Biomedical Engineering Reference
In-Depth Information
OH
1.
130
, CH(OCH
3
)
3
/CH
2
Cl
2
then NaBH
3
CN, AcOH
MeOH/THF, rt
O
2. Allyl chloroformate
DIPEA, CH
2
Cl
2
, rt
3. Piperidine, THF, rt
4. PhI(OAc)
2
(CF
3
)
2
CHOH/CH
2
Cl
2
, rt
Pd(PPh
3
)
4
morpholine/THF, rt
O
O
Br
H
2
N
Br
H OR
H
OR
O
CHO
N
O
O
130
131
132
O
Si
R =
i
-Pr
i
-Pr
R
4
1. R
1
OH, PPh
3
, DIAD, THF
0°C (twice)
2. R
2
SH, 2,6-lutidine
n
-BuLi, THF, 0-40°C
3. Electrophile, rt
4. R
4
NH
2
, AcOH
MeOH/CH
2
Cl
2
, rt
5. HF
·
Py, THF, rt
then TMSOMe
O
O
N
N
O
O
R
2
O
Br
Br
S
H OR
OH
S
Br
R
1
OMe
HO
NH
N
O
NH
OH
O
R
3
133
134
135
SCHEME 15.12
Scheme 15.12), appealed by the rigid nature and complexity of the scaffold rather than
its acetylcholinesterase inhibitory properties [58]. It was hypothesized that the
presence of orthogonal functionalities would offer an excellent opportunity to
introduce a variety of side appendages and prepare a large number of diverse
analogues readily available for high-throughput screenings. Aldehyde
130
was thus
coupled via reductive amination to the solid-supported tyrosine
131
, which after
132
protection and oxidative cyclization led to precursor
. Palladium-mediated allyl
deprotection and subsequent 1,4-addition led to polycyclic structures
analogous
to galanthamine. The scaffold was then functionalized by a Mitsunobu reaction
involving the free phenol moiety, a 1,4-addition of thiols onto the
a
,
b
-unsaturated
cyclohexenone, followed by the alkylation, acylation, or isocyanation of the cyclic
amine, and finally the introduction of hydrazines and hydroxylamines onto the
remaining cyclohexanone. Each of the 2527 compounds
133
134
was individually released
by HF
Py treatment and arrayed in 384-well plates. The small library was evaluated
using a cell-based phenotypic assay, where protein trafficking can be monitored by the
diffusion of a fluorescent VSVG-GFP protein. Secramine
was shown to prevent
the transport of proteins from the Golgi apparatus to the plasma membrane, whereas
the parent natural product galanthamine had no detectable effect. Another 5 years of
research led to the identification of RhoGTPase cdc43 as a central element responsible
for the phenotype induced by secramine [59]. Cellular trafficking are generally rapid
and dynamic processes, which make them rather difficult to study. The fast and
reversible perturbation induced by small molecules such as secramine provides a
means to study these processes with a valuable temporal resolution. Once again, this
example demonstrates the impact of diversity-oriented synthesis and unbiased high-
throughput screening on the discovery of small molecule probes.
135
15.6.3. Gemmacin
During a campaign dedicated to the discovery of novel antibiotics, Spring and
coworkers prepared a 242 small molecule-containing library based on 18 different
scaffolds, a subset of which is represented in Scheme 15.13 [60]. The solid-supported
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