Chemistry Reference
In-Depth Information
Fig. 8.13
Sterically unhindered, water soluble
54
, was an ineffective inhibitor of arginase
The most complex of the silanediols, in terms of the core silanediol amino
acid component, is
48
, an inhibitor of the enzyme angiotensin-converting enzyme
(ACE). Inhibitor
48
was modeled after ketone inhibitor
49
, with
K
i
values of 3.8 nM
and 1.0 nM, respectively [
52
]. Four diastereomers of both
48
and
49
were prepared,
changing the stereogenic centers flanking the silane and the ketone, and their poten-
cies as ACE inhibitors were evaluated [
53
].
These three silanes, all successful as protease inhibitors, suggest that incorpora-
tion of the silanediol group can be a useful drug design strategy.
The least sterically hindered silanediol amino acid is
54
, which was proposed
as an inhibitor of arginase, Fig.
8.13
. This enzyme catalyzes the hydration and hy-
drolysis of the guanidine unit of arginine
50
, producing urea
52
and ornithine
53
.
Arginase is a pharmaceutical target because of its role in regulating NO production
[
54
,
55
]. Silanediol
54
was, however, not effective as a mimic of hydrated guani-
dine
51
and did not inhibit the enzyme. Nevertheless, silane
54
is of interest for its
relationship to silanol
31
(Fig.
8.8
) and as a tool for understanding the role of water
solubility in modulating siloxane formation [
56
].
8.4.2
Silanediol Synthesis
To assemble the silanediols
5
, a protecting group was needed, Fig.
8.14
. The abil-
ity of unsaturated groups on silicon to undergo “protodesilylation” under acidic
conditions, fundamentally a hydrolysis reaction, seemed a reasonable approach and
phenyl was selected as a suitably robust group to carry through synthetic sequences
[
57
,
58
]. Strongly acidic conditions (e.g., triflic acid in trifluoroacetic acid) has
been widely used for deprotection of synthetic peptides [
59
]. Protodesilylation is
