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S-isoalkyl derivatives of thiosalicylic acid (isopropyl-(L1), isobutyl-(L2) and isoamyl-(L3)) were selected in order to investigate the binding interaction with the human serum albumin (HSA) using different spectroscopic methods and molecular docking simulation. Association constants and number of binding sites were used to analyze the quenching mechanism. The experimental results showed that the fluorescence quenching of HSA by L1, L2 and L3 occurs because of static quenching and that binding processes were spontaneous, with the leading forces in bonding by hydrogen bonding, hydrophobic interactions, and electrostatic interactions. Fluorescence spectroscopy, UV-Vis spectroscopy and synchronous fluorescence spectroscopy showed that ligands (L1, L2 and L3) can bind to HSA and that the binding of ligands induced some microenvironmental and conformational changes in HSA. The calculated distance between the donor and the acceptor according to fiFörster's theory confirms the energy transfer efficiency between the acceptor and HSA. Results of site marker competitive experiments showed that the tested compounds bind to HSA in domain IIA (Site I). Molecular dynamics and docking calculations demonstrated that L3 binds to the Sudlow site I of HSA with lower values of binding energies compared to L1 and L2, indicating the formation of the most stable ligand-HSA complex. Understanding the binding mechanisms of S-isoalkyl derivatives of the thiosalicylic acid to HSA may provide valuable data for the future studies of their biological activity and application as potential antitumor drugs.Communicated by Ramaswamy H. Sarma.
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The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5'-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1ß, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver.
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B cell malignancies are, despite the development of targeted therapy in a certain percentage of the patients still a chronic disease with relapses, requiring multiple lines of therapy. Regimens that include platinum-based drugs provide high response rates in different B cell lymphomas, high-risk chronic lymphocytic leukemia (CLL), and devastating complication of CLL, Richter's syndrome. The aim of this study was to explore the potential antitumor activity of previously synthetized platinum(IV) complex with alkyl derivatives of thyosalicilc acid, PtCl2(S-pr-thiosal)2, toward murine BCL1 cells and to delineate possible mechanisms of action. The PtCl2(S-pr-thiosal)2 reduced the viability of BCL1 cells in vitro but also reduced the growth of metastases in the leukemia lymphoma model in BALB/c mice. PtCl2(S-pr-thiosal)2 induced apoptosis, inhibited proliferation of BCL1 cells, and induced cell cycle disturbance. Treatment of BCL1 cells with PtCl2(S-pr-thiosal)2 inhibited expression of cyclin D3 and cyclin E and enhanced expression of cyclin-dependent kinase inhibitors p16, p21, and p27 resulting in cell cycle arrest in the G1 phase, reduced the percentage of BCL1 cells in the S phase, and decreased expression of Ki-67. PtCl2(S-pr-thiosal)2 treatment reduced expression of phosphorylated STAT3 and downstream-regulated molecules associated with cancer stemness and proliferation, NANOG, cyclin D3, and c-Myc, and expression of phosphorylated NFκB in vitro and in vivo. In conclusion, PtCl2(S-pr-thiosal)2 reduces STAT3 and NFκB phosphorylation resulting in inhibition of BCL1 cell proliferation and the triggering of apoptotic cell death.
