Design and synthesis of α-naphthoflavone chimera derivatives able to eliminate cytochrome P450 (CYP)1B1-mediated drug resistance via targeted CYP1B1 degradation

Extrahepatic cytochrome P450 1B1 (CYP1B1), which is highly expressed in various tumors, is an attractive and potential target for cancer prevention, therapy, and reversal of drug resistance. CYP1B1 inhibition is the current predominant therapeutic paradigm to treating CYP1B1-mediated malignancy, but...

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Veröffentlicht in:European journal of medicinal chemistry 2020-03, Vol.189, p.112028-112028, Article 112028
Hauptverfasser: Zhou, Li, Chen, Wenming, Cao, Chenyang, Shi, Yonghui, Ye, Wenchong, Hu, Jiliang, Wang, LingLi, Zhou, Wen
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container_title European journal of medicinal chemistry
container_volume 189
creator Zhou, Li
Chen, Wenming
Cao, Chenyang
Shi, Yonghui
Ye, Wenchong
Hu, Jiliang
Wang, LingLi
Zhou, Wen
description Extrahepatic cytochrome P450 1B1 (CYP1B1), which is highly expressed in various tumors, is an attractive and potential target for cancer prevention, therapy, and reversal of drug resistance. CYP1B1 inhibition is the current predominant therapeutic paradigm to treating CYP1B1-mediated malignancy, but therapeutic effect has little success. Herein, we reported CYP1B1 degradation in place of CYP1B1 inhibition for reversing drug resistance toward docetaxel in CYP1B1-overexpressing prostate cancer cell line DU145 using a PROTAC strategy. Replacing chlorine atom of a CYP1B1 selective inhibitor we found previously with ethynyl, we got the resulting α-naphthoflavone derivative 5 which kept strong inhibition against CYP1B1 (IC50 = 0.4 ± 0.2 nM) and high selectivity. Coupling of 5 with thalidomide derivatives of varying chain lengths afforded conjugates 6A-Dvia click reaction. In vitro cell-based assay indicated that 6C was more effective in eliminating drug resistance of CYP1B1-overexpressed DU145 cells compared with other analogues. Western blotting analysis showed CYP1B1 degradation was one main reason for the reversal of drug resistance to docetaxel and the effect was obtained in a concentration-dependent manner. This work is the first attempt to overcome CYP1B1-mediated drug resistance via CYP1B1 degradation instead of CYP1B1 inhibition, which could provide a new direction toward eliminating drug resistance. α-naphthoflavone chimera derivatives for targeted CYP1B1 degradation were developed. Among these, compound 6C can significantly induce CYP1B1 degradation in a concentration-dependent manner and reverse drug resistance of DU145 cells caused by overexpressed CYP1B1 towards docetaxel. [Display omitted] •Design and synthesis of α-naphthoflavone derivatives with high specificity to CYP1B1.•Design and synthesis of α-naphthoflavone-based conjugates able to targeted CYP1B1 degradation.•Drug resistance of transfected DU145/CY cells eliminated by α-naphthoflavone-based conjugate 6C.•CYP1B1 degradation by conjugate 6C in a dose dependent manner.
doi_str_mv 10.1016/j.ejmech.2019.112028
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CYP1B1 inhibition is the current predominant therapeutic paradigm to treating CYP1B1-mediated malignancy, but therapeutic effect has little success. Herein, we reported CYP1B1 degradation in place of CYP1B1 inhibition for reversing drug resistance toward docetaxel in CYP1B1-overexpressing prostate cancer cell line DU145 using a PROTAC strategy. Replacing chlorine atom of a CYP1B1 selective inhibitor we found previously with ethynyl, we got the resulting α-naphthoflavone derivative 5 which kept strong inhibition against CYP1B1 (IC50 = 0.4 ± 0.2 nM) and high selectivity. Coupling of 5 with thalidomide derivatives of varying chain lengths afforded conjugates 6A-Dvia click reaction. In vitro cell-based assay indicated that 6C was more effective in eliminating drug resistance of CYP1B1-overexpressed DU145 cells compared with other analogues. Western blotting analysis showed CYP1B1 degradation was one main reason for the reversal of drug resistance to docetaxel and the effect was obtained in a concentration-dependent manner. This work is the first attempt to overcome CYP1B1-mediated drug resistance via CYP1B1 degradation instead of CYP1B1 inhibition, which could provide a new direction toward eliminating drug resistance. α-naphthoflavone chimera derivatives for targeted CYP1B1 degradation were developed. Among these, compound 6C can significantly induce CYP1B1 degradation in a concentration-dependent manner and reverse drug resistance of DU145 cells caused by overexpressed CYP1B1 towards docetaxel. 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Western blotting analysis showed CYP1B1 degradation was one main reason for the reversal of drug resistance to docetaxel and the effect was obtained in a concentration-dependent manner. This work is the first attempt to overcome CYP1B1-mediated drug resistance via CYP1B1 degradation instead of CYP1B1 inhibition, which could provide a new direction toward eliminating drug resistance. α-naphthoflavone chimera derivatives for targeted CYP1B1 degradation were developed. Among these, compound 6C can significantly induce CYP1B1 degradation in a concentration-dependent manner and reverse drug resistance of DU145 cells caused by overexpressed CYP1B1 towards docetaxel. 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Western blotting analysis showed CYP1B1 degradation was one main reason for the reversal of drug resistance to docetaxel and the effect was obtained in a concentration-dependent manner. This work is the first attempt to overcome CYP1B1-mediated drug resistance via CYP1B1 degradation instead of CYP1B1 inhibition, which could provide a new direction toward eliminating drug resistance. α-naphthoflavone chimera derivatives for targeted CYP1B1 degradation were developed. Among these, compound 6C can significantly induce CYP1B1 degradation in a concentration-dependent manner and reverse drug resistance of DU145 cells caused by overexpressed CYP1B1 towards docetaxel. [Display omitted] •Design and synthesis of α-naphthoflavone derivatives with high specificity to CYP1B1.•Design and synthesis of α-naphthoflavone-based conjugates able to targeted CYP1B1 degradation.•Drug resistance of transfected DU145/CY cells eliminated by α-naphthoflavone-based conjugate 6C.•CYP1B1 degradation by conjugate 6C in a dose dependent manner.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>31945665</pmid><doi>10.1016/j.ejmech.2019.112028</doi><tpages>1</tpages></addata></record>
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subjects Click reaction
CYP1B1
PROTACs
Reversal of drug resistance
α-Naphthoflavone-based conjugates
title Design and synthesis of α-naphthoflavone chimera derivatives able to eliminate cytochrome P450 (CYP)1B1-mediated drug resistance via targeted CYP1B1 degradation
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