Design and syntheses of permethyl ningalin B analogues: potent multidrug resistance (MDR) reversal agents of cancer cells.

Abstract

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.

• Authors: Pu Yong Zhang, Iris L K Wong, Clare S W Yan, Xiao Yu Zhang, Tao Jiang, Larry M C Chow, Sheng Biao Wan
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 14 Pg. 5108-20 (Jul 22 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20560605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Heterocyclic Compounds, 3-Ring
• Pyrroles
• ningalin B
• Vincristine
• Doxorubicin
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis)
• 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)
• Humans
• Paclitaxel (pharmacology)
• Pyrroles (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Vincristine (pharmacology)