) character of (1-3) has been confirmed, thus indicating the possibility of use in CO-based therapies. The importance of UV-induced modification has been investigated in the context of anticancer properties. Complexes (1) and (2) have been thoroughly screened for their in vitro cytotoxicity against various cancer cell lines: MCF-7 (breast cancer), HeLa (cervical cancer) and C32 (melanoma), as well as L929 normal fibroblasts in the dark and presence of UV-A light (365 nm). The results were compared with those for cisplatin and two reference ruthenium complexes, namely NAMI-A and KP1019. The most hydrophilic [Ru2(CO)4(µ-OOCCH3)2(tp)2] (1) (log P = -1.12) was found to be more cytotoxic than (2), despite the lower cellular uptake measured by ICP-MS toward HeLa cells. Importantly, photo-induced stimulation of cells with (1) resulted in a lower decrease in the viability of L929 normal cells (IC50 = 154.7 ± 6.5 µM) in comparison with HeLa cancer cells (IC50 = 66.7 ± 3.4 µM). The photo-induced stimulation of (1) and (2) increases ROS generation, and their anticancer activity may be a partially ROS-dependent phenomenon.


Assuntos
Antineoplásicos , Complexos de Coordenação , Rutênio , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Células HeLa , Humanos , Ligantes , Pirimidinas/química , Pirimidinas/farmacologia , Espécies Reativas de Oxigênio , Rutênio/química , Rutênio/farmacologia , Triazóis/química , Triazóis/farmacologia
5.
Int J Mol Sci ; 23(7)2022 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-35409016

RESUMO

The platinum(II) complexes of general formula [PtCl2(dstp)(S-donor)] were dstp 5,7-dimethyl-1,2,4-triazolo[1,5-a]-pyrimidine (dmtp), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp), 5-methyl-7-isobutyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) or 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp), whereas S-tetrahydrothio-phene-1-oxide (TMSO) or diphenyl sulfoxide (DPSO) were synthesized in a one-pot reaction. Here, we present experimental data (1H, 13C, 15N, 195Pt NMR, IR, X-ray) combined with density functional theory (DFT) computations to support and characterize structure-spectra relationships and determine the geometry of dichloride platinum(II) complexes with selected triazolopyrimidines and sulfoxides. Based on the experimental and theoretical data, factors affecting the stability of platinum(II) complexes have been determined.


Assuntos
Antineoplásicos , Platina , Antineoplásicos/química , Derivados de Benzeno , Linhagem Celular Tumoral , Óxidos , Platina/química , Pirimidinas , Sulfóxidos , Tiofenos , Triazóis/química
6.
Food Chem ; 368: 130890, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34438182

RESUMO

Dietary supplements containing vitamin K2 are often used to prevent osteoporosis, vascular calcification and coronary heart disease. It has been shown that some of these products contain a mixture of menaquinone-7 geometric isomers. Since the geometric shape may influence biological activity, there was a need for a semipreparative method to isolate single compounds for further studies. Here, we present an argentation chromatographic method for the separation of menaquinone-7 isomers and an nuclear magnetic resonance (NMR) methodology for the configuration assignment of isoprenoid side chain. The DFT calculations were performed to determine more energetically favorable complexes between the cis or trans menaquinone-7 isomers and the silver cation. Seventeen components were resolved, and fractions were collected and subjected to NMR study. Structures and chemical shifts for thirteen new compounds were assigned, and the identity of three known compounds was confirmed.


Assuntos
Prata , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Vitamina K 2/análogos & derivados
7.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638762

RESUMO

It was proven that sterols subjected to high-temperature treatment can be concatenated, which results in polymeric structures, e.g., 3ß,3'ß-disteryl ethers. However, it was also proven that due to increased temperature in oxygen-containing conditions, sterols can undergo various oxidation reactions. This study aimed to prove the existence and perform quantitative analysis of oxidized 3ß,3'ß-disteryl ethers, which could form during high-temperature treatment of sterol-rich samples. Samples were heated at 180, 200 and 220 °C for 0.5 to 4 h. Quantitative analyses of the oxidized 3ß,3'ß-disteryl ethers were performed with liquid extraction, solid-phase extraction and liquid chromatography coupled with mass spectrometry. Additionally, to perform this analysis, the appropriate standards of all oxidized 3ß,3'ß-disteryl ethers were prepared. Eighteen various oxidized 3ß,3'ß-disteryl ethers (derivatives of 3ß,3'ß-dicholesteryl ether, 3ß,3'ß-disitosteryl ether and 3ß,3'ß-distigmasteryl ether) were prepared. Additionally, the influence of metal compounds on the mechanism of ether formation at high temperatures was investigated.


