title: Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel type of nonapoptotic cell death.
abstract: Methuosis is a novel caspase-independent form of cell death in which massive accumulation of vacuoles derived from macropinosomes ultimately causes cells to detach from the substratum and rupture. We recently described a chalcone-like compound, 3-(2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (i.e., MIPP), which can induce methuosis in glioblastoma and other types of cancer cells. Herein, we describe the synthesis and structure-activity relationships of a directed library of related compounds, providing insights into the contributions of the two aryl ring systems and highlighting a potent derivative, 3-(5-methoxy, 2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (i.e., MOMIPP) that can induce methuosis at low micromolar concentrations. We have also generated biologically active azide derivatives that may be useful for future studies aimed at identifying the protein targets of MOMIPP by photoaffinity labeling techniques. The potential significance of these studies is underscored by the finding that MOMIPP effectively reduces the growth and viability of Temozolomide-resistant glioblastoma and doxorubicin-resistant breast cancer cells. Thus, it may serve as a prototype for drugs that could be used to trigger death by methuosis in cancers that are resistant to conventional forms of cell death (e.g., apoptosis).
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, 3000 Arlington Ave., Toledo, Ohio 43614, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Robinson
authors.forename: Jean H
authors.initials: JH
authors.lastname: Overmeyer
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Young
authors.forename: Paul W
authors.initials: PW
authors.lastname: Erhardt
authors.forename: William A
authors.initials: WA
authors.lastname: Maltese
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019920:Photoaffinity Labels / Q000138:chemical synthesis / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C573286:3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one; D000970:Antineoplastic Agents; D001386:Azides; D047188:Chalcones; D007211:Indoles; D019920:Photoaffinity Labels; D011725:Pyridines