Structure鈭扐ctivity Relationship and Multidrug Resistance Study of New S-trityl-l-Cysteine Derivatives As Inhibitors of Eg5

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• 作者：Hung Yi Kristal Kaan ; Johanna Weiss ; Dominik Menger ; Venkatasubramanian Ulaganathan ; Katarzyna Tkocz ; Christian Laggner ; Florence Popowycz ; Benoi虃t Joseph ; Frank Kozielski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 24, 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1576-1586
• 全文大小：1045K
• 年卷期：v.54,no.6(March 24, 2011)
• ISSN：1520-4804

文摘

The mitotic spindle is a validated target for cancer chemotherapy. Drugs such as taxanes and vinca alkaloids specifically target microtubules and cause the mitotic spindle to collapse. However, toxicity and resistance are problems associated with these drugs. Thus, alternative approaches to inhibiting the mitotic spindle are being pursued. These include targeting Eg5, a human kinesin involved in the formation of the bipolar spindle. We previously identified S-trityl-l-cysteine (STLC) as a potent allosteric inhibitor of Eg5. Here, we report the synthesis of a new series of STLC-like compounds with in vitro inhibition in the low nanomolar range. We also performed a multidrug resistance study in cell lines overexpressing P-glycoprotein and showed that some of these inhibitors may have the potential to overcome susceptibility to this efflux pump. Finally, we performed molecular docking of the compounds and determined the structures of two Eg5鈭抜nhibitor complexes to explain the structure鈭抋ctivity relationship of these compounds.