Synthesis and biological evaluation of sulfonyl acrylonitriles as novel inhibitors to peritoneal carcinomatosis Craig A. Zificsak a,⇑,  , Yi Shen b,  , Joseph G. Lisko a , Jay P. Theroff a , Xuegang Lao b , Oana Bollt b , Xiufen Li b , Bruce D. Dorsey a , Scott K. Kuwada b a Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA b Department of Medicine, University of Hawaii, Honolulu, HI 96813, USA article info Article history: Received 29 November 2011 Revised 20 January 2012 Accepted 23 January 2012 Available online 30 January 2012 Keywords: Peritoneal carcinomatosis BAY 11-7085 abstract The vast majority of cancer patients die from metastasis, the process by which cancer cells spread to sec- ondary tissues through body fluids. Peritoneal carcinomatosis is a type of metastasis in which cancer cells gain access to the intra-abdominal cavity and then implant in the peritoneum, the thin tissue that lines the abdominal wall and internal organs. Unfortunately, peritoneal carcinomatosis can occur following surgical resection of intra-abdominal malignancies. We previously reported proapoptotic activity of (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2-propenenitrile (BAY 11-7085, 1) on colon and pancre- atic cancer cells during adhesion and demonstrated that this compound could significantly inhibit peri- toneal carcinomatosis in mice. 1,2 In order to determine the chemical basis of the anti-metastatic properties of BAY 11-7085, a series of analogs were synthesized and evaluated for their ability to induce apoptosis in pancreatic and ovarian cancer cells during adhesion to mesothelial cells, which line the sur- face of the peritoneum. The co-culture assay results were validated using a murine peritoneal carcinoma- tosis model. These analogs may greatly benefit patients undergoing surgical resections of colorectal, pancreatic, and ovarian cancers depending on their tolerability. Ó 2012 Elsevier Ltd. All rights reserved. Peritoneal carcinomatosis, a uniformly fatal form of metastasis, results from the peritoneal implantation of cancer cells, which are shed from intra-abdominal cancers or dislodged during surgical resection. At the time patients with abdominal malignancies un- dergo resection of their tumors, seeding of the peritoneal cavity and the circulatory system can occur. 3,4 Perhaps the best evidence for the iatrogenic spread of cancer cells to the peritoneum is from studies demonstrating seeding of tracts created in the abdominal wall to allow laparoscopic resection of intra-abdominal cancers. 5 The small molecule BAY 11-7085 (1, Fig. 1), a known NF-jB inhibitor, was shown to induce apoptosis of colon and pancreatic cancer cells during cell adhesion and reduce colon and pancreatic cancer cell implantation in a murine peritoneal seeding model. 1,2 The molecular mechanism of BAY 11-7085 relates to its ability to inhibit the expression of c-FLIP L (FLICE Inhibitory Protein) which restores death receptor signaling in cancer cells. 2 c-FLIP L is com- monly overexpressed in cancer cells of many types and inhibits the recruitment of caspase 8 to activated death receptors of the TNFa superfamily. 6–8 Many types of cancer cells paradoxically ex- press death receptors which mediate pleiotropic effects, such as proliferation, despite what their name implies. 9,10 Mesothelial cells lining the peritoneum express the cognate ligands of these death receptors, which activate death receptor-mediated signaling. 2 Inhi- bition of c-FLIP allows activated death receptors to recruit caspase 8 and 10, which in turn initiate the cleavage of downstream ‘exe- cutioner’ caspases that effect apoptosis. Although restoration of death receptor-mediated apoptosis has been demonstrated in can- cer cell cultures, we were the first to demonstrate this occurs in a juxtacrine fashion when cancer cells come into contact with nor- mal human mesothelial cells. 2 As a first study, we designed analogs of 1 wherein a methyl of the t-butyl group is replaced by a carboxylic acid, or alkyl, aryl or benzyl amide. An in vitro model of peritoneal tumor implantation was uti- lized in which pancreatic or ovarian cancer cells in suspension were allowed to adhere to confluent monolayers of mesothelial cells. The cancer cells were transduced with a constitutively expressing firefly 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2012.01.085 ⇑ Corresponding author. Tel.: +1 610 738 6745; fax: +1 610 738 6643. E-mail address: czificsa@cephalon.com (C.A. Zificsak).   These co-authors contributed equally to this paper. S CN O O R S CN O O 1 BAY 11-7085 2 R = CONR 1 R 2 Figure 1. BAY 11-7085 (1) and novel inhibitors 2. Bioorganic & Medicinal Chemistry Letters 22 (2012) 1850–1853 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl