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Sci Rep ; 10(1): 4827, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179835


Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. Furthermore, it was shown that the carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.

ChemMedChem ; 14(24): 2061-2074, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31675152


The role of autophagy in cancer is often complex, ranging from tumor-promoting to -suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo-[3-(η6 -p-cymene)-1-(quinolin-8-yl-acetate)-3,1,2-RuC2 B9 H10 ] (4) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor-promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy-prone glioblastomas.

ACS Omega ; 4(5): 8824-8833, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459970


Ketoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) that also exhibits cytotoxic activity against various cancers. This makes ketoprofen an attractive structural lead for the development of new NSAIDs and cytotoxic agents. Recently, the incorporation of carboranes as phenyl mimetics in structures of established drugs has emerged as an attractive strategy in drug design. Herein, we report the synthesis and evaluation of four novel carborane-containing derivatives of ketoprofen, two of which are prodrug esters with an nitric oxide-releasing moiety. One of these prodrug esters exhibited high cytostatic activity against melanoma and colon cancer cell lines. The most pronounced activity was found in cell lines that are sensitive to oxidative stress, which was apparently induced by the ketoprofen analogue.

ChemMedChem ; 14(2): 255-261, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30471171


5-Lipoxygenase converts arachidonic acid into leukotrienes, which are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. Herein we report the syntheses of several carborane-based inhibitors of the 5-lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity toward several melanoma and colon cancer cell lines. For the colon cancer cell line HCT116, the co-inhibition of heat shock protein 90 was observed.

Boranos/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Desenho de Fármacos , Células HCT116 , Humanos
ChemMedChem ; 12(13): 1081-1086, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28569429


The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5-lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5-lipoxygenase pathway is Rev-5901, which, however, lacks in in vivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors. Carboranes are icosahedral boron clusters that are remarkably stable and used to increase the metabolic stability of unstable pharmaceutics without changing their biological activity. By introduction of meta-carborane into Rev-5901, the first carborane-based inhibitor of the 5-lipoxygenase pathway was obtained. We report the synthesis and inhibitory and cytotoxic behavior of these compounds toward several melanoma and colon cancer cell lines and their related anticancer mechanisms.

Antineoplásicos/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Compostos de Boro/farmacologia , Inibidores de Lipoxigenase/farmacologia , Quinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Compostos de Boro/síntese química , Compostos de Boro/toxicidade , Linhagem Celular Tumoral , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/toxicidade , Simulação de Acoplamento Molecular , Óxido Nítrico/metabolismo , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais