Abstract |
The P-glycoprotein (Pgp) is a major transporter involved in multidrug resistance (MDR) of cancer cells leading to chemotherapy failure. In our previous study, we demonstrated that the amide derivatives of pyxinol are promising modulators against Pgp-mediated MDR in cancer. In the present study, we designed and synthesized novel pyxinol derivatives linked to amino acid residues. We evaluated MDR ( paclitaxel (Ptx) resistance) reversal potency of forty pyxinol derivatives in KBV cells and analyzed their structure-activity relationships. Half of our derivatives sensitized KBV cells to Ptx at non-toxic concentrations, among which the pyxinol compound bearing a methionine residue (3c) exhibited the best activity in MDR reversal. Compound 3c was found to possess high selectivity toward Pgp and sensitize the KBV cells to Pgp substrates by blocking the efflux function of Pgp. This manifestation may be attributed to its high binding affinity with Pgp, as suggested by docking studies. Overall, the biological profile and ease of synthesizing these pyxinol derivatives render them promising lead compounds for further development for Pgp-mediated MDR.
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Authors | Conghui Wang, Meng Gao, Shuqi Liu, Zongji Zou, Ruiyin Ren, Chen Zhang, Hao Xie, Jingxian Sun, Yupeng Qi, Qi Qu, Zhihua Song, Gangqiang Yang, Hongbo Wang |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 216
Pg. 113317
(Apr 15 2021)
ISSN: 1768-3254 [Electronic] France |
PMID | 33706147
(Publication Type: Journal Article)
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Copyright | Copyright © 2021 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Amino Acids
- Antineoplastic Agents
- Sapogenins
- Paclitaxel
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(chemistry, metabolism)
- Amino Acids
(chemistry)
- Antineoplastic Agents
(chemistry, pharmacology)
- Apoptosis
(drug effects)
- Binding Sites
- Catalytic Domain
- Cell Cycle Checkpoints
(drug effects)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Drug Resistance, Neoplasm
(drug effects)
- Humans
- Molecular Dynamics Simulation
- Paclitaxel
(pharmacology)
- Sapogenins
(chemistry)
- Structure-Activity Relationship
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