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1.
Inorg Chem ; 60(16): 12172-12185, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34346215

RESUMO

Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a metal complex, six bidentate N,O-donor ligands with or without a pendant morpholine unit and their corresponding ruthenium(II) p-cymene complexes (1-6) are synthesized, purified, and structurally characterized by various analytical methods including X-ray diffraction. Complexes 2-4 crystallized in the P21/c space group, whereas 5 and 6 crystallized in the P1̅ space group. The solution stability studies using 1H NMR support instantaneous hydrolysis of the native complexes to form monoaquated species in a solution of 3:7 (v/v) dimethyl sulfoxide-d6 and 20 mM phosphate buffer (pH* 7.4, containing 4 mM NaCl). The monoaquated complexes are stable for at least up to 24 h. The complexes display excellent in vitro antiproliferative activity (IC50 ca. 1-14 µM) in various cancer cell lines, viz., MDA-MB-231, MiaPaCa2, and Hep-G2. The presence of the pendant morpholine does not improve the dose efficacy, but rather, with 2-[[(2,6-dimethylphenyl)imino]methyl]phenol (HL1) and its pendant morpholine analogue (HL3) giving complexes 1 and 3, respectively, the antiproliferative activity was poorer with 3. MDA-MB-231 cells treated with the complexes show that the acidic vesicles remain acidic, but the population of acidic vesicles increases or decreases with time of exposure, as observed from the dispersed red puncta, depending on the complex used. The presence of the 2,6-disubstituted aniline and the naphthyl group seems to improve the antiproliferative dose. The complex treated MDA-MB-231 cells show that cathepsin D, which is otherwise present in the cytosolic lysosomes, translocates to the nucleus as a result of exposure to the complexes. Irrespective of the presence of a morpholine motif, the complexes do not activate caspase-3 to induce apoptosis and seem to favor the necrotic pathway of cell killing.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cimenos/química , Morfolinas/química , Rutênio/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Complexos de Coordenação/química , Humanos , Modelos Moleculares , Conformação Molecular
2.
Molecules ; 26(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279368

RESUMO

The purpose of this study was to identify new metal-based anticancer drugs; to this end, we synthesized two new copper(II) complexes, namely [Cu(ncba)4(phen)] (1) and [Cu(ncba)4(bpy)] (2), comprised 4-chloro-3-nitrobenzoic acid as the main ligand. The single-crystal XRD approach was employed to determine the copper(II) complex structures. Binding between these complexes and calf thymus DNA (CT-DNA) and human serum albumin (HSA) was explored by electronic absorption, fluorescence spectroscopy, and viscometry. Both complexes intercalatively bound CT-DNA and statically and spontaneously quenched DNA/HSA fluorescence. A CCK-8 assay revealed that complex 1 and complex 2 had substantial antiproliferative influences against human cancer cell lines. Moreover, complex 1 had greater antitumor efficacy than the positive control cisplatin. Flow cytometry assessment of the cell cycle demonstrated that these complexes arrested the HepG2 cell cycle and caused the accumulation of G0/G1-phase cells. The mechanism of cell death was elucidated by flow cytometry-based apoptosis assays. Western blotting revealed that both copper(II) complexes induced apoptosis by regulating the expression of the Bcl-2(Bcl-2, B cell lymphoma 2) protein family.


Assuntos
Antineoplásicos/síntese química , Clorobenzoatos/química , Complexos de Coordenação/síntese química , Cobre/química , Albumina Sérica Humana/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacologia , DNA/química , Células Hep G2 , Humanos
3.
Inorg Chem ; 60(15): 11154-11163, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34264627

