RESUMO
This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. An in-depth analysis of the structure-activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds' antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c·2HCl (IC50 = 5.4 ± 2.4 µM), 13d (IC50 = 4.9 ± 2.9 µM), and 12f·2HCl (IC50 = 4.98 ± 2.9 µM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d·2HCl (IC50 = 4.55 ± 0.35 µM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e·2HCl (IC50 = 11.00 ± 2.2 µM), 7f (IC50 = 11.54 ± 2.06 µM), and 7f·2HCl (IC50 = 9.82 ± 1.92 µM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e·2HCl, 12d·2HCl, 13c·HCl, and 13d, were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant (Ksv) ranged from 9.59 × 104 to 10.74 × 104 M-1, indicating a good affinity to the BSA protein.
Assuntos
Acridinas , Antineoplásicos , Desenho de Fármacos , Tiazolidinedionas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Tiazolidinedionas/síntese química , Acridinas/química , Acridinas/farmacologia , Acridinas/síntese química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura MolecularRESUMO
A series of novel Ga(III)-pyridine carboxylates ([Ga(Pic)3]·H2O (GaPic; HPic = picolinic acid), H3O[Ga(Dpic)2]·H2O (GaDpic; H2Dpic = dipicolinic acid), [Ga(Chel)(H2O)(OH)]2·4H2O (GaChel; H2Chel = chelidamic acid) and [Ga(Cldpic)(H2O)(OH)]2 (GaCldpic; H2Cldpic = 4-chlorodipicolinic acid)) have been synthesized by simple one-step procedure. Vibrational spectroscopy (mid-IR), elemental analysis, thermogravimetric analysis and X-ray diffraction confirmed complexes molecular structure, inter and intramolecular interactions and their influence to spectral and thermal properties. Moreover, complex species speciation was described in Ga(III)-HPic and Ga(III)-H2Dpic systems by potentiometry and 1H NMR spectroscopy and mononuclear complex species were determined; [Ga(Pic)2]+ (logß021 = 16.23(6)), [Ga(Pic)3] (logß031 = 20.86(2)), [Ga(Dpic)2]- (logß021 = 15.42(9)) and [Ga(Dpic)2(OH)]2- (logß-121 = 11.08(4)). To confirm the complexes stability in 1% DMSO (primary solvent for biological testing), timescale 1H NMR spectra were measured (immediately after dissolution up to 96 h). Antimicrobial activity evaluated by IC50 (0.05 mM) is significant for GaDpic and GaCldpic against difficult to treat and multi-resistant P. aeruginosa. On the other hand, the GaPic complex is most effective against Jurkat, MDA-MB-231 and A2058 cancer cell lines and significantly also decreases the HepG2 cancer cells viability at 75 and 100 µM concentrations in a relatively short time (up to 48 h). In addition, fluorescence measurements have been used to elucidate bovine serum albumin binding activity between ligands, Ga(III) complexes and bovine serum albumin.
Assuntos
Complexos de Coordenação , Neoplasias , Humanos , Soroalbumina Bovina/metabolismo , Piridinas/farmacologia , Estrutura Molecular , Linhagem Celular , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , LigantesRESUMO
Heterocycles have long been the focus of intensive study in attempts to develop novel therapeutic compounds, and acridine, a polynuclear nitrogen molecule containing a heterocycle, has attracted a considerable amount of scientific attention. Acridine derivatives have been studied in detail and have been found to possess multitarget properties, which inhibit topoisomerase enzymes that regulate topological changes in DNA and interfere with the essential biological function of DNA. This article describes some recent advancements in the field of new 9-substituted acridine heterocyclic agents and describes both the structure and the structure-activity relationship of the most promising molecules. The article will also present the IC50 values of the novel derivatives against various human cancer cell lines. The mini review also investigates the topoisomerase inhibition and antibacterial and antimalarial activity of these polycyclic aromatic derivatives.
