Cleavage of the cyclohexyl-subunit of rapamycin results in loss of immunosuppressive activity

The cyclohexyl-subunit of rapamycin was cleaved by a sequence involving a B aeyer-Villiger reaction and acid hydrolysis of the resulting lactone-acetal as key steps. Binding of this new rapamycin derivative to FKBP12 was only slightly reduced by this modification, whereas the loss of antiproliferativ e and immunosuppressive activity was dramatic. These findings indicate that part of the cyclohexyl-subunit of rapamycin could belong to its effector d omain. (C) 1999 Elsevier Science Ltd. All rights reserved.