Chemistry Reference
In-Depth Information
90
91
Both compounds are 100-fold more potent than cyclosporin as immunosuppres-
sants and are less toxic. Their mechanism of action centers on its formation of a
complex with the immunophilin FKBP12 (FK-binding protein), causing an inhi-
bition of calcineurin. This inhibition of calcineurin decreases the presentation
of Th1- and Th2-type cytokines in cells and reduces the production of inter-
leukins IL-2, 4, and 10, leading to immunosuppression (61). Tacrolimus and
rapamycin sales in global markets reached US$2 and US$1.5 billion in 2007,
respectively (1).
Tautomycetin (
91
) was isolated from
Streptomyces griseochromogenes
(62)
and is 100-fold more potent than cyclosporine. It acts by blocking the induction
of tyrosine phosphorylation of T-cell-specific signaling mediators downstream
of Src tyrosine kinases, leading to apoptosis (63). This immunosuppressant has
been assayed in organ transplantation; however, it needs to be synergistically
combined to cyclosporine A to avoid rejection (64).
Recently, the immunosuppressants dalesconols A and B (
92
) were isolated
from the amantis-associated fungus
Daldinia eschscholtzii
(65).
3.10.4
Immunosuppressive Pyrrole Compounds
Prodiginines are characterized by a common tripyrrylmethene skeleton (a struc-
ture called prodigiosene). Some members of this family have been shown to
possess immunosuppressive effects resulting from the inhibition of phosphoryla-
tion and the activation of JAK-3, a cytoplasmic tyrosine kinase associated with a
cell surface receptor component called the common
γ
-chain. This component is
