Biomedical Engineering Reference
In-Depth Information
Sirolimus
OH
OCH
2
CH
2
OH
Everolimus
OCH
2
CH
2
OR
Biolimus
N
N
Zotarolimus
N
N
FIGURE 6.28
Structures of R groups of sirolimus analogues.
Calcinuerin inhibitors have two members, tacrolimus and pimecrolimus. This family has a
macrolide comprising 27 elements. The two differ in the pendent R group at the 4-cyclohexyl-1
attached to macrocyclic position 3 and the structure at position 8 (Figure 6.29) (Billich et al.,
2004). The R group of pimecrolimus is chloride with an ethyl at position 8 whereas tacrolimus
has a derivative of hydroxyl group for an R group, with a propenyl at position 8. In contrast to
sirolimus analogues, the macrolide has no lactone structure but a hydroxyl group at the mac-
rocyclic point 5. The macrolide does not possess the 6-carbon mTOR binding site but has the
characteristic Limus FKBP-binding site at macrocyclic positions 16-22.
Pimecrolimus does not block mTOR and inhibits to a much lesser degree the endothelial
cell proliferation (Zollinger et al., 2006). Tacrolimus is water-insoluble and isolated from
Streptomyces tsukubaensis
. It is also sold as Prograf, a drug widely used to prevent allograft
rejection after organ transplantation. Tacrolimus is a noncytotoxic T-cell inhibitor, which
holds cells at G
0
in the cell cycle. It inhibits smooth muscle cell proliferation more potently
and has less effect on endothelial cells compared to sirolimus (Hofma et al., 2006; Steffel
et al., 2005).
Paclitaxel is a diterpenoid with a taxane skeleton (Figure 6.30). It is highly lipophilic
with a molecular weight of 853.9 Da (Duda et al., 2003). The drug promotes the stabiliza-
tion of microtubules, which inhibits the action of cell division during all phases, but has
the most significant effect at the M phase (Figure 6.31), disrupting SMC migration and
(a)
HO
(b)
Cl
O
O
O
O
3
5
3
8
8
OH
OH
O
O
O
O
N
22
N
O
O
O
O
O
O
HO
HO
O
O
16
O
O
FIGURE 6.29
Structure of macrolide in calcinuerin inhibitors: (a) tacrolimus and (b) pimecrolimus.
