RESUMO
Gold(I) and gold(III) complexes have been previously investigated for potential biomedical applications including as anti-HIV agents. The oxidising nature of some gold(III) complexes yields well-documented cellular toxicity in cell-based assays but the effect in direct biochemical assays has not been fully investigated. In this study, gold(III) complexes were evaluated in HIV-1 reverse transcriptase and HIV-1 integrase biochemical assays. The gold(III) tetrachlorides KAuCl(4) and HAuCl(4) yielded sub-micromolar IC(50)'s of 0.947 and 0.983µM in the direct HIV-1 RT assay, respectively, while IC(50)'s ranging from 0.461 to 8.796µM were obtained for seven selected gold(III) complexes. The gold(III) tetrachlorides were also effective inhibitors of integrase enzymatic activity with >80% inhibition obtained at a single dose evaluation of 10µM. RT inhibition was decreased in the presence of a reducing agent (10mM DTT) and against the M184V HIV-1 RT mutant, while none of the gold(III) complexes were effective inhibitors in cell-based antiviral assays (SI values <5.95). Taken together, the findings of this study demonstrate that gold(III) complexes modify HIV-1 enzyme activity in direct biochemical assays, most likely through protein oxidation.
Assuntos
Complexos de Coordenação/química , Ouro/química , Inibidores de Integrase de HIV/química , Integrase de HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Sítios de Ligação , Simulação por Computador , Complexos de Coordenação/farmacologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
The synthesis of enantiomerically pure palladatricyclo[4.1.0.0(2,4)]heptanes and their modification by an unprecedented and very efficient positional selective transesterification is described. The mild reaction conditions are most probably based on an acceleration of the transesterification due to assistance by the metal. This novel approach allows straightforward access to a large number of structurally diverse organometallic complexes. The functional groups on the newly installed ester moieties were modified by using standard peptide synthesis protocols, Sonogashira reactions, and nucleophilic substitution reactions. The cellular uptake of these organometallic species was traced by confocal microscopy and their biological activity was evaluated by using different cell lines. Inhibition of cell growth and induction of apoptotic cell death by these novel palladium heterocycles are equivalent to Cisplatin.
Assuntos
Alcenos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Cicloeptanos/química , Metais/química , Compostos Organometálicos/química , Paládio/química , Catálise , Esterificação , Humanos , Estrutura Molecular , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , EstereoisomerismoRESUMO
In the title compound, [AuCl(C(25)H(23)N(2)P)], the Au(I) atom is in a typical almost linear coordination environment defined by phosphane P and Cl atoms [bond angle = 175.48â (4)°]. Helical supra-molecular chains along the b axis and mediated by N-Hâ¯Cl hydrogen bonds feature in the crystal packing.
