Structure–Activity Relationships of Carboline and Carbazole Derivatives as a Novel Class of ATP-Competitive Kinesin Spindle Protein Inhibitors

• Published in: Journal of medicinal chemistry 2011-07, Vol.54 (13), p.4839-4846
• Main Authors: Takeuchi, Tomoki, Oishi, Shinya, Watanabe, Toshiaki, Ohno, Hiroaki, Sawada, Jun-ichi, Matsuno, Kenji, Asai, Akira, Asada, Naoya, Kitaura, Kazuo, Fujii, Nobutaka
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphate - metabolism; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - pharmacology; HeLa Cells; Humans; Kinesin - antagonists & inhibitors; Lactams - chemical synthesis; Lactams - chemistry; Lactams - pharmacology; Mitosis - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200448n

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.