| Design and syntheses of permethyl ningalin B analogues: potent multidrug resistance (MDR) reversal agents of cancer cells. | |
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MedLine Citation:
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PMID: 20560605 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A series of novel N-arylalkyl-3,4-diaryl-substituted pyrrole-2,5-diones were synthesized. They exhibited promising P-gp modulating activity in a P-gp overexpressing breast cancer cell line (LCC6MDR). Compound 6 (with three methoxy groups at D-ring) displayed the highest P-gp modulating activity. 6 at 1 microM can sensitize LCC6MDR cells toward paclitaxel by 18.2-fold. Interestingly, a synergy on modulating P-gp was noted when 6 and 25 were used together (fractional inhibitory concentration index FICI = 0.42). Combination of 6 (0.5 microM) and 25 (0.5 microM) resulted in a 66-fold sensitization of LCC6MDR cells toward paclitaxel. They also reversed P-gp mediated doxorubicin (DOX) and vincristine resistance. Kinetic characterization suggests that permethyl ningalin B analogues likely act as a noncompetitive inhibitor of P-gp-mediated DOX transport (K(i) = 5.4-5.8 microM). The present study demonstrates that synthetic analogues of permethyl ningalin B can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells. |
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Authors:
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Pu Yong Zhang; Iris L K Wong; Clare S W Yan; Xiao Yu Zhang; Tao Jiang; Larry M C Chow; Sheng Biao Wan |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 53 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-29 Completed Date: 2010-08-25 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 5108-20 Citation Subset: IM |
Affiliation:
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Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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chemical synthesis*,
chemistry,
pharmacology Cell Line, Tumor Doxorubicin / pharmacology Drug Design Drug Resistance, Multiple / drug effects* Drug Resistance, Neoplasm / drug effects* Heterocyclic Compounds, 3-Ring / chemical synthesis*, chemistry, pharmacology Humans P-Glycoprotein / biosynthesis Paclitaxel / pharmacology Pyrroles / chemical synthesis*, chemistry, pharmacology Stereoisomerism Structure-Activity Relationship Vincristine / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Heterocyclic Compounds, 3-Ring; 0/P-Glycoprotein; 0/Pyrroles; 0/ningalin B; 23214-92-8/Doxorubicin; 33069-62-4/Paclitaxel; 57-22-7/Vincristine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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