Document Detail


Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel type of nonapoptotic cell death.
MedLine Citation:
PMID:  22335538     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Michael W Robinson; Jean H Overmeyer; Ashley M Young; Paul W Erhardt; William A Maltese
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-02-28
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  55     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-08     Completed Date:  2012-07-09     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1940-56     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, 3000 Arlington Ave., Toledo, Ohio 43614, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemical synthesis*,  chemistry,  pharmacology
Azides / chemical synthesis*,  chemistry,  pharmacology
Cell Death / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Chalcones / chemical synthesis*,  chemistry,  pharmacology
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Humans
Indoles / chemical synthesis*,  chemistry,  pharmacology
Photoaffinity Labels / chemical synthesis,  chemistry
Pyridines / chemical synthesis*,  chemistry,  pharmacology
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
R01 CA115495/CA/NCI NIH HHS; R01 CA115495-03/CA/NCI NIH HHS; R01 CA115495-03S1/CA/NCI NIH HHS; R01 CA115495-04/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one; 0/Antineoplastic Agents; 0/Azides; 0/Chalcones; 0/Indoles; 0/Photoaffinity Labels; 0/Pyridines
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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