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1.
Chem Biodivers ; 17(2): e1900577, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31823465

RESUMO

Organopromoter, 2-aminoethanesulfonic acid was used to catalyze the synthesis of a series of structurally intriguing new hybrids thiazolyl acridine-1,8(2H,5H)-diones and dihydropyrido[2,3-d : 6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones for the first time. 2-Aminoethanesulfonic acid is a biobased organopromoter, used to generate four new bonds for the synthesis of new coupled thiazole-based decahydroacridine-1,8-diones. Superior green credentials, operational simplicity, easy work-up and recyclability of the catalyst are the key strengths of this method. The broad substrate scope, mild reaction conditions, short reaction time, cost effectiveness, high atom economy and good to excellent yields make the present method a distinct improvement over existing methods. Spectral (IR, 1 H-NMR,13 C-NMR, Mass) data and elemental analyses confirmed the structures of the titled products. A series of thiazolyl acridine-1,8(2H,5H)-diones and dihydropyrido[2,3-d : 6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones were screened for their antimicrobial activity against four bacterial and three fungal strains.


Assuntos
Acridinas/química , Anti-Infecciosos/síntese química , Piridinas/química , Ácidos Sulfônicos/química , Tiazóis/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Aspergillus/efeitos dos fármacos , Candida/efeitos dos fármacos , Catálise , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Água/química
2.
Molecules ; 25(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878135

RESUMO

The antitumor effects of thiophene and acridine compounds have been described; however, the clinical usefulness of these compounds is limited due to the risk of high toxicity and drug resistance. The strategy of molecular hybridization presents the opportunity to develop new drugs which may display better target affinity and less serious side effects. Herein, 2-((6-Chloro-2-methoxy-acridin-9-yl)amino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophene-3-carbonitrile (ACS03), a hybrid thiophene-acridine compound with antileishmanial activity, was tested for toxicity and antitumor activity. The toxicity was evaluated in vitro (on HaCat and peripheral blood mononuclear cells) and in vivo (zebrafish embryos and acute toxicity in mice). Antitumor activity was also assessed in vitro in HCT-116 (human colon carcinoma cell line), K562 (chronic myeloid leukemic cell line), HL-60 (human promyelocytic leukemia cell line), HeLa (human cervical cancer cell line), and MCF-7 (breast cancer cell line) and in vivo (Ehrlich ascites carcinoma model). ACS03 exhibited selectivity toward HCT-116 cells (Half maximal inhibitory concentration, IC50 = 23.11 ± 1.03 µM). In zebrafish embryos, ACS03 induced an increase in lactate dehydrogenase, glutathione S-transferase, and acetylcholinesterase activities. The LD50 (lethal dose 50%) value in mice was estimated to be higher than 5000 mg/kg (intraperitoneally). In vivo, ACS03 (12.5 mg/kg) induced a significant reduction in tumor volume and cell viability. In vivo antitumor activity was associated with the nitric oxide cytotoxic effect. In conclusion, significant antitumor activity and weak toxicity were recorded for this hybrid compound, characterizing it as a potential anticancer compound.


Assuntos
Acridinas/farmacologia , Acridinas/toxicidade , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Tiofenos/farmacologia , Tiofenos/toxicidade , Acridinas/química , Animais , Líquido Ascítico/metabolismo , Biomarcadores/metabolismo , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Embrião não Mamífero/efeitos dos fármacos , Feminino , Fluoruracila/farmacologia , Humanos , Camundongos , Nitritos/metabolismo , Tiofenos/química , Testes de Toxicidade Aguda , Peixe-Zebra/embriologia
3.
Molecules ; 25(1)2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31861795

