RESUMO
A series of 6-amidinobenzothiazoles, linked via phenoxymethylene or directly to the 1,2,3-triazole ring with a p-substituted phenyl or benzyl moiety, were synthesised and evaluated in vitro against four human tumour cell lines and the protozoan parasite Trypanosoma brucei. The influence of the type of amidino substituent and phenoxymethylene linker on antiproliferative and antitrypanosomal activities was observed, showing that the imidazoline moiety had a major impact on both activities. Benzothiazole imidazoline 14a, which was directly connected to N-1-phenyl-1,2,3-triazole, had the most potent growth-inhibitory effect (IC50 = 0.25 µM) on colorectal adenocarcinoma (SW620), while benzothiazole imidazoline 11b, containing a phenoxymethylene linker, exhibited the best antitrypanosomal potency (IC90 = 0.12 µM). DNA binding assays showed a non-covalent interaction of 6-amidinobenzothiazole ligands, indicating both minor groove binding and intercalation modes of DNA interaction. Our findings encourage further development of novel structurally related 6-amidino-2-arylbenzothiazoles to obtain more selective anticancer and anti-HAT agents.
Assuntos
Antiprotozoários/síntese química , Benzotiazóis/síntese química , Substâncias Intercalantes/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Amidinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Benzotiazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , DNA/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazolinas/química , Substâncias Intercalantes/farmacologia , Conformação de Ácido Nucleico , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
The interaction of Cu(NO3)2·3H2O with the sulfonyl o-pyridine carboxamidoxime N'-(4-nitrophenylsulfonyloxy)picolinimidamide (L) resulted in the mononuclear complex [Cu(L1)2](L2)2 (1), where L1 = pyridine-2-carboxamidine ligand and (L2)- = 4-nitrobenzenesulfonate anion derived from the homolytic cleavage of the NO bond of L. The complex was characterized by diverse techniques including single-crystal X-ray crystallography. From the antimicrobial tests performed, complex 1 seems to be active against gram-negative bacterial strains. The complex binds tightly and reversibly to serum albumins and tightly to calf-thymus DNA via an intercalative mode and also via electrostatic interactions (as expected due to its cationic nature). Additionally, it interacts with (pBluescriptSK(+)) plasmid DNA in a concentration-dependent manner. The results from the present in silico molecular modeling simulations provide useful complementary insights for the elucidation of the mechanism of action of the studied complex at a molecular level. Molecular modeling calculations provide a molecular basis for the understanding of both the impairment of DNA by its binding with the studied complex and the ability of this compound to act as an antibacterial agent, most probably by its activity against DNA-gyrase, as well as for transportation through serum albumins and possible interaction with other protein targets involved in various diseases.
Assuntos
Antibacterianos , Bactérias/crescimento & desenvolvimento , Complexos de Coordenação , Cobre , Substâncias Intercalantes , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , DNA/química , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Simulação de Acoplamento Molecular , Piridinas/química , Piridinas/farmacologia , Soroalbumina Bovina/químicaRESUMO
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/químicaRESUMO
XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 µM and 1.3 ± 0.22 µM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility. Furthermore, compound 1 analogs exhibited good specificity for XPA over RPA (replication protein A), another DNA-binding protein that participates in the nucleotide excision repair (NER) pathway. Importantly, there were no significant interactions observed by the X80 class of compounds directly with DNA. Molecular docking studies revealed a mechanistic model for the interaction, and these studies could serve as the basis for continued analysis of structure-activity relationships and drug development efforts of this novel target.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Proteína de Xeroderma Pigmentoso Grupo A/antagonistas & inibidores , Antineoplásicos/química , Simulação por Computador , Reparo do DNA/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Substâncias Intercalantes/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Solubilidade , Relação Estrutura-AtividadeRESUMO
A novel series of quinolone triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All the newly prepared compounds were screened for their antimicrobial activities against seven bacteria and four fungi. Bioactive assay manifested that most of new compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains including multi-drug resistant MRSA in comparison with reference drugs Norfloxacin, Chloromycin and Fluconazole. The preliminary interactive investigations of compound 6b with calf thymus DNA by fluorescence and UV-vis spectroscopic methods revealed that compound 6b could effectively intercalate DNA to form compound 6b-DNA complex which might block DNA replication and thus exert its antimicrobial activities.
