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.
Highlights
Lung cancer represents one of the most malignant tumors with the high morbidity and mortality, and non-small cell lung cancer (NSCLC, accounts for 80–85% of lung cancer cases) is the most aggressive type of lung cancer (Willis et al, 2019; Sławiński et al, 2020)
We designed and synthesized the desired 1,2,3-triazole tethered dihydroartemisinin-isatin hybrids 8a-c and 9a-k following the synthetic routes shown in Scheme 1
Dihydroartemisinin 1 reacted with propargyl alcohol 2 in presence of boron trifluoride
Summary
Lung cancer represents one of the most malignant tumors with the high morbidity and mortality, and non-small cell lung cancer (NSCLC, accounts for 80–85% of lung cancer cases) is the most aggressive type of lung cancer (Willis et al, 2019; Sławiński et al, 2020). It is urgent to develop novel drug candidates with high activity and efficacy against lung cancer, especially drug-resistant lung cancer. Artemisinin derivatives such as dihydroartemisinin (DHA, Figure 1) and artesunate, which own a unique sesquiterpene endoperoxide lactone moiety, could form highly reactive free radicals including reactive oxygen species (ROS) in the presence of ferrous ion (FeII) (Yu et al, 2019; Gao et al, 2020). Hybridization of dihydroartemisinin with isatin may open a door to develop potential drug candidates against lung cancers including drugresistant forms It is reported triazoles hold potential cytotoxic towards cancer cells, which attracted us towards the selection of 1,2,3-triazole as a linker. Our major goal is to optimize the anti-lung cancer potency of these hybrids, and preliminary studies on structure-activity relationships (SARs) are taken to facilitate the further development of these hybrids
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