Synthesis of derivatives of the novel cyclophilin-binding immunosuppressant sanglifehrin A with reduced numbers of polar functions.
The syntheses and the biological activities of 53-deoxo sanglifehrin A (2) and 61-deoxy octahydrosanglifehrin A (3) are described. Compound 2 shows intracellular cyclophilin (CyP)-binding and immunosuppressive activity in the mixed-lymphocyte reaction (MLR) similar to that of sanglifehrin A (1). Compound 3 is much less active in the MLR despite unchanged intracellular CyP-binding. This indicates that the 53-keto group is not necessary for immunosuppressive activity, while the 61 hydroxy group is required.
Bänteli
R
R
Novartis Pharma AG, CH-4002 Basel, Switzerland. rolf.baenteli@pharma.novartis.com
Wagner
J
J
Zenke
G
G
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D021983:Cyclophilins / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D007783:Lactones; D013141:Spiro Compounds; C121329:sanglifehrin A; D021983:Cyclophilins