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Eur J Med Chem ; 215: 113288, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33640763

RESUMO

Kinesin spindle protein (KSP) is expressed only in cells undergoing cell division, and hence represents an attractive target for the treatment of cancer. Several KSP inhibitors have been developed and undergone clinical trial, but their clinical use is limited by their toxicity to rapidly proliferating non-cancerous cells. To create new KSP inhibitors that are highly selective for cancer cells, we optimized the amino acid moiety of S-trityl-l-cysteine (STLC) derivative 1 using in silico modeling. Molecular docking and molecular dynamics simulation were performed to investigate the binding mode of 1 with KSP. Consistent with the structure activity relationship studies, we found that a cysteine amino moiety plays an important role in stabilizing the interaction. Based on these findings and the structure of GSH, a substrate of γ-glutamyltransferase (GGT), we designed and synthesized the prodrug N-γ-glutamylated STLC derivative 9, which could be hydrolyzed by GGT to produce 1. The KSP ATPase inhibitory activity of 9 was lower than that of 1, and LC-MS analysis indicated that 9 was converted to 1 only in the presence of GGT in vitro. In addition, the cytotoxic activity of 9 was significantly attenuated in GGT-knockdown A549 cells. Since GGT is overexpressed on the cell membrane of various cancer cells, these results suggest that compound 9 could be a promising prodrug that selectively inhibits the proliferation of GGT-expressing cancer cells.


Assuntos
Antineoplásicos/farmacologia , Cisteína/farmacologia , Dibenzocicloeptenos/farmacologia , Cinesinas/antagonistas & inibidores , Pró-Fármacos/farmacologia , Compostos de Tritil/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Bovinos , Linhagem Celular Tumoral , Cisteína/síntese química , Cisteína/metabolismo , Dibenzocicloeptenos/síntese química , Dibenzocicloeptenos/metabolismo , Humanos , Cinesinas/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Termodinâmica , Compostos de Tritil/síntese química , Compostos de Tritil/metabolismo , gama-Glutamiltransferase/metabolismo
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