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Leucemia Linfocítica Crônica de Células B , Leucemia , Linfoma Difuso de Grandes Células B , Animais , Ciclo Celular , Ciclina D3 , Leucemia Linfocítica Crônica de Células B/patologia , CamundongosRESUMO
Four new complexes of copper(II) with S,O-tetradentate ligands, derivatives of thiosalicylic acid, encompassing an ethylene-, propylene-, butylene- and pentylene- bridge, were synthesized and characterized by microanalysis, molecular conductance and infrared (IR) spectra. The structures were assumed based on the previously mentioned analyses and confirmed with the results of electron paramagnetic resonance (EPR) spectra. The reactivity of complexes towards L-methionine (L-Met), L-cysteine (L-Cys) and guanosine-5'-monophosphate (5'-GMP) was also examined. Complex C1 ([Cu(S,O-ethylene-thiosalicylic acid)(H2O)2]) containing two inert methylene groups in the side chain of ligand shows the highest reactivity, while the least reactive is complex C4 ([Cu(S,O-pentylene-thiosalicylic acid)(H2O)2]) with five methylene groups. All complexes showed the highest reactivity towards L-Met and the lowest reactivity towards 5'-GMP. The interactions of complexes C1-C4 with calf thymus DNA (ct-DNA) were examined by ultraviolet-visible (UV-Vis) absorption and fluorescence spectral studies, revealing good DNA interaction abilities. All synthesized complexes C1-C4 show to interact with human serum albumin (HSA) with high values of binding constants. Complexes interaction with DNA/HSA was also confirmed using molecular docking simulations. All synthesized complexes reduce viability of human colon, breast and lung cancer cells, evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric technique. The complex [Cu(S,O-pentylene- thiosalicylic acid)(H2O)2] showed the highest binding affinity constants to DNA/HSA and highest cytotoxicity, thus presenting a good candidate for further pharmacological research in the field of colon, breast and lung cancer therapy.
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Antineoplásicos , Complexos de Coordenação , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Cobre/química , Cobre/metabolismo , DNA/química , DNA/metabolismo , Etilenos/metabolismo , Guanosina Monofosfato/metabolismo , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Albumina Sérica Humana/químicaRESUMO
Due to the length of time required to develop specific antiviral agents, the World Health Organization adopted the strategy of repurposing existing medications to treat Coronavirus disease 2019 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease is possible biological target for potential antiviral drugs. We selected various compounds from PubChem database based on the structure of main protease inhibitors in Protein Data Bank database. Ten compounds showed nontumorigenic and nonmutagenic potential and met Egan's and Lipinski's rules. Molecular docking analysis was performed using AutoDock Vina software. Based on number and type of key binding interactions, as well as docking scores, we selected compounds 6, 8, and 17 that demonstrated the highest binding affinity for the target protein. Molecular dynamics simulations were then carried out on the protein-top docked ligand complexes which were subjected to molecular mechanics/generalized Born and surface area calculations. The molecular dynamics simulation results indicated that protein-top docked ligand complexes showed good conformational stability. Among analyzed molecules, compound 17 emerged as the best in silico hit based on the docking score, MM/GBSA binding energy and MD results.
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Isoalkyl (isoalkylâ¯=â¯isopropyl-(L1), isobutyl-(L2) and isoamyl-(L3)) derivatives of thiosalicylic acid (TSA) were prepared by alkylation of TSA with corresponding isoalkyl-chlorides in the alkaline water-ethanol solution. The new free copper(II)-complexes with corresponding S-isoalkyl derivatives of TSA (C1-copper(II)-complex with S-isopropyl derivative of thiosalicylic acid, C2-copper(II)-complex with S-isobutyl derivative of thiosalicylic acid and C3-copper(II)-complex with S-isoamyl derivative of thiosalicylic acid) have been synthesized by direct reaction of copper(II)-nitrate with ligand precursor and then characterized by microanalysis, infrared spectra (IR) and EPR (electron paramagnetic resonance) spectra. The spectroscopically predicted structure of the obtained binuclear copper(II)-complex with S-isopropyl derivative of thiosalicylic acid was confirmed by X-ray analysis. Single crystals suitable for X-ray measurements were obtained by slow crystallization from a water solution. Newly synthesized precursors S-isoalkyl derivatives of thiosalicylic acid and corresponding copper(II)-complexes moderately reduced viability of human and murine lung cancer cells, they showed similar cytotoxic effect on human colorectal cancer cells as cisplatin and lower cytotoxic effect than cisplatin toward normal fibroblasts, evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) colorimetric technique. All new complexes exhibited apoptotic effect toward lung cancer cells, stronger than cisplatin, whereas only C3 induced significant apoptosis of colorectal cancer cells. Complex C1 showed significant antiproliferative effect against murine lung cancer cells, LLC1, while C2 reduced expression of Ki67 in human colorectal cancer cells. All tested complexes induced cell cycle arrest of HCT116 cells in G2/M phase.
