Discovery of structurally simplified analogs of colchicine as an immunosuppressant |
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Institution: | 1. The Second Clinical School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China;2. Emergency Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China |
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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. |
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Keywords: | Immunosuppressant Transplants rejection Autoimmune-disease Colchicine Cyclosporine A (CsA) |
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