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J Med Chem. 2011 Jul 14;54(13):4839-46. doi: 10.1021/jm200448n. Epub 2011 Jun 7.

Structure-activity relationships of carboline and carbazole derivatives as a novel class of ATP-competitive kinesin spindle protein inhibitors.

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Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.


The kinesin spindle protein (KSP) is a mitotic kinesin involved in the establishment of a functional bipolar mitotic spindle during cell division. It is considered to be an attractive target for cancer chemotherapy with reduced side effects. Based on natural product scaffold-derived fused indole-based inhibitors and known biphenyl-type KSP inhibitors, various carboline and carbazole derivatives were synthesized and biologically evaluated. β-Carboline and lactam-fused carbazole derivatives exhibited remarkably potent KSP inhibitory activity and mitotic arrest in prometaphase with formation of an irregular monopolar spindle. The planar tri- and tetracyclic analogs inhibited KSP ATPase in an ATP-competitive manner just like biphenyl-type inhibitors.

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