RESUMO

Photodynamic therapy (PDT), which involves the photoinduced sensitization of singlet oxygen, is an attractive treatment for certain types of cancer. The development of new photochemotherapeutic agents remains an important area of research. Macrocyclic tetrapyrrole compounds including porphyrins, phthalocyanines, chlorins, and bacteriochlorins have been pursued as sensitizers of singlet oxygen for PDT applications but historically are difficult to prepare/purify and can also suffer from high nonspecific dark toxicity, poor solubility in biological media, and/or slow clearance from biological tissues. In response to these shortcomings, we have developed a series of novel linear tetrapyrrole architectures complexed to late transition metals as potential PDT agents. We find that these dimethylbiladiene (DMBil1) tetrapyrrole complexes can efficiently photosensitize generation of 1O2 oxygen upon irradiation with visible light. To extend the absorption profile of the DMBil1 platform, alkynyl-aryl groups have been conjugated to the periphery of the tetrapyrrole using Sonogashira methods. Derivatives of this type containing ancillary phenyl (DMBil-PE), naphthyl (DMBil-NE), and anthracenyl (DMBil-AE) groups have been prepared and characterized. In addition to structurally characterizing Pd[DMBil-NE] and Pd[DMBil-AE], we find that extension of the tetrapyrrole conjugation successfully red-shifts the absorption of the DMBil-Ar family of biladienes further into the phototherapeutic window (i.e., 600-900 nm). Photochemical sensitization studies demonstrate that our series of new palladium biladiene complexes (Pd[DMBil-Ar]) can sensitize the formation of 1O2 with quantum yields in the range ΦΔ = 0.59-0.73 upon irradiation with light of λ ≥ 650 nm. The improved absorption properties of the Pd[DMBil-Ar] complexes in the phototherapeutic window, together with their high 1O2 quantum yields, highlight the promise of these compounds as potential agents for PDT.


Assuntos
Alcinos/química , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Paládio/química , Porfirinas/química , Oxigênio Singlete/química , Técnicas de Química Sintética , Complexos de Coordenação/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química
4.
Inorg Chem ; 60(15): 11297-11319, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34279079

RESUMO

Three new thiosemicarbazones (TSCs) HL1-HL3 as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of HL1-HL3 with CuCl2·2H2O in anoxic methanol afforded three copper(II) complexes, namely, Cu(HL1)Cl2 (1), [Cu(L2)Cl] (2'), and Cu(HL3)Cl2 (3), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as HL1-HL3 at pH 7.4, while being air-sensitive in the basic pH range. In dimethyl sulfoxide they exist as a mixture of E and Z isomers. A mechanism of the E/Z isomerization with an inversion at the nitrogen atom of the Schiff base imine bond is proposed. The monocationic complexes [Cu(L1-3)]+ are the most abundant species in aqueous solutions at pH 7.4. Electrochemical and spectroelectrochemical studies of 1, 2', and 3 confirmed their redox activity in both the cathodic and the anodic region of potentials. The one-electron reduction was identified as metal-centered by electron paramagnetic resonance spectroelectrochemistry. An electrochemical oxidation pointed out the ligand-centered oxidation, while chemical oxidations of HL1 and HL2 as well as 1 and 2' afforded several two-electron and four-electron oxidation products, which were isolated and comprehensively characterized. Complexes 1 and 2' showed an antiproliferative activity in Colo205 and Colo320 cancer cell lines with half-maximal inhibitory concentration values in the low micromolar concentration range, while 3 with the most closely related ligand to triapine displayed the best selectivity for cancer cells versus normal fibroblast cells (MRC-5). HL1 and 1 in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Piridinas/química , Tiossemicarbazonas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Complexos de Coordenação/química , Eletroquímica , Humanos , Oxirredução , Soluções , Estereoisomerismo
5.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198604

