Chemistry Reference
In-Depth Information
Fig. 8.11
Stability of silanols toward self condensation is structure dependent
Fig. 8.12
Silanediol protease inhibitors
Three silanediol protease inhibitors are shown in Fig.
8.12
, in order of increasing
complexity: the C
2
symmetric
44
has identical organic substituents on the silandiol,
silanediol
46
has two different organic structures on the silicon and
48
has very
different structures on each side of the silanediol group, each with stereochemistry.
The symmetry of
44
matches the (unusual!)
C
2
symmetric HIV protease, and was
modeled after the corresponding carbinol
45
reported by Merck [
47
]. Testing of
44
,
45
and the commercial HIV protease inhibitor indinavir (not shown) found them to in-
hibit the enzyme to a similar degree, with
K
i
values of 2.7 nM, 0.38 nM and 0.37 nM,
respectively [
48
]. In addition, IC
90
values for protection of whole cells against HIV
infection gave parallel values, indicating that they all penetrated cell membranes to
the same degree, thereby demonstrating the drug-like properties of silanediol
44
.
Phosphinic acid
47
was the starting point for design of silanediol
46
, two struc-
tures that inhibit the metalloprotease thermolysin [
49
]. Compounds
46
and
47
have
thermolysin inhibition
K
i
values of 41 nM and 10 nM, respectively. The Cbz group
on the amine of
47
was replaced by a dihydrocinnamoyl group in
46
after the dis-
covery that a Cbz group did not withstand the strongly acidic conditions used to
deprotect the silanediol precursor (see below) [
50
]. A crystal structure of
46
bound
to the active site of thermolysin was determined by Juers and Matthews and showed
the anticipated interaction of the silanediol with the active site zinc ion [
51
].
