De novo design, synthesis and biological evaluation of 1,4-dihydroquinolin-4-ones and 1,2,3,4-tetrahydroquinazolin-4-ones as potent kinesin spindle protein (KSP) inhibitors.

Article Details

Citation

Copy to clipboard

Jiang C, Yang L, Wu WT, Guo QL, You QD

De novo design, synthesis and biological evaluation of 1,4-dihydroquinolin-4-ones and 1,2,3,4-tetrahydroquinazolin-4-ones as potent kinesin spindle protein (KSP) inhibitors.

Bioorg Med Chem. 2011 Sep 15;19(18):5612-27. doi: 10.1016/j.bmc.2011.07.029. Epub 2011 Jul 22.

PubMed ID

21856161 [ View in PubMed

]

Abstract

Kinesin spindle protein (KSP) inhibitors are a promising class of anticancer agents that cause mitotic arrest in cells from a failure to form functional bipolar mitotic spindles. Here, we report the design, synthesis and biological evaluation of a novel series of 1,4-dihydroquinolin-4-ones and 1,2,3,4-tetrahydroquinazolin-4-ones using de novo design method. The synthesized compound was evaluated and proved to have potent inhibitory activities in the KSP ATPase. Compounds 15j and 15p show potent inhibitory activities in cell proliferation assays. Preferred compound 15j markedly induced G2/M phase cell cycle arrest with characteristic monoastral spindles and subsequent cell death in A549 cells. In vivo evaluation of 15j on the growth of transplantable S180 sarcoma in mice suggested its therapeutic potential for further development.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Monastrol	Kinesin-like protein KIF11	IC 50 (nM)	7452	N/A	N/A	Details