Document Detail

Design and syntheses of permethyl ningalin B analogues: potent multidrug resistance (MDR) reversal agents of cancer cells.
MedLine Citation:
PMID:  20560605     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  53     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-29     Completed Date:  2010-08-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5108-20     Citation Subset:  IM    
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
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MeSH Terms
Antineoplastic Agents / 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
P-Glycoprotein / biosynthesis
Paclitaxel / pharmacology
Pyrroles / chemical synthesis*,  chemistry,  pharmacology
Structure-Activity Relationship
Vincristine / pharmacology
Reg. No./Substance:
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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