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Complexos de Coordenação , Cobre , Citotoxinas , Salicilatos , Células A549 , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Cristalografia por Raios X , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Estrutura Molecular , Salicilatos/síntese química , Salicilatos/química , Salicilatos/farmacologiaRESUMO
Aim: We investigated the antitumor effects of zinc(II) complex with S-propyl thiosalicylic acid [Zn(S-pr-thiosal)2] in 4T1 murine breast cancer model. Results: The Zn(S-pr-thiosal)2 complex reduced primary tumor growth in vivo and induced tumor cell apoptosis. The Zn(S-pr-thiosal)2 complex disrupted the balance between pro- and antiapoptotic Bcl-2 family members in 4T1 cells and induced G1/S cell cycle arrest. The Zn(S-pr-thiosal)2 complex increased the percentage of p16, p21 and p27 positive 4T1 cells. There was a significantly decrease in expression of STAT3 and its targets c-Myc and cyclin D3 in 4T1 cells treated with the Zn(S-pr-thiosal)2 complex thus contributing to G1/S cell cycle arrest and/or apoptosis. Conclusion: Our data suggest that the Zn(S-pr-thiosal)2 complex restricted tumor growth through induction of mitochondrial-driven apoptosis and suppression of cell cycle progression.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Complexos de Coordenação/farmacologia , Compostos de Sulfidrila/farmacologia , Zinco/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Compostos de Sulfidrila/química , Zinco/químicaRESUMO
Four new ligands and their palladium(II) complexes of general formula R2-S,S-eddtyr (L1-L4) and [PdCl2(R2-S,S-eddtyr)] (C1-C4) (R=ethyl, n-propyl, n-butyl and n-pentyl; S,S-eddtyr·2HCl=ethylenediamine-N,N'-di-(2,2'-di(4-hydroxy-benzyl))-acetic acid dihydrochloride have been synthesized and characterized by microanalysis, infrared, (1)H and (13)C NMR spectroscopy. Cytotoxicity for ligands and complexes on two different cell lines (human breast cancer, MDA-MB-231 and human lung cancer, A549 cell lines) and human chronic lymphocytic leukemia cells (CLL) was investigated using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay.
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Acetatos , Antineoplásicos , Citotoxinas , Neoplasias/tratamento farmacológico , Acetatos/síntese química , Acetatos/química , Acetatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Neoplasias/metabolismo , Neoplasias/patologia , Paládio/química , Paládio/farmacologia , EstereoisomerismoRESUMO
The new coumarine derivative, 3-(1-(2-hydroxyethylamino)ethylidene)chroman-2,4--dione, and corresponding palladium(II) complex have been synthesized and characterized by microanalysis, infrared, (1)H and (13)C NMR spectroscopy. The proposed structure of the complex was confirmed on the basis of the X-ray structural study. The palladium(II) complex decreased viability of L929 mouse fibrosarcoma, U251 human glioma and B16 mouse melanoma cell lines in a dose dependent manner, while its ligand exhibited no significant cytotoxicity. The cytotoxic effect of the complex was comparable to that of cisplatin, and mediated by apoptosis associated with oxidative stress, mitochondrial depolarization and caspase activation. Therefore, our results indicate that newly synthesized palladium(II) complex might be a potential candidate for anticancer therapy.
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Cumarínicos/química , Paládio/química , Animais , Caspases/metabolismo , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Paládio/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
In the title compound, C(21)H(18)O(2)S, the central aromatic ring makes dihedral angles of 5.86â (12) and 72.02â (6)° with the rings of the terminal O-benzyl and S-benzyl groups, respectively. The dihedral angle between the peripheral phenyl rings is 66.16â (6)°. In the crystal, mol-ecules are linked by pairs of C-Hâ¯O hydrogen bonds, forming inversion dimers. These dimers are linked via C-Hâ¯π inter-actions, forming a three-dimensional network.