RESUMO

Two penta-coordinated [Co(MorphBPT)Cl2]; 1 and [Co(PipBPT)Cl2]; 2 complexes with the bis-pyrazolyl-s-triazine pincer ligands MorphBPT and PipBPT were synthesized and characterized. Both MorphBPT and PipBPT act as NNN-tridentate pincer chelates coordinating the Co(II) center with one short Co-N(s-triazine) and two longer Co-N(pyrazole) bonds. The coordination number of Co(II) is five in both complexes, and the geometry around Co(II) ion is a distorted square pyramidal in 1, while 2 shows more distortion. In both complexes, the packing is dominated by Cl…H, C-H…π, and Cl…C (anion-π stacking) interactions in addition to O…H interactions, which are found only in 1. The UV-Vis spectral band at 564 nm was assigned to metal-ligand charge transfer transitions based on TD-DFT calculations. Complexes 1 and 2 showed higher antimicrobial activity compared to the respective free ligand MorphBPT and PipBPT, which were not active. MIC values indicated that 2 had better activity against S. aureus, B. subtilis, and P. vulgaris than 1. DPPH free radical scavenging assay revealed that all the studied compounds showed weak to moderate antioxidant activity where the nature of the substituent at the s-triazine core has a significant impact on the antioxidant activity.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Cobalto/química , Complexos de Coordenação/síntese química , Cristalografia por Raios X/métodos , Pirazóis/química , Triazinas/química , Antibacterianos/síntese química , Antioxidantes/química , Complexos de Coordenação/farmacologia , Ligantes , Testes de Sensibilidade Microbiana/métodos , Modelos Moleculares
6.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209921

RESUMO

Three novel gold(III) complexes (1-3) of general composition [Au(Bipydc)(S2CNR2)]Cl2 (Bipydc = 2,2'-bipyridine-3,3'-dicarboxylic acid and R = methyl for dimethyldithiocarbamate (DMDTC), ethyl for diethyldithiocarbamate (DEDTC), and benzyl for dibenzyldithiocarbamate (DBDTC)) have been synthesized and characterized by elemental analysis, FTIR and NMR spectroscopic techniques. The spectral results confirmed the presence of both the Bipydc and dithiocarbamate ligands in the complexes. The in vitro cytotoxic studies demonstrated that compounds 1-3 were highly cytotoxic to A549, HeLa, MDA-231, and MCF-7 cancer cells with activities much higher (about 25-fold) than cisplatin. In order to know the possible mode of cell death complex 2, [Au(Bipydc)(DEDTC)]Cl2 was further tested for induction of apoptosis towards the MCF-7 cells. The results indicated that complex 2 induces cell death through apoptosis.


Assuntos
Antineoplásicos , Complexos de Coordenação , Ouro/química , Piridinas/química , Tiocarbamatos/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Células HeLa , Humanos , Células MCF-7
7.
J Med Chem ; 64(12): 8523-8544, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34077212

RESUMO

Boron neutron capture therapy (BNCT) is a binary therapeutic method for cancer treatment based on the use of a combination of a cancer-specific drug containing boron-10 (10B) and thermal neutron irradiation. For successful BNCT, 10B-containing molecules need to accumulate specifically in cancer cells, because destructive effect of the generated heavy particles is limited basically to boron-containing cells. Herein, we report on the design and synthesis of boron compounds that are functionalized with 9-, 12-, and 15-membered macrocyclic polyamines and their Zn2+ complexes. Their cytotoxicity, intracellular uptake activity into cancer cells and normal cells, and BNCT effect are also reported. The experimental data suggest that mono- and/or diprotonated forms of metal-free [12]aneN4- and [15]aneN5-type ligands are uptaken into cancer cells, and their complexes with intracellular metals such as Zn2+ would induce cell death upon thermal neutron irradiation, possibly via interactions with DNA.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Complexos de Coordenação/farmacologia , Compostos Macrocíclicos/farmacologia , Poliaminas/farmacologia , Antineoplásicos/síntese química , Compostos de Boro/síntese química , Terapia por Captura de Nêutron de Boro , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Desenho de Fármacos , Humanos , Compostos Macrocíclicos/síntese química , Poliaminas/síntese química , Zinco/química
8.
Eur J Med Chem ; 222: 113610, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34144354