Assuntos
Éteres , Esteróis/química , Éteres/síntese química , Éteres/química , Espectrometria de Massas , Oxirredução , Extração em Fase Sólida
8.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360955

RESUMO

Novel nontoxic derivatives of SN38 with favorable antineoplastic properties were characterized in water solution using NMR. The phenomena observed by NMR were linked to basic pharmacological properties, such as solubility, bioavailability, chemical and stereochemical stability, and binding to natural DNA oligomers through the terminal G-C base pair, which is commonly considered a biological target of Topo I inhibitors. Compound 1, with bulky substituents at both C5(R) and C20(S) on the same side of a camptothecin core, manifests self-association, whereas diastereomers 2, with bulky C5(S) and C20(S) substituents are mostly monomeric in solution. The stereogenic center at C5 is stable in water solution at pH 5-6. The compound with an (N-azetidinyl)methyl substituent at C9 can undergo the retro Mannich reaction after a prolonged time in water solution. Both diastereomers exhibit different abilities in terms of binding to DNA oligomers: compound 1 is strongly bound, whereas the binding of compound 2 is rather weak. Molecular modeling produced results consistent with NMR experiments. These complementary data allow linking of the observed phenomena in NMR experiments to basic preliminary information on the pharmacodynamic character of compounds and are essential for planning further development research.


Assuntos
Antineoplásicos/química , DNA/química , Irinotecano/análogos & derivados , Simulação de Acoplamento Molecular , Inibidores da Topoisomerase I/química , Antineoplásicos/toxicidade , Irinotecano/toxicidade , Inibidores da Topoisomerase I/toxicidade
9.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299090

RESUMO

The compounds 7-ethyl-9-(N-methylamino)methyl-10-hydroxycamptothecin (2) and 7-ethyl-9-(N-morpholino)methyl-10-hydroxycamptothecin (3) are potential topoisomerase I poisons. Moreover, they were shown to have favorable anti-neoplastic effects on several tumor cell lines. Due to these properties, the compounds are being considered for advancement to the preclinical development stage. To gain better insights into the molecular mechanism with the biological target, here, we conducted an investigation into their interactions with model nicked DNA (1) using different techniques. In this work, we observed the complexity of the mechanism of action of the compounds 2 and 3, in addition to their decomposition products: compound 4 and SN38. Using DOSY experiments, evidence of the formation of strongly bonded molecular complexes of SN38 derivatives with DNA duplexes was provided. The molecular modeling based on cross-peaks from the NOESY spectrum also allowed us to assign the geometry of a molecular complex of DNA with compound 2. Confirmation of the alkylation reaction of both compounds was obtained using MALDI-MS. Additionally, in the case of 3, alkylation was confirmed in the recording of cross-peaks in the 1H/13C HSQC spectrum of 13C-enriched compound 3. In this work, we showed that the studied compounds-parent compounds 2 and 3, and their potential metabolite 4 and SN38-interact inside the nick of 1, either forming the molecular complex or alkylating the DNA nitrogen bases. In order to confirm the influence of the studied compounds on the topoisomerase I relaxation activity of supercoiled DNA, the test was performed based upon the measurement of the fluorescence of DNA stain which can differentiate between supercoiled and relaxed DNA. The presented results confirmed that studied SN38 derivatives effectively block DNA relaxation mediated by Topo I, which means that they stop the machinery of Topo I activity.


