title: Synthesis and biological evaluation of indolyl-pyridinyl-propenones having either methuosis or microtubule disruption activity.
abstract: Methuosis is a form of nonapoptotic cell death characterized by an accumulation of macropinosome-derived vacuoles with eventual loss of membrane integrity. Small molecules inducing methuosis could offer significant advantages compared to more traditional anticancer drug therapies that typically rely on apoptosis. Herein we further define the effects of chemical substitutions at the 2- and 5-indolyl positions on our lead compound 3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propene-1-one (MOMIPP). We have identified a number of compounds that induce methuosis at similar potencies, including an interesting analogue having a hydroxypropyl substituent at the 2-position. In addition, we have discovered that certain substitutions on the 2-indolyl position redirect the mode of cytotoxicity from methuosis to microtubule disruption. This switch in activity is associated with an increase in potency as large as 2 orders of magnitude. These compounds appear to represent a new class of potent microtubule-active anticancer agents.
authors: Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences , 3000 Arlington Avenue, Toledo, Ohio 43614, United States.
authors: Christopher J
authors: CJ
authors: Trabbic
authors: Jean H
authors: JH
authors: Overmeyer
authors: Evan M
authors: EM
authors: Alexander
authors: Emily J
authors: EJ
authors: Crissman
authors: Heather M
authors: HM
authors: Kvale
authors: Marcie A
authors: MA
authors: Smith
authors: Paul W
authors: PW
authors: Erhardt
authors: William A
authors: WA
authors: Maltese
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C573286:3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one; D000475:Alkenes; D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D014404:Tubulin; C013658:propylene
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