title: Design, synthesis, and biological evaluation of sulfonyl acrylonitriles as novel inhibitors of cancer metastasis and spread.
abstract: 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.
authors.affiliation: John A. Burns School of Medicine, University of Hawaii , 651 Ilalo Street, Honolulu, Hawaii 96813, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Craig A
authors.initials: CA
authors.lastname: Zificsak
authors.forename: Jill E
authors.initials: JE
authors.lastname: Shea
authors.forename: Xuegang
authors.initials: X
authors.lastname: Lao
authors.forename: Oana
authors.initials: O
authors.lastname: Bollt
authors.forename: Xiufen
authors.initials: X
authors.lastname: Li
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Lisko
authors.forename: Jay P
authors.initials: JP
authors.lastname: Theroff
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Scaife
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: Scott K
authors.initials: SK
authors.lastname: Kuwada
mesh_terms: D000181:Acrylonitrile / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013450:Sulfones; D000181:Acrylonitrile