Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids
A series of 1,2,3-triazole tethered dihydroartemisinin-isatin hybrids 8a-c and 9a-k were designed and synthesized. Their antiproliferative activity against A549, doxorubicin-resistant A549 (A549/DOX) as well as cisplatin-resistant A549 (A549/DDP) lung cancer cell lines was also investigated in this...
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.801580/full |
| _version_ | 1819239217023156224 |
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| author | Haodong Hou Bin Qu Chen Su Guihua Hou Feng Gao |
| author_facet | Haodong Hou Bin Qu Chen Su Guihua Hou Feng Gao |
| author_sort | Haodong Hou |
| collection | DOAJ |
| description | A series of 1,2,3-triazole tethered dihydroartemisinin-isatin hybrids 8a-c and 9a-k were designed and synthesized. Their antiproliferative activity against A549, doxorubicin-resistant A549 (A549/DOX) as well as cisplatin-resistant A549 (A549/DDP) lung cancer cell lines was also investigated in this study. All hybrids (half maximal inhibitory concentration/IC50: 7.54–73.8 μM) were more potent than the parent drug dihydroartemisinin (IC50: 69.4–88.0 μM) and also non-cytotoxic towards mouse embryonic fibroblast cells NIH/3T3 (IC50: >100 μM). The structure-activity relationships illustrated that the substituents on C-3 and C-5 position of isatin moiety influenced the activity significantly. Imine at C-3 position decreased the activity, whereas fluoro at C-5 position enhanced the activity. In particular, hybrids 8a,c (IC50: 7.54–12.1 μM) and 9i (IC50: 9.10–15.9 μM) were comparable to cisplatin (IC50: 7.54–15.9 μM vs 9.38–19.7 μM) against A549 and A549/DOX, but 4.6–7.6 folds more potent than that of cisplatin (IC50: 8.77–14.3 μM vs 66.9 μM) against A549/DDP cells. Moreover, hybrids 8a,c exhibited excellent stability (liver microsomes: 68–83%) in mouse/human microsomes and good pharmacokinetic properties, demonstrating their potential as a novel anti-lung cancer chemotherapeutic candidates. |
| first_indexed | 2024-12-23T13:48:36Z |
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| id | doaj.art-235ba9a8a5614c7faf4d951f2c38e34e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-23T13:48:36Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-235ba9a8a5614c7faf4d951f2c38e34e2022-12-21T17:44:39ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-12-011210.3389/fphar.2021.801580801580Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin HybridsHaodong HouBin QuChen SuGuihua HouFeng GaoA series of 1,2,3-triazole tethered dihydroartemisinin-isatin hybrids 8a-c and 9a-k were designed and synthesized. Their antiproliferative activity against A549, doxorubicin-resistant A549 (A549/DOX) as well as cisplatin-resistant A549 (A549/DDP) lung cancer cell lines was also investigated in this study. All hybrids (half maximal inhibitory concentration/IC50: 7.54–73.8 μM) were more potent than the parent drug dihydroartemisinin (IC50: 69.4–88.0 μM) and also non-cytotoxic towards mouse embryonic fibroblast cells NIH/3T3 (IC50: >100 μM). The structure-activity relationships illustrated that the substituents on C-3 and C-5 position of isatin moiety influenced the activity significantly. Imine at C-3 position decreased the activity, whereas fluoro at C-5 position enhanced the activity. In particular, hybrids 8a,c (IC50: 7.54–12.1 μM) and 9i (IC50: 9.10–15.9 μM) were comparable to cisplatin (IC50: 7.54–15.9 μM vs 9.38–19.7 μM) against A549 and A549/DOX, but 4.6–7.6 folds more potent than that of cisplatin (IC50: 8.77–14.3 μM vs 66.9 μM) against A549/DDP cells. Moreover, hybrids 8a,c exhibited excellent stability (liver microsomes: 68–83%) in mouse/human microsomes and good pharmacokinetic properties, demonstrating their potential as a novel anti-lung cancer chemotherapeutic candidates.https://www.frontiersin.org/articles/10.3389/fphar.2021.801580/fullartemisinindihydroartemisininisatin1,2,3-triazolehybrid moleculesmultidrug resistance |
| spellingShingle | Haodong Hou Bin Qu Chen Su Guihua Hou Feng Gao Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids Frontiers in Pharmacology artemisinin dihydroartemisinin isatin 1,2,3-triazole hybrid molecules multidrug resistance |
| title | Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids |
| title_full | Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids |
| title_fullStr | Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids |
| title_full_unstemmed | Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids |
| title_short | Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids |
| title_sort | design synthesis and anti lung cancer evaluation of 1 2 3 triazole tethered dihydroartemisinin isatin hybrids |
| topic | artemisinin dihydroartemisinin isatin 1,2,3-triazole hybrid molecules multidrug resistance |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.801580/full |
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