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

Abstract

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.

A Novel KSP Inhibitor, KPYB10602, Induces Mitotic Arrest and Cell Death in Breast Cancer Cells

“…Five anti-tumor agents were used in the study: KSP inhibitors KPYB10602, KPYC12688, and KPYC12687 were synthesized according to a previously described method 10) , and S-(methoxytrityl)-Lcysteine was purchased from Watanabe Chemical Industries, LTD (Hiroshima, Japan). Paclitaxel was purchased from Sigma-Aldrich Inc. (St. Louis, MO, USA).…”

“…KSP inhibitors are seen as candidate chemotherapeutic agents, the use of which would avoid toxicity in post-mitotic neurons. KPYB10602 has been shown to selectively inhibit KSP ATPase activity with an IC50 of 0.031 µM in human cervical cancer cell lines 10) . In our study, the anti-proliferative effect of KPYB10602 in breast cancer cells was more efficient than that of the other inhibitors.…”

Potential new chemotherapy strategy for human ovarian carcinoma with a novel KSP inhibitor

“…KSP inhibitors were synthesized according to the method by previously reported [25]. The inhibitors tested in this study were KPYB10602 (a six-member lactam-fused carbazole derivative), KPYC12688 (a five-member lactam-fused carbazole derivative), and KPYC12687 (a pyrrole-fused carbazole derivative) ( Fig.…”

“…We have also designed a variety of KSP inhibitors [22e24], and have demonstrated that carbazole derivatives exhibit strong antitumor activity in vitro [25]. Our present study was aimed to evaluate the in vivo activity against human ovarian cancer of the most potent KSP inhibitor that we have identified, and investigate the underlying mechanisms in vitro and neurotoxicity in vivo.…”

Química de alcaloides carbazólicos: síntese de Claurailas e de biblioteca de análogos estruturais

“…A proteína cinesina do fuso mitótico (KSP, também conhecida como Eg5) tem papel essencial na formação e manutenção do FUMAGALLI, F. INTRODUÇÃO fuso mitótico bipolar. Portanto a inibição de KSP interrompe o processo de mitose levando a morte celular apoptótica (Takeuchi et al, 2011 (Li et al, 2006). Outro mecanismo de ação explorado no tratamento da diabetes é a inibição da proteína tirosina fosfatase 1B (PTP-1B), que desempenha importante papel no processo de transdução de sinal da insulina (Tang et al, 2014).…”