Discovery of a Clinical Stage Multi-Kinase Inhibitor Sodium (E)-2-{2-Methoxy-5-[(2鈥?4鈥?6鈥?trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): Synthesis, Structure鈥揂ctivity Relati

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• 作者：M. V. Ramana Reddy ; Padmavathi Venkatapuram ; Muralidhar R. Mallireddigari ; Venkat R. Pallela ; Stephen C. Cosenza ; Kimberly A. Robell ; Balaiah Akula ; Benjamin S. Hoffman ; E. Premkumar Reddy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：September 22, 2011
• 年：2011
• 卷：54
• 期：18
• 页码：6254-6276
• 全文大小：1342K
• 年卷期：v.54,no.18(September 22, 2011)
• ISSN：1520-4804

文摘

Cyclin D proteins are elevated in many cancer cells, and targeted deletion of cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel nonenzymatic target for cancer therapeutics. We have developed novel, nonalkylating styrylbenzylsulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized styrylbenzylsulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure鈥揳ctivity relationships of novel, nonalkylating (E)-styrylbenzylsulfones and the development of the novel anticancer agent sodium (E)-2-{2-methoxy-5-[(2鈥?4鈥?6鈥?trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na), which is in phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.