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Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids.

ABSTRACT: 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.

SUBMITTER: Hou H

PROVIDER: S-EPMC8716824 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Design, synthesis and anti-breast cancer properties of butyric ester tethered dihydroartemisinin-isatin hybrids.

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