Extending the structure-activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors
| Autor: | Tao Jiang, Tingfu Jiang, Peng Wang, Iris L. K. Wong, Larry M.C. Chow, Sheng Biao Wan, Kai Peng, Zhen Liu, Chao Yang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Aquatic Organisms ATP Binding Cassette Transporter Subfamily B Chemosensitizer Drug resistance Pharmacology 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Cell Line Tumor Drug Discovery medicine Structure–activity relationship Humans P-glycoprotein Inhibitor Chemistry Organic Chemistry General Medicine Vinblastine 030104 developmental biology Paclitaxel Drug Resistance Neoplasm 030220 oncology & carcinogenesis ATP-Binding Cassette Transporters Female Pharmacophore Heterocyclic Compounds 3-Ring Intracellular medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 125 |
| ISSN: | 1768-3254 |
| Popis: | In the present study, a total of 25 novel ningalin B analogues were synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Preliminary structure-activity study shows that A ring and its two methoxy groups are important pharmacophores for P-gp inhibiting activity. Among all derivatives, 23 is the most potent P-gp modulator with EC 50 of 120–165 nM in reversing paclitaxel, DOX, vinblastine and vincristine resistance. It is relatively safe to use with selective index at least greater than 606 compared to verapamil. Mechanistic study demonstrates that compound 23 reverses P-gp mediated drug resistance by inhibiting transport activity of P-gp, thereby restoring intracellular drug accumulation. In summary, our study demonstrates that ningalin B analogue 23 is a non-cytotoxic and effective P-gp chemosensitizer that can be used in the future for reversing P-gp mediated clinical cancer drug resistance. |
| Databáze: | OpenAIRE |
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