Synthesis and biological evaluation of sulfonyl acrylonitriles as novel inhibitors to peritoneal carcinomatosis.
The vast majority of cancer patients die from metastasis, the process by which cancer cells spread to secondary 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 pancreatic cancer cells during adhesion and demonstrated that this compound could significantly inhibit peritoneal 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 surface of the peritoneum. The co-culture assay results were validated using a murine peritoneal carcinomatosis model. These analogs may greatly benefit patients undergoing surgical resections of colorectal, pancreatic, and ovarian cancers depending on their tolerability.
Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. czificsa@cephalon.com
Craig A
CA
Zificsak
Yi
Y
Shen
Joseph G
JG
Lisko
Jay P
JP
Theroff
Xuegang
X
Lao
Oana
O
Bollt
Xiufen
X
Li
Bruce D
BD
Dorsey
Scott K
SK
Kuwada
D000181:Acrylonitrile / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D010537:Peritoneum / Q000187:drug effects / Q000473:pathology; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use
D000970:Antineoplastic Agents; C416282:BAY 11-7085; D009570:Nitriles; D013450:Sulfones; D000181:Acrylonitrile