RESUMO

A structure activity relationship (SAR) study of a library of 56 compounds (54 ruthenium and 2 osmium derivatives) based on the trithiolato-bridged dinuclear ruthenium(II)-arene scaffold (general formula [(η6-arene)2Ru2(µ2-SR)3]+, symmetric and [(η6-arene)2Ru2(µ2-SR1)2(µ2-SR2)]+, mixed, respectively) is reported. The 56 compounds (of which 34 are newly designed drug candidates) were synthesized by introducing chemical modifications at the level of bridge thiols, and they were grouped into eight families according to their structural features. The selected fittings were guided by previous results and focused on a fine-tuning of the physico-chemical and steric properties. Newly synthesized complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis, and four single-crystal X-ray structures were obtained. The in vitro biological assessment of the compounds was realized by applying a three-step screening cascade: (i) evaluation of the activity against Toxoplasma gondii RH strain tachyzoites expressing ß-galactosidase (T. gondii-ß-gal) grown in human foreskin fibroblast monolayers (HFF) and assessment of toxicity in non-infected HFF host cells; (ii) dose-response assays using selected compound, and (iii) studies on the effects in murine splenocytes. A primary screening was performed at 1 and 0.1 µM, and resulted in the selection of 39 compounds that inhibited parasite proliferation at 1 µM by more than 95% and reduced the viability of HFF by less than 49%. In the secondary screening, dose-response assays showed that the selected compounds exhibited half maximal inhibitory concentration (IC50) values for T. gondii-ß-gal between 0.01 µM and 0.45 µM, with 30 compounds displaying an IC50 lower than 0.1 µM. When applied to non-infected HFF monolayers at 2.5 µM, 8 compounds caused more than 90% and 31 compounds more than 30% viability impairment. The tertiary screening included 14 compounds that did not cause HFF viability loss higher than 50% at 2.5 µM. These derivatives were assessed for potential immunosuppressive activities. First, splenocyte viability was assessed after treatment of cells with concanavalin A (ConA) and lipopolysaccharide (LPS) with compounds applied at 0.1 and 0.5 µM. Subsequently, the 5 compounds exhibiting the lowest splenocyte toxicity were further evaluated for their potential to inhibit B and T cell proliferation. Overall, compound 55 [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-o-CF3)2(µ2-SC6H4-p-OH)]Cl exhibited the most favorable features, and will be investigated as a scaffold for further optimization in terms of anti-parasitic efficacy and drug-like properties.


Assuntos
Antiparasitários/farmacologia , Complexos de Coordenação/farmacologia , Rutênio/farmacologia , Compostos de Sulfidrila/farmacologia , Toxoplasma/efeitos dos fármacos , Antiparasitários/síntese química , Antiparasitários/química , Linhagem Celular , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Rutênio/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/química
9.
Eur J Med Chem ; 222: 113640, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34147908

RESUMO

The genome packaging of human cytomegalovirus (HCMV) requires a divalent metal-dependent endonuclease activity localized to the C-terminus of pUL89 (pUL89-C), which is reminiscent of RNase H-like enzymes in active site structure and catalytic mechanism. Our previous work has shown that metal-binding small molecules can effectively inhibit pUL89-C while conferring significant antiviral activities. In this report we generated a collection of 43 metal-binding small molecules by repurposing analogs of the 6-arylthio-3-hydroxypyrimidine-2,4-dione chemotype previously synthesized for targeting HIV-1 RNase H, and by chemically synthesizing new N-1 analogs. The analogs were subjected to two parallel screening assays: the pUL89-C biochemical assay and the HCMV antiviral assay. Compounds with significant inhibition from each assay were further tested in a dose-response fashion. Single dose cell viability and PAMPA cell permeability were also conducted and considered in selecting compounds for the dose-response antiviral testing. These assays identified a few analogs displaying low µM inhibition against pUL89-C in the biochemical assay and HCMV replication in the antiviral assay. The target engagement was further evaluated via a thermal shift assay using recombinant pUL89-C and molecular docking. Overall, our current work identified novel inhibitors of pUL89-C with significant antiviral activities and further supports targeting pUL89-C with metal-binding small molecules as an antiviral approach against HCMV.


