The kinesin spindle protein (KSP) is a motor protein which is essential in the bipolar spindle formation and maintenance during mitosis. Because KSP inhibition induces mitotic arrest in prometaphase without affecting microtubules, resulting in apoptotic cell death, the inhibitors could be therapeutic agents with reduced side effects for the treatment of malignant tumors. Recently, we reported that substituted carbazole such as 1  is a core scaffold for KSP inhibitory activity.1) The structure�activity relationship studies of the scaffold combined with the known biaryl-type KSP inhibitors 2  also demonstrated that b-carboline 3  and lactam-fused carbazole 4  exhibited potent KSP inhibition and cytotoxicity.2) However, the low aqueous solubility rendered these derivatives undesirable development candidates. In an attempt to overcome this problem, various diaryl amine derivatives such as 5  and 6  were designed and synthesized. Evaluation of bioactivity and physicochemical properties of these derivatives revealed that positively charged and nonplanar diaryl amine structure is a promising novel scaffold for KSP inhibitors with improved aqueous solubility. References1) Oishi, S.; Watanabe, T.; Sawada, J.; Asai, A.; Ohno, H.; Fujii, N. J. Med. Chem. 2010 , 53, 5054-5058.2) Takeuchi, T.; Oishi, S.; Watanabe, T.; Ohno, H.; Sawada, J.; Matsuno, K.; Asai, A.; Asada, N.; Kitaura, K.; Fujii, N. J. Med. Chem. 2011 , 54, 4839-4846.

Kinesin spindle protein (KSP) inhibitors with carbazole and diaryl amine scaffolds

246th National Meeting (2013)

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