title: Discovery of structurally simplified analogs of colchicine as an immunosuppressant.
abstract: We have discovered a new class of colchicine-derived therapeutic agents for immune diseases including rejection of organ-transplantation and autoimmune disease. Compound 2, which had been developed to overcome poor pharmacokinetic properties of compound 1, a first-generation colchicine analog, turned out to show toxicity such as intestinal toxicity and loss of weight during in vivo tests. The deletion of 7-carboxamide group and middle ring-truncation in colchicine allowed us to have structurally simplified analogs with strong immunosuppressive activity. Herein, we report non-alkaloid tricyclic compound 7 and 12 as immunosuppressants which exhibited a strong immunosuppressive in vivo efficacy on the T-dependent antibody response, the Zymosan A-induced arthritis model and the Carrageenan-induced edema model. Compound 7 and 12 revealed less toxicity than the previous lead compound 2, and their minimum lethal doses (MLD) were proved to exceed 100 mg/kg.
authors.affiliation: College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon, Jeollanam-do 540-950, Republic of Korea. Electronic address: djchang@sunchon.ac.kr.
authors.forename: Dong-Jo
authors.initials: DJ
authors.lastname: Chang
authors.affiliation: Team of Biotechnology and Drug Discovery Chem-Tech Research Incorporation, 778-1 Ilpae Dong, Namyangju City, Gyeonggi-do 472-930, Republic of Korea.
authors.forename: Wan-Joo
authors.initials: WJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D001402:B-Lymphocytes / Q000187:drug effects; D002351:Carrageenan; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives* / Q000737:chemistry*; D003208:Concanavalin A / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects; D015054:Zymosan
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D003208:Concanavalin A; D002351:Carrageenan; D015054:Zymosan; D003078:Colchicine
keywords: Autoimmune-disease; Colchicine; Cyclosporine A (CsA); Immunosuppressant; Transplants rejection