Assuntos
Antivirais/farmacologia , Complexos de Coordenação/farmacologia , Citomegalovirus/efeitos dos fármacos , Endonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Citomegalovirus/enzimologia , Relação Dose-Resposta a Droga , Endonucleases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
10.
J Med Chem ; 64(13): 9381-9388, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34137262

RESUMO

Antibiotic resistance (AR) necessitates the discovery of new antimicrobials with alternative mechanisms of action to those employed by conventional antibiotics. One such strategy utilizes Ga3+ to target iron metabolism, a critical process for survival. Still, Ga-based therapies are generally ineffective against Gram-positive bacteria and promote Ga resistance. In response to these drawbacks, we report a lipophilic Ga complex, [Ga2L3(bpy)2] (L = 2,2'-bis(3-hydroxy-1,4-naphthoquinone; bpy = 2,2'-bipyridine)), effective against drug-resistant Pseudomonas aeruginosa (DRPA; minimum inhibitory concentration, MIC = 10 µM = 14.8 µg/mL) and methicillin-resistant Staphylococcus aureus (MRSA, MIC = 100 µM = 148 µg/mL) without iron-limited conditions. Importantly, [Ga2L3(bpy)2] shows noticeably delayed and decreased resistance in both MRSA and DRPA, with only 8× MIC in DRPA and none in MRSA after 30 passages. This is likely due to the dual mode of action afforded by Ga (disruption of iron metabolism) and the ligand (reactive oxygen species production). Overall, [Ga2L3(bpy)2] demonstrates the utility of lipophilic metal complexes with multiple modes of action in combatting AR in Gram-positive and Gram-negative bacteria.


Assuntos
Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Gálio/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Gálio/química , Estrutura Molecular , Relação Estrutura-Atividade
11.
J Med Chem ; 64(13): 9182-9192, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34152137

RESUMO

Liver-specific contrast agents (CAs) can improve the Magnetic resonance imaging (MRI) detection of focal and diffuse liver lesions by increasing the lesion-to-liver contrast. A novel Mn(II) complex, Mn-BnO-TyrEDTA, with a lipophilic group-modified ethylenediaminetetraacetic acid (EDTA) structure as a ligand to regulate its behavior in vivo, is superior to Gd-EOB-DTPA in terms of a liver-specific MRI contrast agent. An MRI study on mice demonstrated that Mn-BnO-TyrEDTA can be rapidly taken up by hepatocytes with a combination of hepatobiliary and renal clearance pathways. Bromosulfophthalein (BSP) inhibition imaging, biodistribution, and cellular uptake studies confirmed that the mechanism of hepatic targeting of Mn-BnO-TyrEDTA is the hepatic uptake of the amphiphilic anion contrast agent mediated by organic anion transporting polypeptides (OATPs) expressed by functional hepatocytes.


Assuntos
Meios de Contraste/farmacocinética , Complexos de Coordenação/farmacocinética , Ácido Edético/farmacocinética , Hepatócitos/metabolismo , Imageamento por Ressonância Magnética , Manganês/farmacocinética , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/síntese química , Meios de Contraste/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ácido Edético/química , Hepatócitos/química , Hepatócitos/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Manganês/química , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
12.
Int J Biol Macromol ; 184: 259-270, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126148

RESUMO

Janus nanomaterials possess remarkable prospects in the design of a series of smart materials with unique asymmetric properties. In this work, surface functionalized Janus cellulose nanocrystalline-type (CNCs-type) nanomaterials were manufactured by Pickering emulsion template and the construction of self-healing nanocomposite hydrogels has been realized. During emulsification, the mussel-inspired chemistry was employed to develop Janus nanocomposites. The extension of molecular chain of poly-lysine (PLL) and the polydopamine (PDA) coating were grafted on different sides of CNCs. Afterwards, the prepared nanocomposites were added to poly (acrylic acid) (PAA)-based hydrogels which formed by in-situ polymerization. The collaborative effect of metal-ligand coordination between the molecular chain of PLL, PDA coating, PAA chains and metal ions endowed the nanocomposite hydrogels with excellent mechanical properties (8.8 MPa) and self-healing efficiency (88.9%). Therefore, the synthesized Janus CNCs-PDA/PLL nanocomposites are expected to have diverse application in the development of smart materials with self-healing ability.