RESUMO

Tumor cells have specific features, including angiogenesis induction, cell cycle dysregulation, and immune destruction evasion. By inducing a T helper type 2 (Th2) immune response, tumor cells may favor immune tolerance within the tumor, which allows progression of cancer growth. Drugs with potential antitumor activity are the spiro-acridines, which is a promising new class of acridine compounds. Herein, the novel spiro-acridine (E)-5'-oxo-1'-((3,4,5-trimethoxybenzylidene)amino)-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-17) was synthesized and tested for antitumor effects. Toxicity evaluation was performed in mice after acute treatment (2000 mg/kg, intraperitoneally, i.p.). The Ehrlich ascites carcinoma model was used to investigate the antitumor activity of AMTAC-17 (12.5, 25, or 50 mg/kg, i.p.) after seven days of treatment. Effects on the cell cycle, angiogenesis, and inflammatory responses were investigated. LD50 (lethal dose 50%) was estimated to be higher than 5000 mg/kg. AMTAC-17 reduced the Ehrlich tumor's total viable cancer cells count and peritumoral micro-vessels density, and induced an increase in the sub-G1 peak. Additionally, there was an increase of Th1 cytokine profile levels (IL-1ß, TNF-α, and IL-12). In conclusion, the spiro-acridine compound AMTAC-17 presents low toxicity, and its in vivo antitumor effect involves modulation of the immune system to a cytotoxic Th1 profile and a reduction of tumor angiogenesis.


Assuntos
Acridinas , Inibidores da Angiogênese , Antineoplásicos , Carcinoma de Ehrlich , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Th1/imunologia , Regulação para Cima/efeitos dos fármacos , Acridinas/química , Acridinas/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/imunologia , Carcinoma de Ehrlich/patologia , Regulação Neoplásica da Expressão Gênica/imunologia , Camundongos , Células Th1/patologia , Regulação para Cima/imunologia
4.
Analyst ; 144(22): 6578-6585, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31596276

RESUMO

Low-molecular-weight (LMW) thiols are important small molecules that regulate or maintain redox homeostasis in physiological and pathological processes. Assessing the concentrations of LMW thiols in biological systems may provide valuable information regarding physiological processes and the early diagnosis of some diseases. Here, we developed a method to simultaneously determine the concentrations of multiple LWM thiols in single cells by chemical derivatization assisted liquid chromatography-mass spectrometry (LC-MS). In this method, we synthesized a pair of stable isotope reagents, N-(acridin-9-yl)-2-bromoacetamide (AYBA) and N-(1,2,3,4-[2H4]-acridin-9-yl)-2-bromoacetamide ([2H4]AYBA). AYBA was used to derivatize LWM thiols in human cervical cancer (HeLa) cells, while [2H4]AYBA was used to derivatize standard LWM thiols to prepare internal standards for the LC-MS method development. The proposed AYBA derivatization greatly enhanced the detection sensitivity of LWM thiols by LC-MS, and thereby achieved the simultaneous detection of multiple LWM thiols by LC-MS in ∼1000 HeLa cells. Finally, the developed method was successfully utilized for the quantitative analysis of multiple LWM thiols in a single HeLa cell and the content changes of LWM thiols in a single HeLa cell before and after oxidative stress treatment. Accordingly, six LMW thiols were detected, including cysteamine, cysteine, glutathione, homocysteine, hydrogen sulfide, and pantetheine.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Compostos de Sulfidrila/análise , Espectrometria de Massas em Tandem/métodos , Acetamidas/síntese química , Acetamidas/química , Acridinas/síntese química , Acridinas/química , Células HeLa , Humanos , Indicadores e Reagentes/síntese química , Indicadores e Reagentes/química , Limite de Detecção , Peso Molecular , Compostos de Sulfidrila/química
5.
Analyst ; 144(22): 6512-6516, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31602449

RESUMO

G-quadruplex (G4) nucleic acid structures are involved in a number of different diseases and their drug-induced stabilization is deemed to be a promising therapeutic approach. Herein is reported a proof of principle study on the use of nano differential scanning fluorimetry for a rapid and accurate analysis of G4-stabilizing ligands, exploiting the fluorescence properties of a 2-aminopurine modified G4-forming oligonucleotide.


Assuntos
DNA/análise , Fluorometria/métodos , Quadruplex G , Acridinas/química , Acridinas/metabolismo , Aminoquinolinas/química , Aminoquinolinas/metabolismo , Dicroísmo Circular , DNA/genética , DNA/metabolismo , Humanos , Ligantes , Ácidos Picolínicos/química , Ácidos Picolínicos/metabolismo , Estudo de Prova de Conceito , Temperatura de Transição
6.
Int J Biol Macromol ; 138: 582-589, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323270

RESUMO

In the present study, acridine-thiosemicarbazones (ATD) derivatives were tested for their interaction properties with BSA through UV-Vis absorption and fluorescence spectroscopic studies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated after the derivatives were added to the BSA. Values for the binding constant (Kb) ranged from 1.62 × 104 to 8.71 × 105 M-1 and quenching constant (KSV) from 3.46 × 102 to 7.83 × 103 M-1 indicating a good affinity to BSA protein. Complementary, two compounds were selected to assess their inhibition activity against topoisomerase IIα enzyme, of which derivative 3a presented the best result. Moreover, to evaluate protein-ligand interactions, as well as the antitopoisomerase potential of these compounds, tests of molecular modeling were performed between all compounds using the albumin and Topoisomerase IIα/DNA complex. Finally, in silico studies showed that all derivatives used in this research displayed good oral bioavailability potential.


