The Application of Tandem Aza‐Wittig Reaction to Synthesize Artemisinin–Guanidine Hybrids and Their Anti‐Tumor Activity

Abstract

Three series of novel artemisinin-guanidine hybrids 4a-4f, 8a-8h and 9a-9h have been facilely synthesized via four-component reaction (aza-Wittig reaction) and evaluated for their anti-tumor activities against A549, HT-29 and MDA-MB-231 cell lines in vitro. All of the tested compounds showed enhanced anti-tumor activities with IC(50) values ranging from 0.02 µM to 12.0 µM as compared to DHA (dihydroartemisinin). Among them, artemisinin derived dimers, compounds 9b (IC(50) = 0.05 µM), 9d (IC(50) = 0.06 µM) and 9f (IC(50) = 0.02 µM) were found to be most active against HT29 cells.

Development of artemisinin compounds for cancer treatment

“…The IC 50 s on human HT-29 colon and HeLa cervical cancer cells were between 0.12 and 0.85 μM. Xie et al [123] have also synthesized artemisinin-guanidine hybrids. The Guanidine moiety would make the molecule more water soluble.…”

“…Deoxoartemisinin trimers are even more potent than pacilitaxel, 5-fluorouracil, and cisplatin on oral cancer cells. The artemisinin-guanidine dimers of Xie et al [123] are more potent than its monomer and have IC 50 s of 20-60 nM against HT-29 human colon cancer cells. The highly selective cytotoxicity of artemisinin dimers towards cancer cells makes them an attractive option for development for cancer treatment.…”

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones

“…This hybrid dimer showed up to 600-fold more potent cytotoxicity than DHA ( 2 ) toward the human A549 non-small-cell lung adenocarcinoma, HT-29 colon cancer, and MDA-MB-231 breast cancer cell lines [61]. Recently, three artesunic acid homodimers have been synthesized and evaluated for their activity against human CCRF-CEM and MDR P-glycoprotein-overexpressing CEM/ADR 5000 leukemia cells, and the MDR cells used were found not to be cross-resistant to these new dimers [62].…”

Artemisinin‐derived dimers as potential anticancer agents: Current developments, action mechanisms, and structure–activity relationships

“…Dimer 22a (IC 50 : 680 nM) showed cytotoxicity towards CHO cells, whereas compound 22b (IC 50 : 74,820 nM) displayed low cytotoxicity. The guanidine‐containing dimers 23 (IC 50 : 0.02–2.08 μM, MTT assay) demonstrated considerable activity against A549, HT‐29, and MDA‐MB‐231 cancer cell lines, and all of them were more potent than dihydroartemisinin (IC 50 : 7.8–12.0 μM) . The SAR revealed that all guanidine‐containing dimers were more active than the corresponding monomers, whereas the chalcone‐containing dimers were less potent than the corresponding monomers .…”

“…The guanidine‐containing dimers 23 (IC 50 : 0.02–2.08 μM, MTT assay) demonstrated considerable activity against A549, HT‐29, and MDA‐MB‐231 cancer cell lines, and all of them were more potent than dihydroartemisinin (IC 50 : 7.8–12.0 μM) . The SAR revealed that all guanidine‐containing dimers were more active than the corresponding monomers, whereas the chalcone‐containing dimers were less potent than the corresponding monomers . Moreover, the bis‐substituted dimer 23a (IC 50 : 0.02–1.42 μM) was generally more potent than the monosubstituted analogs against A549, HT‐29, and MDA‐MB‐231 cancer cell lines.…”