Design, Synthesis, and Biological Evaluation of Sulfonyl Acrylonitriles as Novel Inhibitors of Cancer Metastasis and Spread

• Published in: Journal of medicinal chemistry Vol. 58; no. 3; pp. 1140 - 1158
• Main Authors: Shen, Yi, Zificsak, Craig A, Shea, Jill E, Lao, Xuegang, Bollt, Oana, Li, Xiufen, Lisko, Joseph G, Theroff, Jay P, Scaife, Courtney L, Ator, Mark A, Ruggeri, Bruce A, Dorsey, Bruce D, Kuwada, Scott K
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-02-2015
• Subjects: Acrylonitrile - chemical synthesis; Acrylonitrile - chemistry; Acrylonitrile - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Female; HT29 Cells; Humans; Mice; Molecular Structure; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Ovarian Neoplasms - secondary; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - secondary; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501437v

The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)­sulfonyl]­acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.