Assuntos
Acridinas/química , Soroalbumina Bovina/química , Tiossemicarbazonas/química , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologia , Técnicas de Química Sintética , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Soroalbumina Bovina/metabolismo , Análise Espectral , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/metabolismo
7.
Analyst ; 144(15): 4589-4595, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31237262

RESUMO

We present an ultrasensitive immunoassay system for disease biomarkers utilizing the immuno-wall device and an enzymatic amplification reaction. The immuno-wall device consisted of 40 microchannels, each of which contained an antibody-modified wall-like structure along the longitudinal axis of the microchannel. The wall was fabricated with a water-soluble photopolymer containing streptavidin by photolithography, and biotinylated capture antibodies were immobilized on the sides through streptavidin-biotin interaction. For an assay, introducing the target biomarker and secondary and labeled antibodies produced a sandwich complex anchored on the sides of the wall. A conventional immuno-wall device uses a fluorescence-labeled antibody as a labeling antibody. To achieve an ultrasensitive detection of a trace biomarker, we used an enzyme label and amplified the signal with the enzymatic reaction with a fluorogenic substrate in the microchannel. The highest signal/background ratio was obtained by using alkaline phosphatase-labeled antibody and 9H-(1,3-dichloro-9,9-dimethylacridin-2-one-7-yl) phosphate. To evaluate the device performance, we detected human C-reactive protein (CRP) as a model biomarker. The detection limit (LOD) of CRP in phosphate-buffered saline was 2.5 pg mL-1 with a sample volume of 0.25 µL. This LOD was approximately 3 orders of magnitude lower than that obtained with fluorescent-dye (DyLight 650)-labeled antibody. In addition, the present device provided a wide detection range of 0.0025-10 ng mL-1 for CRP. We successfully developed an ultrasensitive immunoassay system with simple operation and only a small sample volume.


Assuntos
Proteína C-Reativa/análise , Imunoensaio/métodos , Dispositivos Lab-On-A-Chip , Acridinas/química , Fosfatase Alcalina/química , Animais , Anticorpos Imobilizados/imunologia , Biomarcadores/sangue , Proteína C-Reativa/imunologia , Corantes Fluorescentes/química , Cabras , Humanos , Imunoensaio/instrumentação , Limite de Detecção , Camundongos , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Coelhos
8.
Biomolecules ; 9(5)2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072044

RESUMO

The anticancer activity of acridone derivatives has attracted increasing interest, therefore, a variety of substituted analogs belonging to this family have been developed and evaluated for their anti-cancer properties. A series of N-alkyl-acridones 1-6 and N,N'-dialkyl-9,9'-biacridylidenes 7-12 with variable alkyl chains were examined for their topoisomerase I activity at neutral and acidic conditions as well as for their binding capacity to calf thymus and possible radical trapping antioxidant activity. It was found that at a neutral pH, topoisomerase I activity of both classes of compounds was similar, while under acidic conditions, enhanced intercalation was observed. N-alkyl-acridone derivatives 1-6 exhibited stronger, dose-dependent, cytotoxic activity against MCF-7 human breast epithelial cancer cells than N,N'-dialkyl-9,9'-biacridylidenes 7-12, revealing that conjugation of the heteroaromatic system plays a significant role on the effective distribution of the compound in the intracellular environment. Cellular investigation of long alkyl derivatives against cell migration exhibited 40-50% wound healing effects and cytoplasm diffusion, while compounds with shorter alkyl chains were accumulated both in the nucleus and cytoplasm. All N,N'-dialkyl-9,9'-biacridylidenes showed unexpected high scavenging activity towards DPPH or ABTS radicals which may be explained by higher stabilization of radical cations by the extended conjugation of heteroaromatic ring system.


