Document Detail


Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells.
MedLine Citation:
PMID:  16220985     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkylamino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropylamino analogue by treatment with triphenylphosphine-carbon tetrachloride. The compounds were evaluated in the A2780 ovarian cancer cell line and its cisplatin-resistant variants (A2780/cp70 and A2780/MCP1). The novel anthraquinones were shown to possess up to 5-fold increased potency against the cisplatin-resistant cells compared to the wild-type cells. Growth curve analysis of the hydroxyethylaminoanthraquinone 8 in the osteosarcoma cell line U-2 OS showed that the cell cycle is not frozen, rather there is a late cell cycle arrest consistent with the action of a DNA-damaging topoisomerase II inhibitor. Accumulative apoptotic events, using time lapse photography, indicate that 8 is capable of fully engaging cell cycle arrest pathways in G2 in the absence of early apoptotic commitment. 8 and its chloropropyl analogue 13 retained significant activity against human A2780/cp70 xenografted tumors in mice.
Authors:
Klaus Pors; Jane A Plumb; Robert Brown; Paul Teesdale-Spittle; Mark Searcey; Paul J Smith; Laurence H Patterson
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  48     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-10-13     Completed Date:  2005-12-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6690-5     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29-39 Brunswick Square, London.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anthraquinones / chemical synthesis*,  chemistry,  pharmacology
Antigens, Neoplasm
Antineoplastic Agents / chemical synthesis*,  chemistry,  pharmacology
Cisplatin / pharmacology*
DNA Topoisomerases, Type II, Eukaryotic / antagonists & inhibitors
DNA-Binding Proteins / antagonists & inhibitors
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Female
Humans
Mice
Mice, Nude
Ovarian Neoplasms
Structure-Activity Relationship
Transplantation, Heterologous
Chemical
Reg. No./Substance:
0/1-((2-dimethylamino)ethylamino)-4-(2-(3-hydroxymethylpiperidin-1-yl)ethylamino)-5,8-dihydroxyanthracene-9,10-dione; 0/Anthraquinones; 0/Antigens, Neoplasm; 0/Antineoplastic Agents; 0/DNA-Binding Proteins; 15663-27-1/Cisplatin; EC 5.99.1.-/DNA Topoisomerases, Type II, Eukaryotic; EC 5.99.1.3/DNA topoisomerase II alpha

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


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