Assuntos
Camptotecina/análogos & derivados , Camptotecina/metabolismo , Quebras de DNA de Cadeia Simples , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , DNA Super-Helicoidal , Inibidores da Topoisomerase II/farmacologia , Alquilação , Humanos
10.
Bioorg Med Chem Lett ; 46: 128146, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34048881

RESUMO

Derivatives of SN38 were synthesized that were either monosubstituted at C-5 or C-9 or disubstituted at both C-5 and C-9. Substitution to C-5 led to the generation of pairs of diastereomers (2c-2 h) in a one-pot reaction and was readily separable by HPLC. The absolute configurations of C-5 were established by electronic circular dichroism experiments. Compounds were tested in vitro against human cancer cell lines as well as a normal cell line. The impact of compounds 2a-2j on cancer cells is significant and the IC50 values against the normal cell line are several times higher than that of SN38. Using the Mannich reaction we obtained a new innovative group of derivatives with unique biological properties that preserves the high cytotoxicity in cancer cells and eliminates the acute toxicity to non-neoplastic cells, which can be considered a breakthrough in chemotherapy with the use of topoisomerase I inhibitors from the camptothecin family.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
11.
Dalton Trans ; 50(16): 5557-5573, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33908935

RESUMO

Three half-sandwich organometallic ruthenium(ii) complexes containing purine analogs such as triazolopyrimidines of general formula [(η6-p-cym)Ru(L)Cl2], where p-cym represents p-cymene and L is 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp for 1), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for 2) and 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO for 3), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, 15N), and single-crystal X-ray diffraction (for 1 and 2). All these complexes have been thoroughly screened for their in vitro cytotoxicity against MCF-7 and HeLa cell lines as well as L929 murine fibroblast cells, indicating [(η6-p-cym)Ru(HmtpO)Cl2] (3) as the most active representative against the HeLa cell line and simultaneously being 64-fold less toxic to normal L929 murine fibroblast cells than cisplatin. At the same time, 3 has shown antimetastatic activity comparable to NAMI-A against HeLa cells both after 24 and 48 h of treatment in a wound healing assay. In order to better understand the mechanism of anticancer action and differences in the cytotoxic activity of 1-3, the studies were expanded to determining their lipophilicity, the kinetic stability at pH 6.5-8, the effect on reactive oxygen species (ROS) production in HeLa cells and interactions with significant biomolecules (DNA and albumin) by using molecular docking and circular dichroism (CD) experiments. Furthermore, antiparasitic studies against L. braziliensis, L. infantum and T. cruzi reveal that the newly synthesized complexes 1-3 are very promising candidates which can compete with commercial antiparasitic drugs. Complex 3 in particular, on top of exhibiting a high antiparasitic effect (IC50 < 1 µM against two strains), reaches a selectivity index >1000.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Rutênio/química , Células HeLa , Humanos , Simulação de Acoplamento Molecular
12.
Bioorg Chem ; 107: 104631, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33476866

RESUMO

In this account we present NMR based results of the interaction of 7-ethyl-9-hydroxymethyl-10-hydroxycamptothecin (1), a derivative of SN38, with a model nicked DNA decamer mimicking the wild type DNA target of Topoisomerase I inhibitors from the camptothecin family. The title compound 1 can be considered a main metabolite of phase I in the metabolic pathway of camptothecin derivatives bearing the alkylamino substituent. Therefore, its pharmacodynamic properties are of interest. It was established by DOSY (Diffusion Ordered Spectroscopy) that compound 1 forms a fairly stable molecular complex with a model nicked DNA decamer with affinity constant Ka 3.02 mM-1. The analysis of NOESY experiments revealed intermolecular cross peaks and mutual induced shifts on both interacting components allowing the conclusion that guest molecule 1 is stacking the nitrogen bases inside the nick. MD (Molecular Dynamics) analysis of four possible inclusions of 1 inside the nick allows establishing the detailed geometry of a complex. Two conformations are suggested as the ones best representing the results of molecular modeling reconciled with experimental NOESY results. The aromatic core of both structures is stacking the nitrogen bases in a nick facing the unbroken strand with ring A. The protons in ring E interact with ribose protons of edge bases of a nick. In conclusion, it can be asserted that SN38 derivative 1 can effectively bind the molecular target of Topo I enzyme and play a role as a Topo I inhibitor.