Assuntos
Acridinas/farmacologia , Acridonas/farmacologia , Neoplasias da Mama/patologia , DNA Topoisomerases Tipo I/metabolismo , Depuradores de Radicais Livres/farmacologia , Acridinas/química , Acridonas/química , Benzotiazóis/química , Compostos de Bifenilo/química , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Feminino , Humanos , Células MCF-7 , Picratos/química , Ácidos Sulfônicos/química , Cicatrização/efeitos dos fármacos
9.
Comput Biol Chem ; 80: 351-363, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31085426

RESUMO

mTOR has become a promising target for many types of cancer like breast, lung and renal cell carcinoma. CoMFA, CoMSIA, Topomer CoMFA and HQSAR were performed on the series of 39 triazine morpholino derivatives. CoMFA analysis showed q2 value of 0.735, r2cv value of 0.722 and r2pred value of 0.769. CoMSIA analysis (SEHD) showed q2 value of 0.761, r2cv value of 0.775 and r2pred value of 0.651. Topomer CoMFA analysis showed q2 value of 0.693, r2 (conventional correlation coefficient) value of 0.940 and r2pred value of 0.720. HQSAR analysis showed q2,r2and r2pred values of 0.694, 0.920 and 0.750, respectively. HQSAR analysis with the combination of atomic number (A), bond type (B) and atomic connections showed q2 and r2 values of 0.655 and 0.891, respectively. Contour maps from all studies provided significant insights. Molecular docking studies with molecular dynamics simulations were carried out on the highly potent compound 36. Furthermore, four acridine derivatives were designed and docking results of these designed compounds showed the same interactions as that of the standard PI-103 which proved the efficiency of 3D-QSAR and MD/MS study. In future, this study might be useful prior to synthesis for the designing of novel mTOR inhibitors.


Assuntos
Morfolinas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Triazinas/metabolismo , Acridinas/química , Acridinas/metabolismo , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Conjuntos de Dados como Assunto , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Análise dos Mínimos Quadrados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Morfolinas/química , Ligação Proteica , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Serina-Treonina Quinases TOR/química , Triazinas/química
10.
Luminescence ; 34(5): 512-519, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30972942

RESUMO

Acridinium salts, due to their chemiluminogenic properties, have found several applications in biomedical analysis as labels and indicators, where the assessment of emission intensity is used for the end-point detection. This work presents the use of chemiluminescent indicators in the form of selected acridinium esters in order to determine the antioxidant properties of exemplary formulations, namely quercetin, vitamin C and the dietary supplement, Apiextract. The principle of measurements is based on a change in the kinetics of emission decay derived from the acridinium cations in alkaline solutions of hydrogen peroxide in the presence of an antioxidant (the analyte). The proposed system makes a beneficial alternative to related methods, which mostly rely on the assessment of emission efficiency and use the luminometric standard luminol - due to superior parameters of acridinium chemiluminescence, among others - high temporary emission efficiency. The features of the proposed method are manifested by a shorter time period of analysis and lower background signals associated with the environmental influences, as compared to typical approaches. The chromatographic (RP-HPLC) analyses of the substrates and products generated during chemiluminogenic oxidation of acridinium cations under assay conditions are also presented.


Assuntos
Acridinas/química , Antioxidantes/química , Suplementos Nutricionais/análise , Medições Luminescentes/métodos , Succinimidas/química , Cinética , Luminescência , Luminol/química
11.
Arch Pharm (Weinheim) ; 352(6): e1800307, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31012156

RESUMO

A new series of novel benzo[c]acridine-diones possessing pharmacophoric elements of antitubulins with central dihydropyridine bridge were designed and synthesized as potential anticancer agents and tubulin polymerization inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against eight cancer cell lines including MCF-7, A2780, HeLa, HepG2, DU145, A549, PC3, and LNCAP cancer cells and normal cells human umbilical vein endothelial cell (HUVEC) through 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, wherein ß-lapachone and combretastatin A-4 were used as positive controls. Some of our compounds (4c and 4g) showed significant cytotoxic activity on cancer cells with IC50 values in the range of 5.23-24.32 µM. None of the synthesized compounds showed significant cytotoxicity on normal HUVEC cells. Among all investigated derivatives, compound 4g showed promising greater antiproliferative activity against all tested cancer cells with the highest sensitivity observed for the PC3 cell line. Results from the flow cytometry analysis of PC3 and MCF-7 cancer cells treated with 4g showed an induced cell-cycle arrest at G2/M, and therefore induced apoptosis which occurred at low concentration of test compound, whereas annexin V-FITC/propidium iodide staining assay in the aforementioned cancer cell lines treated with 4g showed that 4g can cause necrosis in PC3 and MCF-7 cancer cells at higher concentration. Compound 4g proved to be an inhibitor of tubulin polymerization in a mode similar to that of colchicine and in a dose-dependent manner. Molecular docking studies of 4g into the colchicine-binding site of tubulin exhibited a possible mode of interaction between this compound and tubulin.


