Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancer
NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates, which plays an important role in the treatment of non-small cell lung cancer (NSCLC). Based on the indolequinone structure from 5-methoxy-2-methylindole, the indolequinone of NQ...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Arabian Journal of Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535224004775 |
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| author | BinBin Wei Zheng Yang Hui Guo YuWei Wang WenZhuo Chen Jing Zhou RuYi Jin Zheng Wang YuPing Tang |
| author_facet | BinBin Wei Zheng Yang Hui Guo YuWei Wang WenZhuo Chen Jing Zhou RuYi Jin Zheng Wang YuPing Tang |
| author_sort | BinBin Wei |
| collection | DOAJ |
| description | NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates, which plays an important role in the treatment of non-small cell lung cancer (NSCLC). Based on the indolequinone structure from 5-methoxy-2-methylindole, the indolequinone of NQO1 agonists was first coupled with amino-evodiamine derivatives by esterification reaction, and sixteen new compounds targeting NQO1 were developed. Among them, compounds 11b and 12d (IC50 = 2.72 or 3.66 µM, respectively) were showed better activity by cytotoxicity assay than the reference drug EVO (IC50 = 19.65 µM). Furthermore, the results of flow cytometry analysis showed that compounds 11b and 12d promoted apoptosis in A549 cells, blocked the cell cycle to the G2/M stage and caused a burst of reactive oxygen species. Western blotting experiments revealed that compounds 11b and 12d, after 24 h of treatment in A549 cells, downregulate the expression of Keap1 while upregulating the expression of Nrf2, NQO1, and HO-1. This suggests that compounds 11b and 12d increase cellular antioxidant capacity by regulating the Keap1/Nrf2/NQO1 antioxidant pathway. In vivo anti-tumor experiments showed that the reference drugs EVO (TGI = 15.94 %) and 5-Fu (TGI = 27.54 %) inhibited the proliferation of tumor tissue, while compound 11b could better inhibit the proliferation of tumor tissue (TGI = 39.13 %). In conclusion, our research results suggest that compounds 11b and 12d are potent agonism of the NQO1 signaling pathway and provide a potential opportunity to improve the treatment of NSCLC. |
| format | Article |
| id | doaj-art-a4d65def2e0f4476a1bbe0ee2a753ac6 |
| institution | Kabale University |
| issn | 1878-5352 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj-art-a4d65def2e0f4476a1bbe0ee2a753ac62024-12-26T08:52:55ZengElsevierArabian Journal of Chemistry1878-53522025-01-01181106075Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancerBinBin Wei0Zheng Yang1Hui Guo2YuWei Wang3WenZhuo Chen4Jing Zhou5RuYi Jin6Zheng Wang7YuPing Tang8College of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaCollege of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaCorresponding authors.; College of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaCollege of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaCollege of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaCollege of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaCollege of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaCollege of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaCorresponding authors.; College of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, ChinaNQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates, which plays an important role in the treatment of non-small cell lung cancer (NSCLC). Based on the indolequinone structure from 5-methoxy-2-methylindole, the indolequinone of NQO1 agonists was first coupled with amino-evodiamine derivatives by esterification reaction, and sixteen new compounds targeting NQO1 were developed. Among them, compounds 11b and 12d (IC50 = 2.72 or 3.66 µM, respectively) were showed better activity by cytotoxicity assay than the reference drug EVO (IC50 = 19.65 µM). Furthermore, the results of flow cytometry analysis showed that compounds 11b and 12d promoted apoptosis in A549 cells, blocked the cell cycle to the G2/M stage and caused a burst of reactive oxygen species. Western blotting experiments revealed that compounds 11b and 12d, after 24 h of treatment in A549 cells, downregulate the expression of Keap1 while upregulating the expression of Nrf2, NQO1, and HO-1. This suggests that compounds 11b and 12d increase cellular antioxidant capacity by regulating the Keap1/Nrf2/NQO1 antioxidant pathway. In vivo anti-tumor experiments showed that the reference drugs EVO (TGI = 15.94 %) and 5-Fu (TGI = 27.54 %) inhibited the proliferation of tumor tissue, while compound 11b could better inhibit the proliferation of tumor tissue (TGI = 39.13 %). In conclusion, our research results suggest that compounds 11b and 12d are potent agonism of the NQO1 signaling pathway and provide a potential opportunity to improve the treatment of NSCLC.http://www.sciencedirect.com/science/article/pii/S1878535224004775EvodiamineIndolequinoneSynthesisNon-small cell lung cancer (NSCLC)NQO1 |
| spellingShingle | BinBin Wei Zheng Yang Hui Guo YuWei Wang WenZhuo Chen Jing Zhou RuYi Jin Zheng Wang YuPing Tang Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancer Arabian Journal of Chemistry Evodiamine Indolequinone Synthesis Non-small cell lung cancer (NSCLC) NQO1 |
| title | Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancer |
| title_full | Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancer |
| title_fullStr | Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancer |
| title_full_unstemmed | Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancer |
| title_short | Design, synthesis, and biological evaluation of evodiamine-indolequinone hybrids as novel NQO1 agonists against non-small cell lung cancer |
| title_sort | design synthesis and biological evaluation of evodiamine indolequinone hybrids as novel nqo1 agonists against non small cell lung cancer |
| topic | Evodiamine Indolequinone Synthesis Non-small cell lung cancer (NSCLC) NQO1 |
| url | http://www.sciencedirect.com/science/article/pii/S1878535224004775 |
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