MacrolidesChemical modification of rapamycin: the discovery of SDZ RAD
Section snippets
Rapamycin and analogs
RAP was obtained by fermentation of the actinomycete strain A91-259211. The analogs were prepared in our laboratories by chemical modification of RAP. The experimental details of the chemical syntheses will be reported elsewhere.
FKBP12 binding assay
Binding to the FK 506 binding protein (FKBP12) was indirectly assessed by means of an ELISA-type competition assay. FK 506 was included in each individual experiment as a standard, and the inhibitory activity is expressed as relative IC50 compared to FK 506 (rIC50 = IC50
Results and discussion
As can be seen from the data shown in Table 1, alkylation in either position 28 (compound 2) or position 40 (compounds 3–5) did not greatly affect binding to FKBP12. A significant loss in affinity was only observed when the rather bulky phenyl group was added to the C40-hydroxyl (compound 6). Methylation of the C28-hydroxyl (compound 2) resulted in a 1000-fold loss of activity in the MLR. When the same modification was carried out in position 40 (compound 3), the immunosuppressive activity was
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