Synthesis and immunosuppressive activity of new artemisinin derivatives. 1. [12(beta or alpha)-Dihydroartemisininoxy]phen(ox)yl aliphatic acids and esters.
A series of novel dihydroartemisinin derivatives were synthesized and evaluated on their immunosuppressive activity in the search for potential immunosuppressive agents with high efficacy and low toxicity. These compounds were assayed in their cytotoxicity of lymphocyte, inhibition activity on concanavalin A (ConA) induced T cell proliferation and lipopolysaccharide (LPS) induced B cell proliferation. Among them, 11b, 13b, 14d, 15b, 16, and 17 remarkably exhibited lower cytotoxicity and higher inhibition activity on the mitogen-induced T cell and B cell proliferation in comparison with artemisinin, artesunate, and artemether in vitro. More significantly, compound 11b displayed reduced cytotoxicity by over 100-fold compared with cyclosporin A (CsA) and comparable inhibition activity (SI = 848) on ConA-induced T cell proliferation to CsA (SI = 963) and more than 4000 times the inhibitory effect (SI = 28473) on LPS-induced B cell proliferation compared with CsA (SI = 7) in vitro. The in vivo experimental results showed that compound 16 could inhibit 2,4-dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) reaction and sheep red blood cell (SRBC) induced antibody production, respectively. The structure and activity relationships (SAR) of these compounds were also discussed.
Yang
Zhong-Shun
ZS
Department of Synthetic Chemistry, Graduate School of the Chinese Academy of Sciences.
Zhou
Wen-Liang
WL
Sui
Yi
Y
Wang
Jun-Xia
JX
Wu
Jin-Ming
JM
Zhou
Yu
Y
Zhang
Yu
Y
He
Pei-Lan
PL
Han
Ji-Ye
JY
Tang
Wei
W
Li
Ying
Y
Zuo
Jian-Ping
JP
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D037621:Artemisinins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D004139:Dinitrofluorobenzene; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D012756:Sheep; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D037621:Artemisinins; D004952:Esters; D005227:Fatty Acids; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D008934:Mitogens; D012717:Sesquiterpenes; D003208:Concanavalin A; C031327:artemisinin; D004139:Dinitrofluorobenzene