Design, Synthesis and Cytotoxicity of Novel Dihydroartemisinin-Coumarin Hybrids via Click Chemistry.
In order to develop novel chemotherapeutic agents with potent anticancer activities, we designed four series of novel compounds employing hybridization strategy. Twenty novel dihydroartemisinin-coumarin hybrids, 10a-e, 11a-e, 12a-e, 13a-e, were synthesized via click chemistry in this study and their structures were characterized by HRMS and NMR. The cytotoxic activities were measured by MTT assay against three cancer cell lines (HCT-116, MDA-MB-231, and HT-29) under normoxic or anoxic conditions, respectively. The target compounds exhibited moderate activity with IC50 values in the 0.05-125.40 μM range, and these compounds exhibited better activity against HT-29 cell line under anoxic condition. The cytotoxic activities of most compounds under anoxic condition displayed one- to 10-fold greater activity than under normoxic condition. Compounds 10a-e showed better selectivity against the HT-29 cell line than the other two cell lines. These results indicated that our design of CA IX inhibitors does correspond with its action mode to some degree and deserves further investigation.
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. tianye870918@126.com.
Ye
Y
Tian
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. llzz_666@126.com.
Zhen
Z
Liang
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. xuhanglg2@126.com.
Hang
H
Xu
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China. mu_hua_jj@sina.com.
Yanhua
Y
Mou
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. chunguo@syphu.edu.cn.
Chun
C
Guo
D000951:Antigens, Neoplasm; D037621:Artemisinins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D000071231:Carbonic Anhydrase IX / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D057930:Click Chemistry; D003374:Coumarins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D045325:HCT116 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009369:Neoplasms / Q000188:drug therapy*
D000951:Antigens, Neoplasm; D037621:Artemisinins; D003374:Coumarins; D004791:Enzyme Inhibitors; C039060:artenimol; C030123:coumarin; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX
anoxic; anticancer; artemisinin; carbonic anhydrase IX; coumarin; cytotoxicity; hybrid