Assuntos
Acridinas/química , Acridinas/farmacologia , Acridinas/toxicidade , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/toxicidade , Células Tumorais Cultivadas/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Antimaláricos/química , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Humanos , Relação Estrutura-AtividadeRESUMO
Three silver(I) dipeptide complexes [Ag(GlyGly)]n(NO3)n (AgGlyGly), [Ag2(GlyAla)(NO3)2]n (AgGlyAla) and [Ag2(HGlyAsp)(NO3)]n (AgGlyAsp) were prepared, investigated and characterized by vibrational spectroscopy (mid-IR), elemental and thermogravimetric analysis and mass spectrometry. For AgGlyGly, X-ray crystallography was also performed. Their stability in biological testing media was verified by time-dependent NMR measurements. Their in vitro antimicrobial activity was evaluated against selected pathogenic microorganisms. Moreover, the influence of silver(I) dipeptide complexes on microbial film formation was described. Further, the cytotoxicity of the complexes against selected cancer cells (BLM, MDA-MB-231, HeLa, HCT116, MCF-7 and Jurkat) and fibroblasts (BJ-5ta) using a colorimetric MTS assay was tested, and the selectivity index (SI) was identified. The mechanism of action of Ag(I) dipeptide complexes was elucidated and discussed by the study in terms of their binding affinity toward the CT DNA, the ability to cleave the DNA and the ability to influence numbers of cells within each cell cycle phase. The new silver(I) dipeptide complexes are able to bind into DNA by noncovalent interaction, and the topoisomerase I inhibition study showed that the studied complexes inhibit its activity at a concentration of 15 µM.
Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Dipeptídeos/química , Prata/química , Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fenômenos Químicos , Técnicas de Química Sintética , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Humanos , Conformação Molecular , Simulação de Dinâmica Molecular , Análise Espectral , Relação Estrutura-Atividade , TermogravimetriaRESUMO
Proflavine derivatives are extremely interesting chemotherapeutic agents, which have shown promising pharmaceutical potential due to their wide range of biological activities. This review summarizes the current state of research into the anticancer, antimicrobial, antimalarial and antileishmanial properties of these attractive compounds. Our attention has focused on new classes of proflavine conjugates, which display significant levels of anticancer activity. Highly promising cytotoxic properties have been identified in proflavine conjugates with imidazolidinones, ureas and thioureas. In particular, proflavine-dialkyldithioureas displayed substantial cytotoxic effect against the human leukemia HL-60 cells with IC50 values from 7.2 to 34.0 µm. As well, palladium complexes with proflavine ligand have important biologic activity. The LC50 values of these complexes were significantly lower than that of cisplatin against the SK-BR-3 cell line.
Assuntos
Acriflavina/farmacologia , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Proflavina/farmacologia , Acriflavina/análogos & derivados , Acriflavina/toxicidade , Animais , Anti-Infecciosos/toxicidade , Antineoplásicos/toxicidade , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Proflavina/análogos & derivados , Proflavina/toxicidade , Relação Estrutura-AtividadeRESUMO
This review describes the synthesis of a wide range of novel tetrahydroacridine derivatives (tiocyanates, selenocyanates, ureas, selenoureas, thioureas, isothioureas, disulfides, diselenides and several tacrine homo- and hetro-hybrids). These tacrine congeners exhibit significant anticholinesterase and cytotoxic properties and may therefore be of considerable potential for the development of new drugs for the treatment of Alzheimer's disease.