Assuntos
Anti-Infecciosos/síntese química , DNA/metabolismo , Substâncias Intercalantes/síntese química , Quinolonas/química , Quinolonas/síntese química , Triazóis/química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Bovinos , DNA/química , DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fungos/efeitos dos fármacos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Quinolonas/farmacologia , Espectrofotometria Ultravioleta , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
The binding properties of [Ru(bpy)(2)(H(2)IIP)](2+) (1) {bpy=2,2'-bipyridine, H(2)IIP=2-(indole-3-yl)-imidazolo[4,5-f][1,10]phenanthroline} with calf thymus DNA (CT-DNA) and yeast tRNA have been investigated comparatively by different spectroscopic and viscosity measurements. The results suggest that the affinity of complex 1 binding with yeast tRNA is stronger than that of complex 1 binding with CT-DNA, and complex 1 is a better enantioselective binder to yeast tRNA than to CT-DNA. The toxicity of complex 1 was concentration dependent, and HL-60 cells are more sensitive to complex 1 than Hep-G2 cells; complex 1 could induce Hep-G2 cell apoptosis.
Assuntos
2,2'-Dipiridil/análogos & derivados , Citotoxinas , Substâncias Macromoleculares , Ácidos Nucleicos/metabolismo , Rutênio/química , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , Sítios de Ligação/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/metabolismo , Citotoxinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células HL-60 , Células Hep G2 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/metabolismo , Substâncias Intercalantes/farmacologia , Ligantes , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/metabolismo , Substâncias Macromoleculares/farmacologia , Modelos Biológicos , Fenantrolinas/síntese química , Fenantrolinas/química , Fenantrolinas/metabolismo , Fenantrolinas/farmacologia , Polímeros/síntese química , Polímeros/química , Polímeros/metabolismo , Polímeros/farmacologia , Espectrometria de Fluorescência , Especificidade por Substrato , ViscosidadeRESUMO
Liriodenine, an oxoaporphine alkaloid with anticancer activity isolated from Zanthoxylum nitidum (rutaceous anticancer traditional Chinese medicine), was selected as a bioactive ligand to react with HAuCl(4) and NaAuCl(4) to afford [LH][AuCl(4)] (1) and [AuCl(3)L] (2), respectively (where L is liriodenine). The structures of 1 and 2 were characterized by IR spectroscopy, electrospray ionization mass spectrometry, (1)H-NMR spectroscopy, and elemental analysis. The single-crystal X-ray diffraction analysis of 1 revealed that it is an ionic compound consisting of protonated liriodenine cation [LH](+) and [AuCl(4)](-) anion. The spectroscopic analysis showed that 2 is a coordination compound, in which one liriodenine coordinates to gold via its 7-N donor. In aqueous solution, 1 is relatively stable, but 2 undergoes rapid hydrolysis. The in vitro cytotoxicity towards five human tumor cell lines shows that 1 and 2 manifest roughly similar biological behavior and appreciable antiproliferative properties, with IC(50) values falling in the 2-16 µM range. The flow-cytometric analysis of 1 and 2 suggests that both compounds induced an S-phase arrest. Compounds 1 and 2 significantly poison topoisomerase I in vitro at low concentration (25 µM or less). DNA binding studies indicate that both 1 and 2 interact with DNA mainly via intercalation between the neighboring base pairs of the DNA double helix. Electrostatic interactions of 1 and 2 with the polyanionic DNA phosphate backbone may reinforce the intercalation because both 1 and 2 are composed of planar cationic species.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Aporfinas/química , Aporfinas/farmacologia , Compostos Organoáuricos/química , Compostos Organoáuricos/farmacologia , Antineoplásicos/síntese química , Aporfinas/síntese química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/metabolismo , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Medicina Tradicional Chinesa , Neoplasias/tratamento farmacológico , Compostos Organoáuricos/síntese química , Zanthoxylum/químicaRESUMO
Novel tetracyclic allopsoralen derivatives characterized by the condensation of a fourth cyclohexenylic (5-7) or benzenic (8-10) ring at the furan side and a methoxy (5 and 8), a hydroxy (6 and 9), or a dimethylaminopropoxy (7 and 10) side chain in the 10 position of the chromophore were prepared. Compounds 7 and 10 showed a strong photoantiproliferative activity, up to 3 orders of magnitude higher than that of the photochemotherapeutic drug 8-methoxypsoralen (8-MOP). The investigation into the mechanism of action demonstrated for 10 the capacity to intercalate between DNA base pairs in the ground state, to give rise to a covalent photoaddition upon UVA irradiation, and to inhibit polymerase chain reaction (PCR) in a sequence-specific manner. Conversely, compound 7 showed a limited capacity to form an intercalative complex and the lack of ability to photoadd to the macromolecule, thus revealing a novel and unusual behavior for an allopsoralen derivative.