Assuntos
Acridinas/farmacologia , Antineoplásicos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Acridinas/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Polimerização , Relação Estrutura-Atividade , Moduladores de Tubulina/química
12.
Molecules ; 24(6)2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871220

RESUMO

Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 µs molecular dynamics binding simulations with a free ligand (BRACO19) to a DNA duplex and three different topological folds of the human telomeric DNA G-quadruplex (parallel, anti-parallel and hybrid). The most stable binding modes were identified as end stacking and groove binding for the DNA G-quadruplexes and duplex, respectively. Among the three G-quadruplex topologies, the MM-GBSA binding energy analysis suggested that BRACO19's binding to the parallel scaffold was most energetically favorable. The two lines of conflicting evidence plus our binding energy data suggest conformation-selection mechanism: the relative population shift of three scaffolds upon BRACO19 binding (i.e., an increase of population of parallel scaffold, a decrease of populations of antiparallel and/or hybrid scaffold). This hypothesis appears to be consistent with the fact that BRACO19 was specifically designed based on the structural requirements of the parallel scaffold and has since proven effective against a variety of cancer cell lines as well as toward a number of scaffolds. In addition, this binding mode is only slightly more favorable than BRACO19s binding to the duplex, explaining the low binding selectivity of BRACO19 to G-quadruplexes over duplex DNA. Our detailed analysis suggests that BRACO19's groove binding mode may not be stable enough to maintain a prolonged binding event and that the groove binding mode may function as an intermediate state preceding a more energetically favorable end stacking pose; base flipping played an important role in enhancing binding interactions, an integral feature of an induced fit binding mechanism.


Assuntos
Acridinas/farmacologia , Citostáticos/farmacologia , DNA/química , DNA/metabolismo , Acridinas/química , Sítios de Ligação , Linhagem Celular Tumoral , Citostáticos/química , Quadruplex G , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Solventes/química
13.
Chem Res Toxicol ; 32(5): 917-925, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-30882212

RESUMO

Quinone methides are reactive electrophiles that are generated during metabolism of various drugs, natural products, and food additives. Their chemical properties and cellular effects have been described previously, and now their response to packaging DNA in a nucleosome core is described. A model bisquinone methide precursor (bisQMP) was selected based on its ability to form reversible adducts with guanine N7 that allow for their redistribution and transfer after quinone methide regeneration. Assembly of Widom's 601 DNA with the histone octamer of H2A, H2B, H3, and H4 from Xenopus laevis significantly suppressed alkylation of the DNA. This result is a function of DNA packaging since addition of the octamer without nucleosome reconstitution only mildly protected DNA from alkylation. The lack of competition between nucleophiles of DNA and the histones was consistent with the limited number of adducts formed by the histones as detected by tryptic digestion and ultraperformance liquid chromatography-mass spectrometry. Only three peptide adducts were observed after reaction with a monofunctional analogue of bisQMP, and only two peptide adducts were observed after reaction with bisQMP. Histone reaction was also suppressed when reconstituted into the nucleosome core particle. However, bisQMP was capable of cross-linking the DNA and histones in moderate yields (∼20%) that exceeded expectations derived from reaction of cisplatin, nitrogen mustards, and diepoxybutane. The core histones also demonstrated a protective function against dynamic alkylation by trapping the reactive quinone methide after its spontaneous regeneration from DNA adducts.