Assuntos
Antineoplásicos/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Antineoplásicos/química , Antineoplásicos/toxicidade , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Descoberta de Drogas , Humanos , Relação Estrutura-Atividade , TacrinaRESUMO
Acridines possess two characteristics that have led many researchers to consider the agents interesting targets for future development as potential farmacophores: the planar acridine skeleton, which is able to intercalate into DNA, and the intense fluorescence of the agents. This review offers a study of the multifunctional character of acridines and the synthesis of novel acridine derivatives, with particular focus being placed on isothiocyanates and their congeners, e.g. thioureas, isothioureas, quaternary ammonium salts and platinum/gold conjugates. The review provides an overview of the structure, spectral properties, DNA binding and biological activity of acridinylthiourea congeners. These acridinylthiourea derivatives display significant cytotoxic activities against different types of cancer cell lines at micromolar concentrations. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Acridinas/síntese química , Acridinas/farmacologia , Dano ao DNA/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Isotiocianatos/síntese química , Isotiocianatos/farmacologia , Proflavina/síntese química , Proflavina/farmacologia , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/farmacologiaRESUMO
A novel series of trisubstituted acridines were synthesized with the aim of mimicking the effects of BRACO19. These compounds were synthesized by modifying the molecular structure of BRACO19 at positions 3 and 6 with heteroacyclic moieties. All of the derivatives presented in the study exhibited stabilizing effects on the human telomeric DNA quadruplex. UV-vis spectroscopy, circular dichroism, linear dichroism and viscosimetry were used in order to study the nature of the DNA binding in more detail. The results show that all of the novel derivatives were able to fold the single-stranded DNA sequences into antiparallel G-quadruplex structures, with derivative 15 exhibiting the highest stabilizing capability. Cell cycle analysis revealed that a primary trend of the "braco"-like derivatives was to arrest the cells in the S- and G2M-phases of the cell cycle within the first 72h, with derivative 13 and BRACO19 proving particularly effective in suppressing cell proliferation. All studies derivatives were less toxic to human fibroblast cell line in comparison with HT 29 cancer cell line.
Assuntos
Acridinas/química , Acridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , DNA/metabolismo , Quadruplex G/efeitos dos fármacos , Animais , Bovinos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/química , Humanos , Ligantes , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Silver(I) complexes with proline and hydroxyproline were synthesized and structurally characterized and crystal structure analysis shows that the formulas of the compounds are {[Ag2(Pro)2(NO3)]NO3}n (AgPro) (Pro = L-proline) and {[Ag2(Hyp)2(NO3)]NO3}n (AgHyp) (Hyp = trans-4-hydroxy-L-proline). Both complexes crystallize in the monoclinic lattice with space group P21 with a carboxylate bidentate-bridging coordination mode of the organic ligands Pro and Hyp (with NH2+ and COO- groups in zwitterionic form). Both complexes have a distorted seesaw (C2v) geometry around one silver(I) ion with τ4 values of 58% (AgPro) and 51% (AgHyp). Moreover, the results of spectral and thermal analyses correlate with the structural ones. 1H and 13C NMR spectra confirm the complexes species' presence in the DMSO biological testing medium and their stability in the time range of the bioassays. In addition, molar conductivity measurements indicate complexes' behaviour like 1 : 1 electrolytes. Both complexes showed higher or the same antibacterial activity against Bacillus cereus, Pseudomonas aeruginosa and Staphylococcus aureus as AgNO3 (MIC = 0.063 mM) and higher than silver(I) sulfadiazine (AgSD) (MIC > 0.5 mM) against Pseudomonas aeruginosa. In addition, complex AgPro exerted a strong cytotoxic effect against the tested MDA-MB-231 and Jurkat cancer cell lines (IC50 values equal to 3.7 and 3.0 µM, respectively) compared with AgNO3 (IC50 = 6.1 (5.7) µM) and even significantly higher selectivity than cisplatin (cisPt) against MDA-MB-231 cancer cell lines (SI = 3.05 (AgPro); 1.16 (cisPt), SI - selectivity index). The binding constants and the number of binding sites (n) of AgPro and AgHyp complexes with bovine serum albumin (BSA) were determined at four different temperatures, and the zeta potential of BSA in the presence of silver(I) complexes was also measured. The in ovo method shows the safety of the topical and intravenous application of AgPro and AgHyp. Moreover, the complexes' bioavailability was verified by lipophilicity evaluation from the experimental and theoretical points of view.
