Inhibitors of apoptosis proteins (IAPs) are anti-apoptotic regulator which blocks cell death. The cellular IAP (cIAP) modulates tumor necrosis factor-alpha (TNFa) related death receptor signaling pathway, and the X-linked IAP (XIAP) suppresses apoptosis by binding to effectors, caspase-3 and -7, and an initiator, caspase-9. An apoptosis induction by inhibition of both cIAP and XIAP is considered to be a new therapeutic approach to treat cancer. Our previous synthetic studies on IAP antagonists led to the identification of novel octahydropyrrolo[1,2-a]pyrazine A , which showed strong IAP binding inhibition along with significant anti-tumor efficacy in MDA-MB-231 (human breast cancer) xenograft model in mice. However, compound A  displayed insufficient PK profiles due to its low metabolic stability and thus we decided to further investigate to generate IAP antagonists with improved PK profiles. Based on the co-crystal structure of A  in complex with cIAP, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1  and 2  (diastereomer of 1 ). The additional cyclopropane moiety was aimed to block the predicted metabolic site of compound A  without detriment to the binding affinity against cIAP. These novel cyclopropane structures were constructed by diastereoselective Simmons-Smith reaction of 2,3-dihydro-pyrrole which contains asymmetric functional groups at C-2 position. Following sequential formation of requisite amide side chains provided target compounds (1 , 2 ). Compounds 1  and 2  showed strong growth inhibition in MDA-MB-231 cell line with improved metabolic stability compared with that of A . Furthermore, one diastereomer of these compounds exhibited significant in vivo PD effect to increase TNFa mRNA induction in a dose dependent manner. In this poster presentation, design, stereoselective synthesis and biological evaluation of novel octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazine derivatives will be discussed.

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

246th National Meeting (2013)

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