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Chemistry ; 19(36): 12152-60, 2013 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-23878093


A series of Ru(II)-arene complexes (1-6) of the general formula [(η(6)-arene)Ru(L)Cl]PF6 (arene=benzene or p-cymene; L=bidentate ß-carboline derivative, an indole alkaloid with potential cyclin-dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X-ray crystallography. Hydrolytic studies show that ß-carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3- to 12-fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross-resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1-6 may directly target CDK1, because they can block cells in the G2M phase, down-regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial-related pathways and intracellular reactive oxygen species (ROS) elevation.

Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/antagonistas & inibidores , Carbolinas/química , Carbolinas/síntese química , Cisplatino/química , Inibidores Enzimáticos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Antineoplásicos/química , Carbolinas/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Compostos Organometálicos/farmacologia , Rutênio/química
Bioorg Med Chem ; 11(17): 3589-93, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12901903


HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS drugs. In the present study, we have designed, synthesized and tested a series of caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors. Among these compounds, we found that HIV integrase inhibitory activities of compounds III-3 and III-4 were more potent than L-chicoric acid (IC(50)=11.8 microg/mL) and others were comparable to L-chicoric acid. Furthermore, the structure-activity relationships of these compounds were studied. The information gathered from this paper will be useful in the development and design of HIV-1 integrase inhibitors in the future.

Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Fármacos Anti-HIV/síntese química , Integrase de HIV/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Sulfonamidas/síntese química