Assuntos
Alcenos/química , Cicloexanonas/química , DNA/química , Nucleossomos/química , Acridinas/química , Alquilação , Animais , Reagentes para Ligações Cruzadas/química , Adutos de DNA/química , Escherichia coli/genética , Histonas/química , Humanos , Xenopus laevis
14.
Org Biomol Chem ; 17(11): 2992-3002, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30810582

RESUMO

DNA aptamers represent a way to target cancer cells at a molecular level and continue to be developed with a view to improve treatment and imaging in cancer medicine. AT11-L0, derived from the DNA sequence AT11, forms a single major parallel G-quadruplex (G4) conformation and exhibits an anti-proliferative activity similar to that of AT11 and AS1411 aptamers. On the other side, acridine orange derivatives represent a valuable class of G4 ligands. Herein, we evaluate AT11-L0 G4 as a supramolecular carrier for the delivery of acridine ligands C3, C5 and C8 to HeLa cancer cells. The CD titrations suggest no changes in the chiroptical signal upon addition of an excess of ligands maintaining the parallel G4 topology and C8 stabilizes the structure for more than 20 °C. All the ligands exhibit high affinity (micromolar range) towards AT11-L0 G4, and the respective complexes against nucleolin (nanomolar range) suggesting that the ligands do not negatively affect the recognition of the nucleolin by AT11-L0 G4. NMR studies showed that AT11-L0 forms a G4 containing four G-tetrad layers. Ligand C8 binds AT11-L0 G4 through π-π stacking of the acridine moiety onto the top-tetrad with the involvement of additional interactions with the ligand's side chain and iodobenzene ring. In vitro, the complexes lowered the ligand's cytotoxicity towards non-malignant cells but have a weak inhibitory effect in HeLa cancer cells, except for the AT11-L0-C5 complex. All complexes are efficiently internalized into nucleolin-positive HeLa cells. Overall, these results suggest that AT11-L0 can act as an aptamer by targeting nucleolin and a delivery system of cytotoxic ligands for cervical cancer.


Assuntos
Acridinas/farmacologia , Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/química , Neoplasias do Colo do Útero/tratamento farmacológico , Acridinas/química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias do Colo do Útero/patologia
15.
Molecules ; 24(4)2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30795541

RESUMO

Guanine-rich sequences in the genomes of herpesviruses can fold into G-quadruplexes. Compared with the widely-studied G3-quadruplexes, the dynamic G2-quadruplexes are more sensitive to the cell microenvironment, but they attract less attention. Pseudorabies virus (PRV) is the model species for the study of the latency and reactivation of herpesvirus in the nervous system. A total of 1722 G2-PQSs and 205 G3-PQSs without overlap were identified in the PRV genome. Twelve G2-PQSs from the CDS region exhibited high conservation in the genomes of the Varicellovirus genus. Eleven G2-PQSs were 100% conserved in the repeated region of the annotated PRV genomes. There were 212 non-redundant G2-PQSs in the 3' UTR and 19 non-redundant G2-PQSs in the 5' UTR, which would mediate gene expression in the post-transcription and translation processes. The majority of examined G2-PQSs formed parallel structures and exhibited different sensitivities to cations and small molecules in vitro. Two G2-PQSs, respectively, from 3' UTR of UL5 (encoding helicase motif) and UL9 (encoding sequence-specific ori-binding protein) exhibited diverse regulatory activities with/without specific ligands in vivo. The G-quadruplex ligand, NMM, exhibited a potential for reducing the virulence of the PRV Ea strain. The systematic analysis of the distribution of G2-PQSs in the PRV genomes could guide further studies of the G-quadruplexes' functions in the life cycle of herpesviruses.


Assuntos
DNA Viral/química , Quadruplex G/efeitos dos fármacos , Regulação Viral da Expressão Gênica , Genoma Viral , Herpesvirus Suídeo 1/genética , Regiões 3' não Traduzidas/efeitos dos fármacos , Regiões 5' não Traduzidas/efeitos dos fármacos , Acridinas/química , Acridinas/farmacologia , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Animais , Bovinos , Linhagem Celular , Biologia Computacional/métodos , DNA Helicases/genética , DNA Helicases/metabolismo , DNA Primase/genética , DNA Primase/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Células HEK293 , Herpesvirus Suídeo 1/efeitos dos fármacos , Herpesvirus Suídeo 1/metabolismo , Humanos , Ligantes , Mesoporfirinas/química , Mesoporfirinas/farmacologia , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Suínos , Varicellovirus/efeitos dos fármacos , Varicellovirus/genética , Varicellovirus/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Ativação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
Biochemistry ; 58(4): 245-249, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30350580