Assuntos
Celulose/química , Complexos de Coordenação/síntese química , Nanogéis/química , Acrilatos/química , Complexos de Coordenação/química , Emulsões , Lisina/química , Nanopartículas Multifuncionais , Nanocompostos , Nanopartículas
13.
Inorg Chem ; 60(12): 8826-8837, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34060309

RESUMO

How to deliver nitric oxide (NO) to a physiological target and control its release quantitatively is a key issue for biomedical applications. Here, a water-soluble nitrosylruthenium complex, [(CH3)4N][RuCl3(5cqn)(NO)] (H5cqn = 5-chloro-8-quinoline), was synthesized, and its structure was confirmed with 1H NMR and X-ray crystal diffraction. Photoinduced NO release was investigated with time-resolved Fourier transform infrared and electron paramagnetic resonance (EPR) spectroscopies. The binding constant of the [RuCl3(5cqn)(NO)]- complex with human serum albumin (HSA) was determined by fluorescence spectroscopy, and the binding mode was identified by X-ray crystallography of the HSA and Ru-NO complex adduct. The crystal structure reveals that two molecules of the Ru-NO complex are located in the subdomain IB, which is one of the major drug binding regions of HSA. The chemical structures of the Ru complexes were [RuCl3(5cqn)(NO)]- and [RuCl3(Glycerin)NO]-, in which the electron densities for all ligands to Ru are unambiguously identified. EPR spin-trapping data showed that photoirradiation triggered NO radical generation from the HSA complex adduct. Moreover, the near-infrared image of exogenous NO from the nitrosylruthenium complex in living cells was observed using a NO-selective fluorescent probe. This study provides a strategy to design an appropriate delivery system to transport NO and metallodrugs in vivo for potential applications.


Assuntos
Complexos de Coordenação/metabolismo , Óxido Nítrico/metabolismo , Compostos de Rutênio/metabolismo , Albumina Sérica Humana/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Corantes Fluorescentes/química , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/química , Imagem Óptica , Processos Fotoquímicos , Compostos de Rutênio/química , Albumina Sérica Humana/química , Células Tumorais Cultivadas
14.
Inorg Chem ; 60(12): 9199-9211, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34102841

RESUMO

The radionuclide 213Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10-7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.


Assuntos
Bismuto/uso terapêutico , Quelantes/uso terapêutico , Complexos de Coordenação/uso terapêutico , Éteres de Coroa/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Radiofarmacêuticos/uso terapêutico , Bismuto/química , Quelantes/síntese química , Quelantes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Éteres de Coroa/química , Teoria da Densidade Funcional , Humanos , Cinética , Ligantes , Estrutura Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
15.
Inorg Chem ; 60(12): 8651-8664, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34110140

RESUMO

Four high-spin Fe(III) macrocyclic complexes, including three dinuclear and one mononuclear complex, were prepared toward the development of more effective iron-based magnetic resonance imaging (MRI) contrast agents. All four complexes contain a 1,4,7-triazacyclononane macrocyclic backbone with two hydroxypropyl pendant groups, an ancillary aryl or biphenyl group, and a coordination site for a water ligand. The pH potentiometric titrations support one or two deprotonations of the complexes, most likely deprotonation of hydroxypropyl groups at near-neutral pH. Variable-temperature 17O NMR studies suggest that the inner-sphere water ligand is slow to exchange with bulk water on the NMR time scale. Water proton T1 relaxation times measured for solutions of the Fe(III) complexes at pH 7.2 showed that the dinuclear complexes have a 2- to 3-fold increase in r1 relaxivity in comparison to the mononuclear complex per molecule at field strengths ranging from 1.4 T to 9.4 T. The most effective agent, a dinuclear complex with macrocycles linked through para-substitution of an aryl group (Fe2(PARA)), has an r1 of 6.7 mM-1 s-1 at 37 °C and 4.7 T or 3.3 mM-1 s-1 per iron center in the presence of serum albumin and shows enhanced blood pool and kidney contrast in mice MRI studies.


