Design, synthesis, cytotoxicity and mechanism of novel dihydroartemisinin-coumarin hybrids as potential anti-cancer agents

• Published in: European journal of medicinal chemistry Vol. 151; pp. 434 - 449
• Main Authors: Yu, Haonan, Hou, Zhuang, Tian, Ye, Mou, Yanhua, Guo, Chun
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 10.05.2018; Elsevier
• Subjects: Anticancer; Apoptosis; Artemisnin; Chemistry, Medicinal; Coumarin; Ferroptosis; Hybrid; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Artemisnin; Carbonic anhydrases; Hybrid; Acetazolamide; Ferroptosis; doxorubicin; Anticancer; DHA; Coumarin; Apoptosis; CK2; HYPOXIA; CANCER; INHIBITION; ANHYDRASE ISOFORMS IX; PH; XII
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.04.005

To develop novel agents with anticancer activities, thirty-four new dihydroartemisinin-coumarin hybrids were designed and synthesized in this study. Those compounds were identified that had great anticancer activity against two cancer cell lines (MDA-MB-231 and HT-29). The structure-activity relationships of the derivatives were also discussed, and the results of docking analysis had shown that carbonic anhydrases IX (CA IX) was very likely to be one of the drug targets of the hybrids. Meanwhile, to clarify the mechanism of the anticancer activity of the hybrids molecule, we did further exploration in the bioactivity of the hybrids. The results had shown that these derivatives obviously inhibited proliferation of HT-29 cell lines, arrested G0/G1 phase of HT-29 cells, suppressed the migration of tumor cells, and induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells. Interestingly, the hybrids also induced the other cell death pathway-ferroptosis. [Display omitted] •Thirty-four new dihydroartemisinin-coumarin hybrids were designed and synthesized.•The hybrids obviously inhibited proliferation of HT-29 cell lines.•The hybrids induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells.•The hybrids could also induce the other cell death pathway-ferroptosis.