Assuntos
Antibacterianos , Antineoplásicos , Complexos de Coordenação , Hidroxiprolina , Testes de Sensibilidade Microbiana , Prolina , Prata , Prata/química , Prata/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Humanos , Hidroxiprolina/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Prolina/química , Prolina/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Estrutura Molecular , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Pseudomonas aeruginosa/efeitos dos fármacos , Modelos Moleculares , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacosRESUMO
Three new acridine-thiazolidinone derivatives (2a-2c) have been synthesized and their interactions with calf thymus DNA and a number of cell lines (leukemic cells HL-60 and L1210 and human epithelial ovarian cancer cell lines A2780) were studied. The compounds 2a-2c possessed high affinity to calf thymus DNA and their binding constants determined by spectrofluorimetry were in the range of 1.37 × 10(6)-5.89 × 10(6) M(-1). All of the tested derivatives displayed strong cytotoxic activity in vitro, the highest activity in cytotoxic tests was found for 2c with IC(50) = 1.3 ± 0.2 µM (HL-60), 3.1 ± 0.4 µM (L1210), and 7.7 ± 0.5 µM (A2780) after 72 h incubation. The cancer cells accumulated acridine derivatives very fast and the changes of the glutathione level were confirmed. The compounds inhibited proliferation of the cells and induced an arrest of the cell cycle and cell death. Their influence upon cells was associated with their reactivity towards thiols and DNA binding activity.
Assuntos
Acridinas/síntese química , Acridinas/farmacologia , DNA/metabolismo , Glutationa/metabolismo , Tiazolidinas/síntese química , Tiazolidinas/farmacologia , Acridinas/química , Células HL-60 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Modelos Moleculares , Tiazolidinas/químicaRESUMO
In this study, four hybrid organic-inorganic compounds (8-H2Q)2[PdCl4] (1), (H2ClQ)2[PdCl4] (2), (H2NQ)2[PdCl4] (3) and (H2MeQ)2[PdCl4]·2H2O (4) (where 8-H2Q = 8-hydroxyquinolinium, H2ClQ = 5-chloro-8-hydroxyquinolinium, H2NQ = 5-nitro-8-hydroxyquinolinium and H2MeQ = 2-methyl-8-hydroxyquinolinium) were synthesized through organic cation modulation. Single-crystal X-ray structure analysis of compounds 1 and 3 indicates that their structures are planar and consist of [PdCl4]2- anions and 8-H2Q or H2NQ cations, respectively. Both ionic components are held together through ionic interactions and hydrogen bonds forming infinite chains linked through π-π interactions to form 2D structures. Furthermore, NMR spectroscopy, UV-Vis spectroscopy, elemental analysis, and FT-IR spectroscopy were used to explore the synthesized compounds. The DNA interaction, antimicrobial activity, antiproliferative activity, and radical scavenging effect of the compounds were evaluated. The hybrid compounds and their free ligands can interact with the calf thymus DNA via an intercalation mode involving the insertion of the aromatic chromophore between the base pairs of DNA; compound 1 has the highest binding affinity. Moreover, they have high antimicrobial efficacy against the tested 14 strains of microorganisms with minimum inhibitory concentration values ranging from <1.95 to 250 µg/mL. The antiproliferative activity of the compounds was investigated against three different cancer cell lines, and their selectivity was verified on mesenchymal stem cells. Compounds 1 and 2 displayed selective and high cytotoxicity against human lung and breast cancer cells and showed moderate cytotoxicity against colon cancer cells. Accordingly, they might be auspicious candidates for future pharmacological investigations in lung and breast cancer research.
Assuntos
Complexos de Coordenação/química , Hidroxiquinolinas/química , Paládio/química , Compostos de Quinolínio/química , Células A549 , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Quelantes/química , Cristalografia por Raios X/métodos , DNA/química , Sequestradores de Radicais Livres/química , Células HCT116 , Humanos , Hidroxiquinolinas/síntese química , Ligantes , Espectroscopia de Ressonância Magnética/métodos , Testes de Sensibilidade Microbiana/métodos , Estrutura Molecular , Compostos de Quinolínio/síntese química , Espécies Reativas de Oxigênio/metabolismoRESUMO
New acridine derivatives bearing two symmetrical imidazolidinone rings, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides 6a-6e (alkyl=ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl), have been prepared and their interactions with calf thymus DNA and selected cell lines were studied. The DNA-binding of 6a-6e to ctDNA was examined by UV-vis, fluorescence, and CD spectroscopy. The binding constants determined by UV-vis spectroscopy were found in the range 1.9×10(5)-7.1×10(5) M(-1). An electrophoretic separation proved that ligands 6a-6e inhibited topoisomerase I in 40 µM concentration although only those with longer alkyl chains were able to penetrate the membranes and efficiently suppress the cell proliferation. The highest activity in cytotoxic tests was found for 3,6-bis((1-n-hexyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochloride (6e) with IC(50)=2.12 µM (HL 60) and 5.28 µM (L1210) after 72 h incubation. Molecular dynamics simulations and calculations of solvent-accessible surface areas (SASAs) were used to explore the intercalation mechanism. MD simulations favor stacking between adjacent C:G base pairs from the minor groove side. MD and SASAs calculations indicate that the decrease of K with alkyl extension is due to negative entropic change upon binding.
