Design and syntheses of permethyl ningalin B analogues: potent multidrug resistance (MDR) reversal agents of cancer cells
| Autor: | Tao Jiang, Xiaoyu Zhang, Clare S. W. Yan, Pu Yong Zhang, Iris L. K. Wong, Larry M.C. Chow, Sheng Biao Wan |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Paclitaxel
Antineoplastic Agents Pharmacology chemistry.chemical_compound Structure-Activity Relationship Non-competitive inhibition Cell Line Tumor Drug Discovery medicine Structure–activity relationship Humans Doxorubicin Pyrroles ATP Binding Cassette Transporter Subfamily B Member 1 P-glycoprotein biology Stereoisomerism Drug Resistance Multiple Multiple drug resistance chemistry Cell culture Drug Resistance Neoplasm Vincristine Drug Design Cancer cell biology.protein Molecular Medicine Heterocyclic Compounds 3-Ring medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 53(14) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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