Abstract |
In the present study, a total of 9 novel permethyl ningalin B analogs have been synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Among these derivatives, compound 12 with dimethoxy groups at rings A and B and tri-substitution at ring C with ortho-methoxyethylmorpholine, meta-bromo and para-benzyloxy groups displays the most potent P-gp modulating activity with EC50 of 423 nM to reverse paclitaxel resistance. It is non-toxic towards L929 fibroblast with IC50 greater than 100 μM and with selective index greater than 236. Its mechanism to reverse P-gp mediated drug resistance is by virtue of inhibiting transport activity of P-gp, restoring intracellular drug accumulation and eventually chemosensitizing the cancer cells to anticancer drug again. Moreover, compound 12 showed better solubility (405 ng/mL) than hit compound 1 in phosphate buffer (pH 4.0). In summary, our study demonstrates that permethyl ningalin B derivative 12 is non-toxic and efficient P-gp inhibitor that is a potential candidate to be used clinically to reverse P-gp mediated cancer drug resistance.
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Authors | Zhen Wang, Iris L K Wong, Fu Xing Li, Chao Yang, Zhen Liu, Tao Jiang, Ting Fu Jiang, Larry M C Chow, Sheng Biao Wan |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 23
Issue 17
Pg. 5566-73
(Sep 01 2015)
ISSN: 1464-3391 [Electronic] England |
PMID | 26233798
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 Elsevier Ltd. All rights reserved. |
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B
- ATP-Binding Cassette Transporters
- Heterocyclic Compounds, 3-Ring
- ningalin B
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Topics |
- ATP Binding Cassette Transporter, Subfamily B
(antagonists & inhibitors, metabolism)
- ATP-Binding Cassette Transporters
(metabolism)
- Cell Line, Tumor
- Drug Resistance, Multiple
- Heterocyclic Compounds, 3-Ring
(metabolism)
- Humans
- Molecular Structure
- Structure-Activity Relationship
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