AUTHOR=Dong Min , Zheng Guili , Gao Feng , Li Min , Zhong Chen 

TITLE=Three-Carbon Linked Dihydroartemisinin-Isatin Hybrids: Design, Synthesis and Their Antiproliferative Anticancer Activity

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.834317

DOI=10.3389/fphar.2022.834317

ISSN=1663-9812

ABSTRACT=<p>Fifteen dihydroartemisinin-isatin hybrids (<bold>5a-e</bold> and <bold>6a-j)</bold> 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/IC<sub>50</sub>: 5.72–55.52 <italic>μ</italic>M) demonstrated considerable antiproliferative activity, and the activity was superior to that of dihydroartemisinin (IC<sub>50</sub>: 69.42–88.03 <italic>μ</italic>M) and artemisinin (IC<sub>50</sub>: &gt;100 <italic>μ</italic>M). In particular, two hybrids <bold>6a, e</bold> (IC<sub>50</sub>: 5.72–9.84 <italic>μ</italic>M) were not inferior to doxorubicin (IC<sub>50</sub>: 4.06 <italic>μ</italic>M) and cisplatin (IC<sub>50</sub>: 9.38 <italic>μ</italic>M) against drug-sensitive A549 cells and were more potent than doxorubicin (IC<sub>50</sub>: 54.32 and 15.10 <italic>μ</italic>M) and cisplatin (IC<sub>50</sub>: 19.74 and 66.89 <italic>μ</italic>M) against multidrug-resistant A549/DOX and A549/DDP lung cancer cell lines. In addition, hybrids <bold>6a, e</bold> (IC<sub>50</sub>: &gt;100 <italic>μ</italic>M) showed no toxicity towards BEAS-2B cells, proving their excellent selectivity profile. Furthermore, hybrid <bold>6a</bold> also possessed good stability in mouse and human microsomes, as well as excellent pharmacokinetic properties. Accordingly, hybrid <bold>6a</bold> could serve as a promising anti-lung cancer chemotherapeutic candidate for further preclinical evaluations.</p>