Assuntos
Camptotecina/química , DNA Topoisomerases Tipo I/química , DNA/química , Inibidores da Topoisomerase I/química , Sítios de Ligação , Camptotecina/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Humanos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Ressonância Magnética Nuclear Biomolecular , Conformação de Ácido Nucleico , Inibidores da Topoisomerase I/metabolismo
13.
Materials (Basel) ; 13(23)2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33255252

RESUMO

Herein, we present dicarboxylate platinum(II) complexes of the general formula [Pt(mal)(DMSO)(L)] and [Pt(CBDC)(DMSO)(L)], where L is dbtp 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine) or ibmtp (7-isobutyl-5-methyl-1,2,4- triazolo[1,5-a]pyrimidine), as prospective prodrugs. The platinum(II) complexes were synthesized in a one-pot reaction between cis-[PtCl2(DMSO)2], silver malonate or silver cyclobutane-1,1-dicarboxylate and triazolopyrimidines. All platinum(II) compounds were characterized by FT-IR, and 1H, 13C, 15N and 195Pt NMR; and their square planar geometries with one monodentate N(3)-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine, one S-bonded molecule of dimethyl sulfoxide and one O,O-chelating malonato (1, 2) or O,O-chelating cyclobutane-1,1-dicarboxylato (3, 4) was determined. Additionally, [Pt(CBDC)(dbtp)(DMSO)] (3) exhibited (i) substantial in vitro cytotoxicity against the lung adenocarcinoma epithelial cell line (A549) (IC50 = 5.00 µM) and the cisplatin-resistant human ductal breast epithelial tumor cell line (T47D) (IC50 = 6.60 µM); and (ii) definitely exhibited low toxicity against normal murine embryonic fibroblast cells (BALB/3T3).

14.
Materials (Basel) ; 13(16)2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32784666

RESUMO

The oncological use of cisplatin is hindered by its severe side effects and a very important resistance problem. To overcome these problems, scientists have attempted to design new generation transition-metal anticancer complexes. In this study, we present new complexes, ruthenium(II) [(η6-p-cymene)RuCl(py2CO)]PF6 (1), iridium(III) [(η5-Cp)IrCl(py2CO)]PF6 (2), and NH4[IrCl4(py2CO)]·H2O (3), based on di-2-pyridylketone (py2CO). The prepared complexes were characterized by FTIR, 1H, 13C, 15N NMR, UV-Vis, PL and elemental analysis techniques. The single-crystal X-ray structure analysis and comparative data revealed pseudo-octahedral half-sandwich 1 and 2 complexes and octahedral tetrachloroiridate(III) 3 with a rare chelating κ2N,O coordination mode of py2CO. The compounds were tested in vitro against three cancer cell lines-colorectal adenoma (LoVo), myelomonocytic leukaemia (MV-4-11), breast adenocarcinoma (MCF-7), and normal fibroblasts (BALB/3T3). The most promising results were obtained for iridium(III) complex 3 against MV-4-11 (IC50 = 35.8 ± 13.9 µg/mL) without a toxic effect against normal BALB/3T3, which pointed towards its selectivity as a potential anticancer agent. Extensive research into their mode of binding with DNA confirmed for 1 and 2 complexes non-classical binding modes, while the 3D circular dichroism (CD) experiment (ΔTm) suggested that 3 induced the probable formation of covalent bonds with DNA. In addition, the obtained iridium complexes induce ROS, which, in synergy with hydrolysis promoting DNA bonding, may lead to cancer cell death.

