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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716824/ https://www.ncbi.nlm.nih.gov/pubmed/34975498 http://dx.doi.org/10.3389/fphar.2021.801580 |
Sumario: | 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/IC(50): 7.54–73.8 μM) were more potent than the parent drug dihydroartemisinin (IC(50): 69.4–88.0 μM) and also non-cytotoxic towards mouse embryonic fibroblast cells NIH/3T3 (IC(50): >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 (IC(50): 7.54–12.1 μM) and 9i (IC(50): 9.10–15.9 μM) were comparable to cisplatin (IC(50): 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 (IC(50): 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. |
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