RESUMO

Numerous studies have been published stressing the importance of finding ligands that can bind specifically to DNA secondary structures. Several have identified ligands that are presented as having specific binding to the G-quadruplex; however, these were not originally tested on the complementary i-motif structure. The i-motif was overlooked and presumed to be irrelevant due to the belief that the hemiprotonated (cytosine+-cytosine) base pair at the core of the structure required acidic pH. The pathophysiological relevance of i-motifs has since been documented, as well as the discovery of several genomic sequences, which can form i-motif at neutral pH. Using different biophysical methodologies, we provide experimental evidence to show that widely used G-quadruplex ligands interact with i-motif structures at neutral pH, generally leading to their destabilization. Crucially, this has implications both for the search for quadruplex binding compounds as well as for the effects of compounds reported to have G-quadruplex specificity without examining their effects on i-motif.


Assuntos
Quadruplex G , Motivos de Nucleotídeos , Acridinas/química , Acridinas/metabolismo , Aminoquinolinas/química , Aminoquinolinas/metabolismo , Proteínas Reguladoras de Apoptose/genética , Berberina/química , Berberina/metabolismo , Dicroísmo Circular , Concentração de Íons de Hidrogênio , Ligantes , Mitoxantrona/química , Mitoxantrona/metabolismo , Proteínas do Tecido Nervoso/genética , Ácidos Picolínicos/química , Ácidos Picolínicos/metabolismo , Porfirinas/química , Porfirinas/metabolismo , Temperatura de Transição
17.
Chembiochem ; 20(6): 822-830, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30501011

RESUMO

Staining compounds containing heavy elements (electron dyes) can facilitate the visualization of DNA and related biomolecules by using TEM. However, research into the synthesis and utilization of alternative electron dyes has been limited. Here, we report the synthesis of a novel DNA intercalator molecule, bis-acridine uranyl (BAU). NMR spectroscopy and MS confirmed the validity of the synthetic strategy and gel electrophoresis verified the binding of BAU to DNA. For TEM imaging of DNA, two-dimensional DNA origami nanostructures were used as a robust microscopy test object. By using scanning transmission electron microscopy (STEM) imaging, which is favored over conventional wide-field TEM for improved contrast, and therefore, quantitative image analysis, it is found that the synthesized BAU intercalator can render DNA visible, even at the single-molecule scale. For comparison, other staining compounds with a purported affinity towards DNA, such as dichloroplatinum, cisplatin, osmium tetroxide, and uranyl acetate, have been evaluated. The STEM contrast is discussed in terms of the DNA-dye association constants, number of dye molecules bound per base pair, and the electron-scattering capacity of the metal-containing ligands. These findings pave the way for the future development of electron dyes with specific DNA-binding motifs for high-resolution TEM imaging.


Assuntos
Acridinas/química , Complexos de Coordenação/química , DNA/química , Substâncias Intercalantes/química , Imagem Individual de Molécula/métodos , Acridinas/síntese química , Complexos de Coordenação/síntese química , Substâncias Intercalantes/síntese química , Microscopia Eletrônica de Transmissão e Varredura/métodos , Conformação de Ácido Nucleico , Urânio/química
18.
Bioorg Chem ; 82: 6-16, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30267972

RESUMO

Urease is a bacterial enzyme that is responsible for virulence of various pathogenic bacteria such as Staphylococcus aureus, Proteus mirabilis, Klebsiella pneumoniae, Ureaplasma urealyticum, Helicobacter pylori and Mycobacterium tuberculosis. Increased urease activity aids in survival and colonization of pathogenic bacteria causing several disorders especially gastric ulceration. Hence, urease inhibitors are used for treatment of such diseases. In search of new molecules with better urease inhibitory activity, herein we report a series of acridine derived (thio)semicarbazones (4a-4e, 6a-6l) that were found to be active against urease enzyme. Molecular docking studies were carried out to better comprehend the preferential mode of binding of these compounds against urease enzyme. Docking against urease from pathogenic bacterium S. pasteurii was also carried out with favorable results. In silico ADME evaluation was done to determine drug likeness of synthesized compounds.


