Biomedical Engineering Reference
In-Depth Information
O
O
R
HO
O
HO
HO
H
N
N
O
O
S
N
N
N
N
HN
N
N
R
O
R
R
Cl
77
8 examples
Ki (
μ
M) = 1.3 - 14.0
78
4 examples
Ki (
μ
M) = 4.1 - 8.4
79
4 examples
Ki (
μ
M) = 1.2 - 6.8
FIGURE 17.15
Three hit clusters that show inhibition against BCL-2.
BCL-2. The finding of three novel, micromolar BCL-2 inhibitors directly from the
HTS campaign once again is remarkable considering the difficulty of identifying
inhibitors of protein-protein interactions.
The transcription factor HOXA13 has been shown to regulate both tissue and
tumor development. The HOX family of genes, which contain a DNA sequence
known as the
homeobox
, is regulated through interaction with HOX proteins, tran-
scription factors that can modulate specific target genes positively or negatively [66].
Two extreme examples of this regulation connected to a single gene, HOXA13, illus-
trate the role that these genes play in development. Mutations in HOXA13 have led
to protein misfolding, cytoplasmic aggregation, and degradation leading to irregular
limb growth, a symptom observed in the hand-foot-genital syndrome [67]. Alterna-
tively, overexpression of the HOXA13 protein can lead to uncontrolled tumor growth.
HOXA13 knockout mice showed drastically reduced tumor growth compared to that
of wild-type mice, making it an attractable target for treating cancer [68].
Ng et al. took advantage of two different pathways starting from the same imine
to give access to skeletally distinct scaffolds (Scheme 17.9) [69]. They had estab-
lished a stereoselective cycloaddition between imine
80
and an anhydride to yield
highly functionalized pyrrolidinones
83
. Chemistry established by Cushman et al.
[70] used similar imines with the appropriate anhydride to give access to dihy-
droisoquinolinones. Interestingly, complete stereocontrol is observed to give the syn-
product
81
, but when able, complete epimerization will take place, yielding the
anti-product
82
.
Ng et al. used these two synthetic pathways to access skeletal, appendage,
and stereochemical diversity. Library synthesis began with the generation of solid-
supported imine
84
, which then reacted with the appropriate anhydride to give two
different skeletons (Scheme 17.10). Appendage diversity was generated by coupling
the resulting acid with a variety of amines. An additional layer of skeletal diversity
was introduced with select building block combinations to give rise to fused tricyclic
(
86
) and spirocyclic (
89
) ring systems. After cleavage from solid support, greater
than 500 compounds were generated for screening in biological assays.