Assuntos
Acridinas/síntese química , DNA Topoisomerases Tipo I/efeitos dos fármacos , Imidazolidinas/síntese química , Acridinas/química , Acridinas/farmacologia , Animais , Linhagem Celular Tumoral , Dicroísmo Circular , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Imidazolidinas/química , Imidazolidinas/farmacologia , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , TermodinâmicaRESUMO
Novel silver(i) aminoacidate complexes {[Ag(HVal)(H2O)(NO3)]}n (AgVal) and {[Ag3(HAsp)2(NO3)]}n·nH2O (AgAsp) were prepared, investigated and fully characterized by vibrational spectroscopy (mid-IR), elemental analysis, thermogravimetric analysis, X-ray crystallography and mass spectrometry. Their stability in D2O and PBS buffer was verified by time-dependent 1H and 13C NMR measurements. Their in vitro antibacterial activity (against pathogenic Staphylococcus aureus CCM4223, Escherichia coli CCM4787) and that against probiotic bacteria Lactobacillus plantarum CCM7102 and Lactobacillus reuteri (L26) were determined and potential dosing concentration was evaluated. The cytotoxicity of both the complexes against intestinal porcine epithelial (IPEC-1) and human epithelial colorectal adenocarcinoma (CaCo-2) cell lines was determined using the colorimetric MTT assay and against human metastatic melanoma (A2058), human pancreatic adenocarcinoma (PaTu 8902), human cervical adenocarcinoma (HeLa), human colorectal carcinoma (HCT116), human leukaemic T cell lymphoma (Jurkat), and human dermal fibroblasts (HDF) using colorimetric MTS assay. The selectivity index (SI) was identified for intestinal cancer (CaCo-2) and healthy (IPEC-1) cells. The mechanism of action of AgVal and AgAsp was further elucidated and discussed by the study of their binding affinity toward the CT DNA, the ability to cleave the supercoiled form of pUC19 DNA and the ability to influence numbers of cells within each cell cycle.
Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Clivagem do DNA/efeitos dos fármacos , DNA/metabolismo , Intestinos/citologia , Prata/química , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/metabolismo , Humanos , SuínosRESUMO
Two silver(I) aminoacidate complexes {[Ag4(L-HAla)4(NO3)3]NO3}n (AgAla, complex 1, Alaâ¯=â¯alanine) and {[Ag(L-Phe)]}n (AgPhe, complex 2, Pheâ¯=â¯phenylalanine) were prepared and characterized by elemental, spectral analysis (FT-IR, NMR techniques) and single crystal X-ray analysis in solid state and their solution stability was measured in biological testing time-scale by 1H NMR. The bridging coordination modes of the zwitterionic Ala and deprotonated Phe ligands led to the formation of 1D polymeric chains of the complexes. The significant argentophilic interactions are presented in the structure of AgAla. Antimicrobial testing of prepared Ag(I) complexes was evaluated by IC50 and MIC values and were compared with AgGly, silver(I) sulfadiazine and AgNO3 samples. Moreover, MTS test was used to the testing of broad range antiproliferative activity of studied compounds against different cancer cell lines and also to the investigation of calf thymus DNA interactions by absorption spectroscopy, fluorescence spectroscopy, Ethidium bromide/Hoechst 33258 displacement experiments and circular dichroism spectroscopy. To evaluate the pUC19 DNA fragmentation by silver(I) complexes, the agarose gel electrophoresis was used. In addition to biological evaluation we used lipophilicity measurement results in the discussion about structure-activity relationship (SAR).