15.
Food Chem ; 329: 127132, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504917

RESUMO

It has been proven that at increased temperature, sterols can undergo various chemical reactions e.g., oxidation, dehydrogenation, dehydration and polymerisation. The objectives of this study are to prove the existence of dimers and to quantitatively analyse the dimers (3ß,3'ß-disteryl ethers). Sterol-rich samples were heated at 180 °C, 200 °C and 220 °C for 1 to 5 h. Quantitative analyses of the 3ß,3'ß-disteryl ethers were conducted using liquid extraction, solid-phase extraction and gas chromatography coupled with mass spectrometry. Additionally, for the analyses, suitable standards were synthetized from native sterols. To identify the mechanism of 3ß,3'ß-disteryl ether formation at high temperatures, an attempt was made to use the proposed synthesis method. Additionally, due to the association of sterols and sterol derivatives with atherosclerosis, preliminary studies with synthetized 3ß,3'ß-disteryl ethers on endothelial cells were conducted.


Assuntos
Éteres/química , Esteróis/química , Linhagem Celular , Células Endoteliais , Éteres/síntese química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Espectrometria de Massas , Oxirredução , Extração em Fase Sólida , Temperatura
16.
J Inorg Biochem ; 210: 111072, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32563102

RESUMO

Five novel rhodium(II) complexes of general formula [Rh2(µ-OOCCH3)4L2], where L is a triazolopyrimidine derivative, in particular dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) for (1), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp) for (2), 7-isobutyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) for (3), 7-hydroxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (HmtpO) for (4) and 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) for (5) are reported. These first representatives of paddle-wheel dirhodium complexes with triazolopyrimidines have been characterized by IR and NMR spectroscopy as well as by single-crystal X-ray diffraction studies. Three of the new complexes (1), (2) and (5) were thoroughly screened in vitro for their cytotoxicity against human breast cancer cell line MCF-7 and L929 murine fibroblast cells. Favorably, they show significantly less effective inhibition on the cell growth of L929 than cisplatin under identical conditions. Complexes (1) and (5) display moderate cytotoxic activity (IC50 = 16.3-21.5 µM) against MCF-7 cells which is induced via reactive oxygen species-independent pathways. Extensive studies of rhodium complexes (1), (2) and (5) against microorganisms have shown that the tested compounds exhibit antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) while (5) significantly inhibited the growth of Malassezia furfur. The highest antibacterial, and antifungal activity, was observed for (5).


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Antifúngicos/síntese química , Antifúngicos/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Bacillus subtilis/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Ligantes , Células MCF-7 , Malassezia/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Pirimidinas/síntese química , Pirimidinas/toxicidade , Ródio/química , Staphylococcus aureus/efeitos dos fármacos , Triazóis/síntese química , Triazóis/toxicidade
17.
Dalton Trans ; 49(4): 1207-1219, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31903475

RESUMO

Two types of ruthenium(ii) complexes containing 1,2,4-triazolo[1,5-a]pyrimidines of the general formulas [RuCl2(dmso)3(L)] ((1)-(3)) and [RuCl2(dmso)2(L)2] ((4)-(6)), where L represents 1,2,4-triazolo[1,5-a]pyrimidine (tp for (1)), 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp for (2)), 7-isobutyl-5-methyl-1,2,4-trizolo[1,5-a]pyrimidine (ibmtp for (3)), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for (4)), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp for (5)) and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp for (6)), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, and 15N), and X-ray (for (3), (4), and (5)). All these complexes have been thoroughly screened for their in vitro cytotoxicity against melanoma cell lines A375 and Hs294T, indicating cis,cis,cis-[RuCl2(dbtp)2(dmso)2] (5) as the most active representative, in addition to being non-toxic to normal human fibroblasts (NHDF) and not inducing hemolysis of human erythrocytes. In order to develop an intravenous formulation for (5), liposomes composed of soybean phosphatidylcholine (SPC), cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) were prepared and subsequently characterized. (5)-Loaded liposomes, with spherical morphology, assessed by transmission electron microscope (TEM), exhibited satisfactory encapsulation efficiency and stability. In in vitro experiments, PEG-modified (5)-loaded liposomes were more effective (10-fold) than free (5) for growth inhibition of both human melanoma cell lines. Furthermore, such an approach resulted in the reduction of cancer cell viability that was even 10-fold greater than that observed for free cisplatin.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Lipossomos/química , Melanoma/patologia , Nanoestruturas/química , Pirimidinas/química , Rutênio/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Cápsulas , Linhagem Celular Tumoral , Complexos de Coordenação/administração & dosagem , Humanos , Interações Hidrofóbicas e Hidrofílicas , Triazóis/química
19.
Talanta ; 204: 415-423, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357314

