Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists

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• 作者：Moriteru Asano ; Kentaro Hashimoto ; Bunnai Saito ; Zenyu Shiokawa ; Hiroyuki Sumi ; Masato Yabuki ; Mie Yoshimatsu ; Kazunobu Aoyama ; Teruki Hamada ; Nao Morishita ; Douglas R. Dougan ; Clifford D. Mol ; Sei Yoshida ; Tomoyasu Ishikawa
• 关键词：Inhibitor of apoptosis proteins (IAP) ; Octahydro-1H-cyclopropa[4 ; 5]pyrrolo[1 ; 2-a]pyrazine ; Simmons&minus ; Smith cyclopropanation
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 September, 2013
• 年：2013
• 卷：21
• 期：18
• 页码：5725-5737
• 全文大小：1678 K

文摘

We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b¡ä, which were obtained by Simmons?Smith cyclopropanation of ethylester 3a and silyl ether 3b¡ä. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.