title: Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity.
abstract: Certain indolyl-pyridinyl-propenone analogues kill glioblastoma cells that have become resistant to conventional therapeutic drugs. Some of these analogues induce a novel form of non-apoptotic cell death called methuosis, while others primarily cause microtubule disruption. Ready access to 5-indole substitution has allowed characterization of this position to be important for both types of mechanisms when a simple methoxy group is present. We now report the syntheses and biological effects of isomeric methoxy substitutions on the indole ring. Additionally, analogues containing a trimethoxyphenyl group in place of the pyridinyl moiety were evaluated for anticancer activity. The results demonstrate that the location of the methoxy group can alter both the potency and the mechanism of cell death. Remarkably, changing the methoxy from the 5-position to the 6-position switched the biological activity from induction of methuosis to disruption of microtubules. The latter may represent a prototype for a new class of mitotic inhibitors with potential therapeutic utility.
authors.affiliation: Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft Ave., Toledo, OH 4360, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Trabbic
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Arlington Ave., Toledo, OH 43614, USA.
authors.forename: Sage M
authors.initials: SM
authors.lastname: George
authors.affiliation: Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft Ave., Toledo, OH 4360, USA.
authors.forename: Evan M
authors.initials: EM
authors.lastname: Alexander
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Arlington Ave., Toledo, OH 43614, USA.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Du
authors.affiliation: Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft Ave., Toledo, OH 4360, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Offenbacher
authors.affiliation: Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft Ave., Toledo, OH 4360, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Crissman
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Arlington Ave., Toledo, OH 43614, USA.
authors.forename: Jean H
authors.initials: JH
authors.lastname: Overmeyer
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Arlington Ave., Toledo, OH 43614, USA. Electronic address: william.maltese@utoledo.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Maltese
authors.affiliation: Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, 2801 W. Bancroft Ave., Toledo, OH 4360, USA. Electronic address: paul.erhardt@utoledo.edu.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Erhardt
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007536:Isomerism; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; C030374:indole; C023666:pyridine
keywords: Cell death; Glioblastoma; Indolyl-pyridinyl-propenones; Methuosis; Microtubule disruption