RESUMO

A cyclic-organophosphate, specifically 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide, was used to derivatise the hydroxyl group at the C3 position of selected steroid hormones to analyse the derivatives using UPLC-MS/MS (ultra-performance liquid chromatography-tandem mass spectrometry). Reactions were performed in an anhydrous pyridine environment in the presence of AlCl3 at 50 °C. The developed reaction is suitable for analytical chemistry applications and was validated by analysis of selected contraceptive drugs. The sensitivity of the method depends on hormone tested and the limit of detection ranges from 130 pg/mL for ß-estradiol to 240 pg/mL for estriol. The estimated efficiency of derivatisation reactions varies in the range from 77.5 to 95.7%, and depends upon the hormone undergoing derivatisation. The method's recovery rate for the lowest concentration tested (800 pg/mL) is 88.1-96.3%. The method exhibits linearity in the 390 pg/mL to 2.5 µg/mL range, with R2 = 0.997. The developed steroid hormone derivatisation reaction was validated experimentally using UHPLC-QTOF-MS (ultra-high performance liquid chromatography quadrupole time of flight mass spectrometry) and NMR (nuclear magnetic resonance) spectroscopy. These studies show that the developed derivatisation reaction provides a precise and repeatable determination of selected steroid hormones in contraceptive drugs. At n = 10, CV (Coefficient of Variation) did not exceed 7%, which is a very good result compared with other analytical methods.


Assuntos
Congêneres do Estradiol/análise , Indicadores e Reagentes/química , Organofosfatos/química , Esteroides/análise , Cromatografia Líquida de Alta Pressão/métodos , Congêneres do Estradiol/química , Limite de Detecção , Fosforilação , Esteroides/química , Espectrometria de Massas em Tandem/métodos
20.
J Biol Inorg Chem ; 24(4): 591-606, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31115765

RESUMO

In this paper, we discussed the similarities and differences in d6 low-spin half-sandwich ruthenium, rhodium and iridium complexes containing 2,2'-biimidazole (H2biim). Three new complexes, {[RuCl(H2biim)(η6-p-cymene)]PF6}2·H2O (1), [(η5-Cp)RhCl(H2biim)]PF6 (2), and [(η5-Cp)IrCl(H2biim)]PF6 (3), were fully characterized by CHN, X-ray diffraction analysis, UV-Vis, FTIR, and 1H, 13C and 15N NMR spectroscopies. The complexes exhibit a typical pseudooctahedral piano-stool geometry, in which the aromatic arene ring (p-cymene or Cp) forms the seat, while the bidentate 2,2'-biimidazole and chloride ion form the three legs of the piano stool. Moreover, the cytotoxic activities of the compounds were examined in the LoVo, HL-60, MV-4-11, MCF-7 human cancer cell lines and BALB/3T3 normal mouse fibroblasts. Notably, the investigated complexes showed no cytotoxic effects towards the normal BALB/3T3 cell line compared to cisplatin, which has an IC50 value of 2.20 µg. Importantly, 1 displayed the highest activity against HL-60 (IC50 4.35 µg). To predict a binding mode, we explored the potential interactions of the metal complexes with CT-DNA and protein using UV absorption and circular dichroism. The obtained data suggest that the complexes could interact with CT-DNA via an outside binding mode. Moreover, binding of the complexes with the GSH via UV-Vis and ESI mass spectra was determined. Comparative studies have shown that the rhodium complex (2) is the most GSH reactive, which is probably responsible for its deactivation towards LoVo and MCF-7 tumour cells. The influence of the metal ion on the biological activity of isostructural Rh(III) and Ir(III) complexes was an important goal of the presented investigation.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Irídio/química , Ródio/química , Rutênio/química , Células 3T3 , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Modelos Moleculares , Conformação Molecular , Albumina Sérica Humana/metabolismo
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