- Discovery of structurally simplified analogs of colchicine as an immunosuppressant
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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.
- Chang, Dong-Jo,Kim, Wan-Joo
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p. 3121 - 3125
(2014/06/24)
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- Improved and highly versatile synthesis of 5-aryltropones
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The use of 5-iodo-2-methoxytropone in palladium(0)-catalyzed coupling reactions with a variety of arylboronic acids has resulted in significantly improved reaction yields and times for a sterically and electronically diverse series of novel 5-aryltropones
- Potenziano, James,Spitale, Robert,Janik, Mark E.
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p. 2005 - 2016
(2007/10/03)
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- Efforts directed toward the synthesis of colchicine: Application of palladium-catalyzed siloxane cross-coupling methodology
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Colchicine is an important and synthetically challenging natural product. The key synthetic step in this approach to the synthesis of colchicine involved a palladium-catalyzed cross-coupling reaction between 5-bromotropolone (4) and an aryl siloxane to form the aryl-tropolone bond. The coupling of a variety of highly functionalized aryl siloxane derivatives was investigated and optimized coupling conditions were developed. It was discovered that a palladium catalyst with a high degree of phosphine ligand coordination (5 equiv of phosphine/mol Pd) was necessary to efficiently couple aryl siloxanes with 5-bromotropolone (4). In addition, the coupling approach has provided a direct comparison between siloxane and boronic acid coupling technologies that demonstrated that aryl siloxanes and boronic acids produce similar yields of highly functionalized biaryl products.
- Seganish, W. Michael,Handy, Christopher J.,DeShong, Philip
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p. 8948 - 8955
(2007/10/03)
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- A CONVENIENT SYNTHESIS OF 5-ARYLTROPONES
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2-methoxy-5-oxy>tropone was coupled to a variety of arylzinc chlorides in the presence of a palladium catalyst to furnish 5-aryltropones in good to excelent yields.
- Keenan, Richard M.,Kruse, Lawrence I.
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p. 793 - 798
(2007/10/02)
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