RESUMO
Cancer diagnosis and its stage-wise assessment are determined through invasive solid tissue biopsies. Conversely, cancer imaging is enriched through emission tomography and longitudinal high-resolution analysis for the early detection of cancer through altered cell morphology and cell-deformation. Similarly, in post multiple chemo-cycle exposures, the tumor regression and progression thereafter are not well understood. Here, we report chemo-cycles of doxorubicin (Dox) carrying nanoparticles (NPs) to be highly indicative of cell deformation and a progressive indicator of phenotypic expressions of acquired drug resistance (ADR). We designed graphene (G) based nanocarriers by chemically conjugating multiple components: (i) G; (ii) iron oxide (Fe3O4) NPs; and (iii) Dox through a cysteine (Cys) linker (G-Dox and G-Cys-Fe3O4-Dox). Although Dox underwent cell diffusion, the G-based nanocarriers followed a receptor-mediated endocytosis which created a profound impact on the cell membrane integrity. ADR owing to Dox and G-based nanocarriers was analyzed through a cytotoxicity assay, cell morphology deformation parameters and cellular uptake kinetic patterns. Interestingly, after the third chemo-cycle, G-Dox incubated cells showed the greatest decrease in the alteration of the nuclear surface area (NSA) of â¼28%, a â¼40% reduction of the cell surface area (CSA) and a â¼32% increase in the cell roundness (CRd). Our results suggested that the G-based nanocarriers induced the cell deformation process, subsequently resulting in ADR. Although the G-based nanocarriers initiated ADR, G-Dox was most cytotoxic to cancer cells and induced the maximum cell morphology deformation within our scope of study. This outcome implies caution is needed when using G-based nanocarriers and other multi-component nanosystems for Dox delivery as they lead to possible phenotypic expressions of drug resistance in cancer cells.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Grafite/química , Nanopartículas/química , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Humanos , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Filamenting temperature-sensitive mutant (FtsZ) is a novel target for the treatment of tuberculosis. A series of (R)-2-(4'-chlorophenyl)-3-(4'-nitrophenyl)-1,2,3,5-tetrahydrobenzo[4,5] imidazo[1,2-c]pyrimidin-4-ol derivatives were designed and docked on the FtsZ protein crystal structure (PDB Id: 1RLU, resolution 2.08 Å). Compound 7t showed the highest docking score and H-bond interaction with Arg140 and Gly19. Our strategy for synthesis of (R)-2-(4'-chlorophenyl)-3-(4'-nitrophenyl)-1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2-c]pyrimidin-4-ol derivatives from o-phenylenediamine as illustrated in scheme. All the synthesized compounds were characterized by FTIR, Mass spectra, (1)H NMR, (13)C NMR, elemental analysis and purity was confirmed by HPLC and LCMS. Compound 7g was also confirmed by single crystal X-ray analysis. The in silico results are also validated with in vitro antitubercular activity of compound 7t. Compound 7b exhibited in vitro antitubercular activity 3.13 µg/mL and 4.7 µg/mL whereas compound 7t exhibited in vitro antitubercular activity 6.25 µg/mL and 9.4 µg/mL using GAST/Fe medium after week 1 and week 2 respectively against Mycobacterium tuberculosis H37Rv. Medium 7H9/ADC/Tween was found to be very less effective for in vitro antitubercular activity of all the benzimidazole derivatives. Assays for in vitro cytotoxicity against VERO cells of all the synthesized compounds was found to be very less cytotoxic.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Desenho de Fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Simulação de Acoplamento Molecular , Piridinas/síntese química , Piridinas/farmacologia , Animais , Antituberculosos/metabolismo , Antituberculosos/toxicidade , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Técnicas de Química Sintética , Chlorocebus aethiops , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/metabolismo , Imidazóis/metabolismo , Imidazóis/toxicidade , Mycobacterium tuberculosis/efeitos dos fármacos , Conformação Proteica , Piridinas/metabolismo , Piridinas/toxicidade , Relação Estrutura-Atividade , Células VeroRESUMO
A few thienyl substituted pyrazole derivatives were synthesized to aid in the characterization of the cannabinoid receptor antagonist and also to serve as potentially useful antiobesity agent. Structural requirements for selective CB1 receptor antagonistic activity of 5-thienyl pyrazole derivatives included the structural similarity with potent, specific antagonist rimonabant 1. Compound 3 has been identified as a hair growth stimulator and an antiobesity agent in animal models.
Assuntos
Química Farmacêutica/métodos , Cabelo/efeitos dos fármacos , Obesidade/tratamento farmacológico , Piperidinas/síntese química , Pirazóis/síntese química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Benzoxazinas/farmacologia , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Desenho de Fármacos , Concentração Inibidora 50 , Modelos Químicos , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , RimonabantoRESUMO
Design and synthesis of novel piperazinylaryloxazolidinones possessing heteroaryl groups are described and their in vitro antibacterial activities have been evaluated by MIC assay. Compounds (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6o), (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrothien-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6p) and N-oxide of (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (9) showed superior antibacterial activities than linezolid and also active against the linezolid resistant Staphylococcus aureus strains.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Acetamidas/farmacologia , Antibacterianos/química , Desenho de Fármacos , Linezolida , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazolidinonas/química , Relação Estrutura-AtividadeRESUMO
Design and synthesis of a few novel methylamino piperidinyl substituted oxazolidinones are reported. Their antibacterial activities have been evaluated in a MIC assay against broader panel of both susceptible and resistant Gram-positive strains. (S)-N-{3-[3-Fluoro-4-(methyl-{1-[3-(5-nitrofuran-2-yl)-acryloyl]-piperidin-4-yl}-amino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4i has shown comparable antibacterial activity to linezolid and eperezolid in the MIC assay, additionally compound 4i showed good antibacterial activity with an in vitro MIC value of 2-4 microg/mL against linezolid resistant Staphylococcus aureus (linezolid 16 microg/mL).
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Piperidinas/química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Oxazolidinonas/químicaRESUMO
New ferrocenylphosphinoimidazolidines containing central chirality and planar chirality were found to act as highly effective chiral ligands in Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate.
RESUMO
A number of substituted piperazinyl oxazolidinone derivatives have been synthesized and their antibacterial activities were evaluated by MIC determination. A systematic SAR was carried out to get highly potent oxazolidinone derivatives.