Assuntos
Acridinas/química , Inibidores Enzimáticos/química , Hidrazonas/química , Semicarbazonas/química , Urease/antagonistas & inibidores , Acridinas/síntese química , Acridinas/farmacocinética , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacocinética , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Hidrazonas/síntese química , Hidrazonas/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Semicarbazonas/síntese química , Semicarbazonas/farmacocinética , Sporosarcina/enzimologia , Relação Estrutura-Atividade , Urease/química
19.
Int J Biol Macromol ; 122: 289-297, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30401647

RESUMO

Here, we evaluate spiroacridines as inhibitors of tyrosinase, a key enzyme to melanogenesis. For this purpose, the spiroacridines 3-(acridin-9-yl)-N-benzylidene-2-cyanoacrylohydrazide (AMTAC-01) and 3-(acridin-9-yl)-2-cyano-N-(4-metoxybenzylidene)-acrylohydrazide (AMTAC-02) were synthesized and their enzymatic inhibition types and mechanisms were investigated. In addition, the interaction of these compounds with the enzyme were studied by UV-Vis spectroscopy, spectrofluorimetry, 1H NMR titration as well as molecular docking. Spectroscopic results reveals that the acridine derivatives interact strongly (Ka ≅ 104 - 105 M-1) with the mushroom tyrosinase and the enzyme undergoes small structural modifications due to the interaction with AMTAC-01 compound. The interaction studies support the enzymatic inhibition results, which suggests that AMTAC-01 compounds inhibit the enzyme reversibly and follows a noncompetitive type (AMTAC-01) and mixed type (AMTAC-02) of inhibition. Nevertheless, AMTAC-02 (IC50 = 96.29 µM) inhibits the enzyme more effectively than AMTAC-01 (IC50 = 189.40 µM), which suggests a highly relevant role of AMTAC-02's methoxy group to the inhibition activity, which is confirmed by docking studies to mushroom tyrosinase. Docking also indicates this interaction to be absent in human tyrosinase. SIGNIFICANCE: Based on previous results which evidenced the relevant activity of two spiroacridinic compounds for cell growth inhibition against melanoma cells, here we improve our understanding about the spiroacridines in the biological media by exploring the molecular mechanism that govern the activities of these two compounds using mushroom tyrosinase (mTYR) enzyme as molecular target. The paper not only will have a major impact upon molecular mechanism that regulates melanin inhibition by spiroacridinic compounds, but also by guiding the search for enzyme inhibitors and the development of new anti-melanoma prophylaxis.


Assuntos
Acridinas/química , Acridinas/farmacologia , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Compostos de Espiro/química , Acridinas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Ligantes , Monofenol Mono-Oxigenase/química , Ligação Proteica , Conformação Proteica
20.
Xenobiotica ; 49(8): 922-934, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30301406

RESUMO

Here, we report the metabolic profile and the results of associated metabolic studies of 2-hydroxy-acridinone (2-OH-AC), the reference compound for antitumor-active imidazo- and triazoloacridinones. Electrochemistry coupled with mass spectrometry was applied to simulate the general oxidative metabolism of 2-OH-AC for the first time. The reactivity of 2-OH-AC products to biomolecules was also examined. The usefulness of the electrochemistry for studying the reactive drug metabolite trapping (conjugation reactions) was evaluated by the comparison with conventional electrochemical (controlled-potential electrolysis) and enzymatic (microsomal incubation) approaches. 2-OH-AC oxidation products were generated in an electrochemical thin-layer cell. Their tentative structures were assigned based on tandem mass spectrometry in combination with accurate mass measurements. Moreover, the electrochemical conversion of 2-OH-AC in the presence of reduced glutathione and/or N-acetylcysteine unveiled the formation of reactive metabolite-nucleophilic trapping agent conjugates (m/z 517 and m/z 373, respectively) through the thiol group. This glutathione S-conjugate was also identified after electrolysis experiment as well as was detected in liver microsomes. Summing up, the present work illustrates that the electrochemical simulation of metabolic reactions successfully supports the results of classical electrochemical and enzymatic studies. Therefore, it can be a useful tool for synthesis of drug metabolites, including reactive metabolites.


Assuntos
Acridinas/metabolismo , Antineoplásicos/metabolismo , Eletroquímica , Espectrometria de Massas , Desintoxicação Metabólica Fase II , Desentoxicação Metabólica Fase I , Acridinas/química , Animais , Eletrólise , Feminino , Glutationa/metabolismo , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Oxirredução , Ratos Sprague-Dawley
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