Biomedical Engineering Reference
In-Depth Information
Modiications allowed
O
R2
O
O
OH
10
R1
NH
O
7
9
2'
3'
13
Ph
1'
O
5
4
1
2
OH
O
H
HO
OBz
OAc
Essential groups
R1 = -C
6
H
5
, R2 = Ac; (Taxol)
R1 = O-tBu, R2 = H; (Taxotere)
(A)
Gly 370
Asp 26
Thr 276
His 229
(B)
FIGURE 23.5
(A) Chemical structures of the taxanes with associated SAR information; (B) crystal struc-
ture of taxol bound to β-tubulin. (Computer model courtesy of Dr. S. Vadlamudi, Topotarget, U.K.)
activity, even though some specii c alteration is found to be useful for improving the parent com-
pound. For example, can the C2¢-hydroxyl group be used as attachment point for a prodrug ester
that results in a compound with in vivo activity, but not in vitro potency. Limited modii cations of
C2¢ and C3¢ are allowed, and the stereochemistry at these positions is important for high activity,
with preference for the natural 2¢
R
,3¢
S
isomer. Based on the SAR for Taxol, many derivatives have
been prepared in particular with the aim of identifying new compounds with increased solubility,
since this is a major problem for taxol having a solubility <0.3
g/mL. Consequently, taxol needs to
be administered with a solubilizing carrier such as polyethoxylated castor oil. One example of an
approved analogue is docetaxel (Figure 23.5A), which shows potent anticancer activity and better
solubility properties.
μ
23.2.4 Z
OLINZA
HDAC inhibitors together with inhibitors of DNA methyl transferase are drugs interfering with
epigenetic gene regulation. In cells, DNA exists in the form of chromatin where the DNA double
strand helix is wrapped around core histone complexes, which is a protein octamer consisting of two