Assuntos
Alanina/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fenilalanina/farmacologia , Alanina/química , Alanina/metabolismo , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antifúngicos/química , Antifúngicos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Candida parapsilosis/efeitos dos fármacos , Catálise , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , DNA/metabolismo , Clivagem do DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenilalanina/química , Fenilalanina/metabolismo , Prata/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Ten novel, potentially intercalating 4-acridonecarboxamide azomethines and ketimines have been prepared by the condensation reaction of 9-oxo-9,10-dihydroacridine-4-carboxylic acid hydrazide with various aldehydes and ketones. The structures of the compounds were characterized spectroscopically by NMR ((1)H, (13)C, (15)N nuclei and 2D experiments), UV-vis, IR and fluorescence methods and by quantum chemical calculations using DFT at the B3LYP/6-311+G(d,p) level of theory and semiempirical ZINDO and AM1 methods. NMR chemical shift variations for C-4' were assessed due to changes in the polarizability of the imine C(4')=N(3') bond rather than direct inductive effects arising from the C-4' substituents. In concert with this was the reversed order observed for the N-3' chemical shifts with DFT-calculated atomic charges confirming the bond polarization. Both intra- and intermolecular hydrogen bonds between the acridone NH hydrogen and the amidic carbonyl oxygen were found to exist by FT-IR spectroscopy. Quantum chemical calculations were used to evaluate the configurational, tautomeric, conformational and hydrogen bonding states of the molecules as well as predict the NMR and IR data. The hypsochromic shifts observed in the UV-vis spectra upon changing from m-cresol to DMA, DMF or methanol were evaluated in terms of solvent polarity (giving rise to solvated excited state destabilization) and solvent aromaticity (giving rise to solvated excited state stabilization). The fluorescence of the compounds were modest, except for the 2,6-dichloro derivative, with respect to 9-isothiocyanatoacridine.
Assuntos
Acridinas/química , Citotoxinas/química , Iminas/química , Ligação de Hidrogênio , Conformação Molecular , Estrutura Molecular , Análise Espectral/métodosRESUMO
The synthesis of novel 1',1''-(acridin-3,6-diyl)-3',3''-dialkyldiureas was reported. Their biological activity to inhibit cell proliferation was assessed by a MTT assay on two cell lines, HeLa and HCT-116, at micromolar concentration. 1',1''-(Acridin-3,6-diyl)-3',3''-dihexyldiurea hydrochloride was active on a HCT-116 cell line with an IC(50) value of 3.1 microM. The interaction of these compounds with calf thymus DNA was investigated by a variety of spectroscopic techniques including UV-vis, fluorescence and CD spectroscopy. From spectrofluorimetric titrations, binding constants for the DNA-drug complexes were determined (K=0.9-4.2x10(5) M(-1)). Antiproliferative activity of synthesized derivatives might be related to their intercalation into DNA.
Assuntos
Acridinas/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , DNA/química , Proflavina/química , Ureia/síntese química , Ureia/toxicidade , Alquilação , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , DNA/genética , Humanos , Estrutura Molecular , Fotoquímica , Espectrofotometria , Relação Estrutura-Atividade , Titulometria , Ureia/químicaRESUMO
In the current study the ability of silver pyridine-2-sulfonate complex to exert multiple biological activities is compared with the pharmacological action of silver sulfadiazine (AgSD). Polymeric form of {[Ag(py-2-SO3)]}n (AgPS) was synthesized and characterized by analytical techniques (IR, CHN, TG/DTA, MS) and its molecular formula was established. The crystal structure was determined by X-ray diffraction method and the polymeric complex crystallizes in the triclinic P-1 space group. The stability of Ag(I) complex was verified by 1H and 13C NMR measurements and the interaction with calf thymus DNA through UV-VIS and fluorescence quenching experiments was studied. The Ag(I) complex was able to interact with DNA by dual binding mode: partial intercalation along groove binding. The binding constants were calculated to be in the order of 103â¯M-1. Topoisomerase I inhibition study have shown that silver complex is inhibiting its activity at concentration of 30⯵M. The cytotoxic activity of AgPS and AgSD against mouse leukaemia L1210â¯S, R and T cell line was also evaluated. AgPS showed higher cytotoxicity than AgSD after 48â¯h incubation. The results suggest that mechanism of cell death is necrosis with a contribution of late apoptosis. Antimicrobial testing indicates higher growth inhibition effect of AgPS with comparison to commercially available AgSD.
