Biomedical Engineering Reference
In-Depth Information
and subsequent quenching with nucleophiles, followed by carbene formation and
extrusion of nitrogen to give compounds with general structure
2
; and 1,3-dipolar
cycloaddition with a range of dipolarophiles. The products of these reactions were
then subjected to further complexity-generating reactions to complete the library
synthesis. These further transformations included the trapping of cyclohexatriene
3
(generated by electrocyclic ring opening of fused cyclopropane
4
) with primary
amines to give ecgonine-type scaffolds
5
; an unusual Grubbs II-mediated rearrange-
ment of cyclopropene
6
to give furan
7
; and Biginelli-type three-component reactions
to give dihydropyrimidines
8
and
9
.
The second library to use pluripotent functionality was published in 2008 by
Thomas et al. This library used an
E
-selective Horner-Wadsworth-Emmons reac-
tion to generate the solid-supported enone substrate (
10
) that they used as the pluripo-
tent functional group in their initial branching pathway [47]. This group was then
transformed using three catalytic enantioselective processes: a Sharpless asymmetric
dihydroxylation to give
11
,a[3
+
2] cycloaddition with an imino ester to give substi-
tuted pyrrolidine
12
, and a [4
2] cycloaddition with cyclopentadiene to give bridged
bicycle
13
(Scheme 1.2). These initial compounds (and variations of them) were even-
tually transformed into a library of 242 compounds based on 18 distinct molecular
skeletons, including a novel
cis-trans
-fused 7-5-7 tricycle (
14
) generated by ring
opening-ring closing metathesis of a decorated norbornene.
The compounds produced in these libraries were screened for their effects
against three strains of UK epidemic
Staphylococcus aureus
: methicillin-susceptible
S. aureus
(MSSA), and two strains of methicillin-resistant
S. aureus
(EMRSA-15
and EMRSA-16). Of the 223 compounds screened from the library of Wyatt et al.,
64 were found to modulate the growth of EMRSA-15 and EMRSA-16 at concentra-
tions between 10 and 100
+
M [48]. Of these active species, the vast majority were
based around four nitrogen heterocycle frameworks. Inspection of these compounds
led to the identification of a number of structural features generally associated with
higher levels of antibacterial activity, so an additional focused library of 35 com-
pounds was synthesized. The screening of these compounds against the same strains
of bacteria led to the discovery of a number of more potent compounds, the most
potent of which was named
emmacin
[48]. Mode-of-action studies suggested that
emmacin acts as a prokaryote-selective dihydrofolate reductase (DHFR) inhibitor.
The nitrogen heterocycle core of emmacin is reminiscent of that of other reported
DHFR inhibitors [49,50]; however, the exact heterocycle, a dihydropyrimidine, is
believed to represent a new structural subclass.
The library of Thomas et al. produced a lower hit rate; however, three compounds
that reproducibly inhibited the growth of the strains were discovered. The most
active compound,
gemmacin
, showed comparable activity against both strains of
MRSA to the widely used antibiotics erythromycin and oxacillin. In the original
DOS, gemmacin was made racemically, but the enantiomerically pure compounds
were subsequently synthesized and showed comparable activity, with (-)-gemmacin
being slightly more potent. Structure-activity relationship (SAR) studies were then
carried out on gemmacin, resulting in the discovery of the analog gemmacin B, which