Assuntos
Antineoplásicos/síntese química , Furanos/síntese química , Furocumarinas/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Substâncias Intercalantes/síntese química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Adutos de DNA/síntese química , DNA Topoisomerases Tipo II/química , Escuridão , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/farmacologia , Furanos/toxicidade , Furocumarinas/farmacologia , Furocumarinas/toxicidade , Cobaias , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade , Humanos , Substâncias Intercalantes/farmacologia , Substâncias Intercalantes/toxicidade , Terapia PUVA , Reação em Cadeia da Polimerase , Pele/efeitos dos fármacos , Relação Estrutura-Atividade , Timina/química , Testes de Toxicidade , Raios UltravioletaRESUMO
Two novel nitroimidazole-based bioreductive compounds, 10-[3-(2-nitroimidazolyl)-propylamino]-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline hydrochloride (8a) and 10-[3-(2-nitroimidazolyl)propylamino]-2-methyl-1,2,3,4-tetrahydro-benzo[b]-1,6-naphthyridine hydrochloride (8b) have been synthesized and evaluated in V79 cells as hypoxia-selective cytotoxins and radiosensitizers that target DNA through weak intercalation. Both compounds were relatively good radiosensitizers (C(1.6) values of 40.0+/-0.8 and 59.0+/-0.4 microM for 8a and 8b, respectively) but neither of the compounds was superior to 2 which does not carry a second heteroatom in the DNA-intercalating chromophore.
Assuntos
Compostos Heterocíclicos/síntese química , Nitroimidazóis/síntese química , Quinolinas/síntese química , Radiossensibilizantes/síntese química , Animais , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Cricetinae , Avaliação Pré-Clínica de Medicamentos/métodos , Compostos Heterocíclicos/toxicidade , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/toxicidade , Nitroimidazóis/toxicidade , Quinolinas/toxicidade , Radiossensibilizantes/toxicidadeRESUMO
This study reports the synthesis of tetrahydrobenzo- (4-6) and benzopsoralen (7-9) derivatives obtained by condensing the fourth ring to the pyrone side of the tricyclic psoralen moiety. The new compounds are characterized by having a methoxy, a hydroxy, or a dimethylaminopropoxy side chain inserted at position 8 of the psoralen chromophore. The evaluation of the photoantiproliferative activity on human tumor cell lines along with skin phototoxicity on guinea pigs revealed an interesting photobiological pattern for the dimethylaminopropoxy derivatives 6 and 9: they are in fact able to exert an antiproliferative effect up to 1 order of magnitude higher than that of the well-known drug 8-MOP, but they are devoid of skin phototoxicity. The ability of both 6 and 9 to photoadd to DNA is demonstrated by the isolation and characterization of the 4',5'-monoadducts. AM1 calculations were also performed to gain further insight into the molecular basis of their photobiological behavior.
Assuntos
Antineoplásicos/síntese química , Cumarínicos/síntese química , Cicloexanos/síntese química , Furanos/síntese química , Furocumarinas/síntese química , Pironas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Dicroísmo Circular , Cumarínicos/química , Cumarínicos/farmacologia , Reagentes de Ligações Cruzadas/síntese química , Reagentes de Ligações Cruzadas/química , Cicloexanos/química , Cicloexanos/farmacologia , Cicloexenos , Adutos de DNA/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Furanos/farmacologia , Furocumarinas/química , Furocumarinas/farmacologia , Cobaias , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Terapia PUVA , Pironas/química , Pironas/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Raios UltravioletaRESUMO
The tandem amine-exchange/heterocyclization of enaminoketones is successfully applied to the regioselective preparation of a series of new 4,5-diarylpyrazoles by reaction of phenylhydrazine and several 3-N,N-(dimethylamino)-1,2-diarylpropenones. The comparison of a vast array of biaryl coupling procedures provides general, complementary approaches to new phenanthro[9,10-d]pyrazoles. The most efficient procedures for this final step in the construction of the tetracyclic system are based on a Stille-type tandem stannylation-biaryl coupling of o,o'-dihalogenated diarylpyrazoles and an hypervalent iodine-mediated nonphenolic oxidative coupling of nonhalogenated precursors.