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Inorg Chem ; 59(20): 14879-14890, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33003697

RESUMO

Ispinesib is a potent inhibitor of kinesin spindle protein (KSP), which has been identified as a promising target for antimitotic anticancer drugs. Herein, we report the synthesis of half-sandwich complexes of Ru, Os, Rh, and Ir bearing the ispinesib-derived N,N-bidentate ligands (R)- and (S)-2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one and studies on their chemical and biological properties. Using the enantiomerically pure (R)- and (S)-forms of the ligand, depending on the organometallic moiety, either the SM,R or RM,S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η6-p-cymene) compounds, whereas the RM,R or SM,S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η5-pentamethylcyclopentadienyl) derivatives. However, density functional theory (DFT) calculations suggest that the energy difference between the diastereomers is very small, and therefore a mixture of both will be present in solution. The organometallics exhibited varying antiproliferative activity in a series of human cancer cell lines, with the complexes featuring the (R)-enantiomer of the ligand being more potent than the (S)-configured counterparts. Notably, the Rh and Ir complexes demonstrated high KSP inhibitory activity, even at 1 nM concentration, which was independent of the chirality of the ligand, whereas the Ru and especially the Os derivatives were much less active.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Complexos de Coordenação/farmacologia , Cinesinas/antagonistas & inibidores , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Benzamidas/síntese química , Benzamidas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cinesinas/metabolismo , Ligantes , Metais Pesados/química , Simulação de Acoplamento Molecular , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Estereoisomerismo
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