Structure–Activity Relationship of S-Trityl-L-Cysteine Analogues as Inhibitors of the Human Mitotic Kinesin Eg5

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• 作者：Salvatore DeBonis ; Dimitrios A. Skoufias ; Rose-Laure Indorato ; Franç ; ois Liger ; Bernard Marquet ; Christian Laggner ; Beno&#xee ; t Joseph ; Frank Kozielski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 13, 2008
• 年：2008
• 卷：51
• 期：5
• 页码：1115 - 1125
• 全文大小：720K
• 年卷期：v.51,no.5(March 13, 2008)
• ISSN：1520-4804

文摘

The human kinesin Eg5 is a potential drug target for cancer chemotherapy. Eg5 specific inhibitors cause cells to block in mitosis with a characteristic monoastral spindle phenotype. Prolonged metaphase block eventually leads to apoptotic cell death. S-trityl-L-cysteine (STLC) is a tight-binding inhibitor of Eg5 that prevents mitotic progression. It has proven antitumor activity as shown in the NCI 60 tumor cell line screen. It is of considerable interest to define the minimum chemical structure that is essential for Eg5 inhibition and to develop more potent STLC analogues. An initial structure–activity relationship study on a series of STLC analogues reveals the minimal skeleton necessary for Eg5 inhibition as well as indications of how to obtain more potent analogues. The most effective compounds investigated with substitutions at the para-position of one phenyl ring have an estimated K_i^app of 100 nM in vitro and induce mitotic arrest with an EC₅₀ of 200 nM.