Assuntos
Meios de Contraste/química , Complexos de Coordenação/química , Compostos Férricos/química , Compostos Macrocíclicos/química , Imageamento por Ressonância Magnética , Animais , Meios de Contraste/síntese química , Meios de Contraste/farmacocinética , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacocinética , Compostos Férricos/farmacocinética , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Albumina Sérica Humana/química
16.
Inorg Chem ; 60(12): 8710-8721, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34110143

RESUMO

A handful of oxygen-activating enzymes has recently been found to contain Fe/Mn active sites, like Class 1c ribonucleotide reductases and R2-like ligand-binding oxidase, which are closely related to their better characterized diiron cousins. These enzymes are proposed to form high-valent intermediates with Fe-O-Mn cores. Herein, we report the first examples of synthetic Fe/Mn complexes that mimic doubly bridged intermediates proposed for enzymatic oxygen activation. Fe K-edge extended X-ray absorption fine structure (EXAFS) analysis has been used to characterize the structures of each of these compounds. Linear compounds accurately model the Fe···Mn distances found in Fe/Mn proteins in their resting states, and doubly bridged diamond core compounds accurately model the distances found in high-valent biological intermediates. Unlike their diiron analogues, the paramagnetic nature of Fe/Mn compounds can be analyzed by EPR, revealing S = 1/2 signals that reflect antiferromagnetic coupling between the high-spin Fe(III) and Mn(III) units of heterobimetallic centers. These compounds undergo electron transfer with various ferrocenes, linear compounds being capable of oxidizing diacetyl ferrocene, a weak reductant, and diamond core compounds being capable of oxidizing acetyl ferrocene. Diamond core compounds can also perform HAT reactions from substrates with X-H bonds with bond dissociation free energies (BDFEs) up to 75 kcal/mol and are capable of oxidizing TEMPO-H at rates of 0.32-0.37 M-1 s-1, which are comparable to those reported for some mononuclear FeIII-OH and MnIII-OH compounds. However, such reactivity is not observed for the corresponding diiron compounds, a difference that Nature may have taken advantage of in evolving enzymes with heterobimetallic active sites.


Assuntos
Complexos de Coordenação/metabolismo , Compostos Férricos/metabolismo , Manganês/metabolismo , Ribonucleotídeo Redutases/metabolismo , Sítios de Ligação , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Compostos Férricos/química , Manganês/química , Modelos Moleculares , Estrutura Molecular , Oxigênio/química , Oxigênio/metabolismo , Ribonucleotídeo Redutases/química
17.
Inorg Chem ; 60(13): 9233-9237, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34111354

RESUMO

Two new desoxo molybdenum(V) complexes have been synthesized and characterized as models for the paramagnetic high-g split intermediate observed in the catalytic cycle of dimethyl sulfoxide reductase (DMSOR). Extended X-ray absorption fine structure (EXAFS) and electron paramagnetic resonance (EPR) data are used to provide new insight into the geometric and electronic structures of high-g split and other EPR-active type II/III DMSOR family enzyme forms. The results support a 6-coordinate [(PDT)2Mo(OH)(OSer)]- structure (PDT = pyranopterin dithiolene) for a high-g split with four S donors from two PDT ligands, a coordinated hydroxyl ligand, and a serinate O donor. This geometry orients the redox orbital toward the substrate access channel for the two-electron reduction of substrates.