Assuntos
Antibacterianos , Bactérias/crescimento & desenvolvimento , Complexos de Coordenação , Piridinas , Prata , Inibidores da Topoisomerase I , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Piridinas/química , Piridinas/farmacologia , Prata/química , Prata/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologiaRESUMO
This study introduces a pair of newly synthesized silver complexes, [Ag2(HGly)2]n(NO3)2n (1) and [Ag(Nam)2]NO3·H2O (2) (Gly - glycine, Nam - nicotinamide), that were prepared and characterized by relevant methods in solid state (elemental, spectral, thermal and structural analysis) and their stability in solution was verified by 1H NMR measurements. Moreover, suitable reaction conditions were observed by potentiometry depending on pH in case of binary system Ag-Gly. X-ray analysis confirmed argentophilic interactions in complex 1 with an Ag1-Ag2 distance of 2.8018(6) Å. Antimicrobial testing indicates higher growth inhibition effect of complex 1 than complex 2. Moreover the effectivity of both complexes against bacteria (Staphylococcus aureus and Escherichia coli) is superior (or similar) to that of the commercially available Ag(I) sulfadiazine, AgSD (used, for example, in Dermazine cream). The binding of the Ag(I) complexes to calf thymus DNA was investigated using electronic absorption, fluorescence and circular dichroism spectrophotometry. The Stern-Volmer quenching constants obtained from the linear quenching plot were estimated in the range from 2.01×103 to 20.34×103M-1. The results of topoisomerase I and topoisomerase II (Topo I and Topo II) inhibition assay suggested that complex 2 inhibits the enzyme activity of both enzymes at a concentration of 2µM. The cytotoxicity of both complexes on L1210 leukemia cells was revealed to be approximately three times higher than that of cisplatin. Moreover, the new Ag(I) complexes also induced apoptosis of the leukemia cells. The high DNA binding activity of these complexes is considered to be responsible for their cytotoxic effects.
Assuntos
Bactérias/efeitos dos fármacos , Complexos de Coordenação/farmacologia , DNA/metabolismo , Glicina/química , Niacinamida/química , Prata/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Cristalografia por Raios X , DNA/química , DNA Topoisomerases/metabolismo , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Prata/químicaRESUMO
Starting from well-defined NH2(CH3)2[PdCl2(XQ)] complexes, coordination compounds of general formula Cat[PdCl2(XQ)] have been prepared by cationic exchange of NH2(CH3)2+ and Cat cations, where XQ are biologically active halogen derivatives of quinolin-8-ol (5-chloro-7-iodo-quinolin-8-ol (CQ), 5,7-dibromo-quinolin-8-ol (dBrQ) and 5,7-dichloro-quinolin-8-ol (dClQ)) and Cat is K+ or Cs+. The cation exchange of all prepared complexes, K[PdCl2(CQ)] (1), K[PdCl2(dClQ)] (2), K[PdCl2(dBrQ)] (3), Cs[PdCl2(CQ)] (4), Cs[PdCl2(dClQ)] (5) and Cs[PdCl2(dBrQ)] (6) was approved using IR spectroscopy, their structures in DMSO solution were elucidated by one- and two-dimensional NMR experiments, whereas their stability in solution was verified by UV-VIS spectroscopy. Interaction of complexes to ctDNA was investigated using UV-VIS and fluorescence emission spectroscopy. The minimum inhibitory concentration and the minimum microbicidal concentration values were detected against 15 bacterial strains and 4 yeast strains to examine the antimicrobial activity for the complexes. The in vitro antitumor properties of the complexes were studied by testing the complexes on leukemic cell line L1210, ovarian cancer cell line A2780 and non-cancerous cell line HEK293. The majority of the prepared compounds exhibited moderate antimicrobial and very high cytotoxic activity.