Abstract
Fifteen dihydroartemisinin-isatin hybrids (5a-e and 6a-j) linked with three-carbon were designed, synthesized. The antiproliferative activity against lung cancer cell lines including drug-sensitive A549, doxorubicin-resistant A549 (A549/DOX) and cisplatin-resistant A549 (A549/DDP) lung cancer cell lines was tested. The cytotocivity towards normal lung epithelial BEAS-2B cell line was also investigated. From the structure-activity relationship (SAR), it was found that hydrogen bond donors (especially hydroxime and thiosemicarbazide) at C-3 position and electron-withdrawing groups (fluoro and chloro) at C-5 position of isatin moiety were beneficial for the activity. A significant part of them (half maximal inhibitory concentration/IC50: 5.72–55.52 μM) demonstrated considerable antiproliferative activity, and the activity was superior to that of dihydroartemisinin (IC50: 69.42–88.03 μM) and artemisinin (IC50: >100 μM). In particular, two hybrids 6a, e (IC50: 5.72–9.84 μM) were not inferior to doxorubicin (IC50: 4.06 μM) and cisplatin (IC50: 9.38 μM) against drug-sensitive A549 cells and were more potent than doxorubicin (IC50: 54.32 and 15.10 μM) and cisplatin (IC50: 19.74 and 66.89 μM) against multidrug-resistant A549/DOX and A549/DDP lung cancer cell lines. In addition, hybrids 6a, e (IC50: >100 μM) showed no toxicity towards BEAS-2B cells, proving their excellent selectivity profile. Furthermore, hybrid 6a also possessed good stability in mouse and human microsomes, as well as excellent pharmacokinetic properties. Accordingly, hybrid 6a could serve as a promising anti-lung cancer chemotherapeutic candidate for further preclinical evaluations.
Highlights
Lung cancer, caused by several environmental and genetic variables (Zhang et al, 2021; Yang et al, 2022), is the leading cause of cancer related deaths and is responsible for around 20% of all cancer deaths with an estimated 1.8 million new cases and 1.6 million deaths annually (Hirsch et al, 2017; Kramer and Annema, 2021)
According to the histopathological characteristics, lung cancer is mainly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and NSCLC accounts for about 80–85% of lung cancers (Sławiński et al, 2020; Xie et al, 2021)
Scheme 1 describes the synthetic route of desired dihydroartemisinin-isatin hybrids 5a-e and 6a-j. (5substituted) isatins 1 alkylating with 3-bromopropanol 2, using potassium carbonate (K2CO3) as base yielded intermediates 3
Summary
Lung cancer, caused by several environmental and genetic variables (Zhang et al, 2021; Yang et al, 2022), is the leading cause of cancer related deaths and is responsible for around 20% of all cancer deaths with an estimated 1.8 million new cases and 1.6 million deaths annually (Hirsch et al, 2017; Kramer and Annema, 2021). Hybrids synthesized by fusing or conjugating different active pharmacophores together are capable to modulate multiple targets, enhancing the efficacy, overcoming drug resistance and reducing side effects (Nepali et al, 2014; Sharma et al, 2014; Mishra and Singh, 2016; Choudhary et al, 2018; Hou et al, 2021). Since both DHA and isatin hold potent anti-lung cancer activity, there is a high possibility that hybridization of DHA with isatin may provide novel anti-lung cancer candidates with high activity and efficacy. The biological activity and the pharmacokinetic properties of the hybrids with two carbon or four carbon linker are still under investigation, and the anticancer characteristics of the hybrids with different length of linkers will be reported in the near future
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