Exploration of novel phthalazinone derivatives as potential efflux transporter inhibitors for reversing multidrug resistance and improving the oral absorption of paclitaxel
Copyright © 2022 Elsevier Masson SAS. All rights reserved..
Chemotherapy is an important means of cancer treatment. However, overexpression of efflux transporters (including but not limited to P-gp and BCRP) can lead to resistance to cancer chemotherapy. Multiple-target inhibitors of efflux transporter can be overcome the resistance and improve the oral bioavailability of chemotherapy drugs. Therefore, we designed and synthesized a series of phthalazinone ring derivatives (1-20) with different aromatic heterocycles substituents on the amide bond for dual inhibition of P-gp and BCRP. Most target compounds significantly increased the accumulation of P-gp substrates in the chemo-resistant cancer cell lines by inhibiting the efflux of transporters. Compound 19 in particular showed stronger MDR reversal compared to Gefitinib and Verapamil, and comparable to that of the BCRP inhibitor Ko143. In addition, compound 19 improved intestinal absorption of paclitaxel (PTX) and enhanced the bioavailability of the orally administered drug in vivo.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:233 |
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| Enthalten in: |
European journal of medicinal chemistry - 233(2022) vom: 05. Apr., Seite 114231 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shi, Wei [VerfasserIn] |
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| Links: |
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| Themen: |
ATP Binding Cassette Transporter, Subfamily G, Member 2 |
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| Anmerkungen: |
Date Completed 22.03.2022 Date Revised 22.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2022.114231 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a Chemotherapy is an important means of cancer treatment. However, overexpression of efflux transporters (including but not limited to P-gp and BCRP) can lead to resistance to cancer chemotherapy. Multiple-target inhibitors of efflux transporter can be overcome the resistance and improve the oral bioavailability of chemotherapy drugs. Therefore, we designed and synthesized a series of phthalazinone ring derivatives (1-20) with different aromatic heterocycles substituents on the amide bond for dual inhibition of P-gp and BCRP. Most target compounds significantly increased the accumulation of P-gp substrates in the chemo-resistant cancer cell lines by inhibiting the efflux of transporters. Compound 19 in particular showed stronger MDR reversal compared to Gefitinib and Verapamil, and comparable to that of the BCRP inhibitor Ko143. In addition, compound 19 improved intestinal absorption of paclitaxel (PTX) and enhanced the bioavailability of the orally administered drug in vivo | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BCRP | |
| 650 | 4 | |a Efflux transporter | |
| 650 | 4 | |a Multidrug resistance | |
| 650 | 4 | |a Oral bioavailability | |
| 650 | 4 | |a P-gp | |
| 650 | 7 | |a ATP Binding Cassette Transporter, Subfamily G, Member 2 |2 NLM | |
| 650 | 7 | |a Neoplasm Proteins |2 NLM | |
| 650 | 7 | |a Paclitaxel |2 NLM | |
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| 700 | 1 | |a Zhang, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Jiaqi |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Ziyu |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Zilong |e verfasserin |4 aut | |
| 700 | 1 | |a Ghaleb, Hesham |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Yuxuan |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Wenlong |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Qianqian |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Hai |e verfasserin |4 aut | |
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