Assuntos
Complexos de Coordenação/metabolismo , Proteínas Ferro-Enxofre/metabolismo , Oxirredutases/metabolismo , Serina/metabolismo , Biocatálise , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Proteínas Ferro-Enxofre/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Molibdênio/química , Molibdênio/metabolismo , Oxirredução , Oxirredutases/química , Serina/química
18.
Inorg Chem ; 60(13): 9805-9819, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34115482

RESUMO

A series of nine RuII arene complexes bearing tridentate naphthoquinone-based N,O,O-ligands was synthesized and characterized. Aqueous stability and their hydrolysis mechanism were investigated via UV/vis photometry, HPLC-MS, and density functional theory calculations. Substituents with a positive inductive effect improved their stability at physiological pH (7.4) intensely, whereas substituents such as halogens accelerated hydrolysis and formation of dimeric pyrazolate and hydroxido bridged dimers. The observed cytotoxic profile is unusual, as complexes exhibited much higher cytotoxicity in SW480 colon cancer cells than in the broadly chemo- (incl. platinum-) sensitive CH1/PA-1 teratocarcinoma cells. This activity pattern as well as reduced or slightly enhanced ROS generation and the lack of DNA interactions indicate a mode of action different from established or previously investigated classes of metallodrugs.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Naftoquinonas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Rutênio/química , Água/química
19.
Inorg Chem ; 60(13): 9880-9898, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34130457

RESUMO

In the search for potential new metal-based antitumor agents, two series of nonclassical palladium(II) pincer complexes based on functionalized amides with S-modified cysteine and homocysteine residues have been prepared and fully characterized by 1D and 2D NMR (1H, 13C, COSY, HMQC or HSQC, 1H-13C, and 1H-15N HMBC) and IR spectroscopy and, in some cases, X-ray diffraction. Most of the resulting complexes exhibit a high level of cytotoxic activity against several human cancer cell lines, including colon (HCT116), breast (MCF7), and prostate (PC3) cancers. Some of the compounds under consideration are also efficient in both native and doxorubicin-resistant transformed breast cells HBL100, suggesting the prospects for the creation of therapeutic agents based on the related compounds that would be able to overcome drug resistance. An analysis of different aspects of their biological effects on living cells has revealed a remarkable ability of the S-modified derivatives to induce cell apoptosis and efficient cellular uptake of their fluorescein-conjugated counterpart, confirming the high anticancer potential of Pd(II) pincer complexes derived from functionalized amides with S-donor amino acid pendant arms.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cisteína/farmacologia , Paládio/farmacologia , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cisteína/análogos & derivados , Cisteína/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Paládio/química
20.
Inorg Chem ; 60(13): 9529-9541, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34156246

RESUMO

Four bipyridine-type ligands variably derivatized with two bioactive groups (taken from ethacrynic acid, flurbiprofen, biotin, and benzylpenicillin) were prepared via sequential esterification steps from commercial 2,2'-bipyridine-4,4'-dicarboxylic acid and subsequently coordinated to ruthenium(II) p-cymene and iridium(III) pentamethylcyclopentadienyl scaffolds. The resulting complexes were isolated as nitrate salts in high yields and fully characterized by analytical and spectroscopic methods. NMR and MS studies in aqueous solution and in cell culture medium highlighted a substantial stability of ligand coordination and a slow release of the bioactive fragments in the latter case. The complexes were assessed for their antiproliferative activity on four cancer cell lines, showing cytotoxicity to the low micromolar level (equipotent with cisplatin). Additional biological experiments revealed a multimodal mechanism of action of the investigated compounds, involving DNA metalation and enzyme inhibition. Synergic effects provided by specific combinations of metal and bioactive fragments were identified, pointing toward an optimal ethacrynic acid/flurbiprofen combination for both Ru(II) and Ir(III) complexes.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Piridinas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Dano ao DNA , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Ligantes , Estrutura Molecular , Piridinas/química , Rutênio/química , Células Tumorais Cultivadas
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