Organic Letters,
Journal Year:
2023,
Volume and Issue:
25(46), P. 8326 - 8331
Published: Nov. 9, 2023
Triazoles
are
privileged
structural
motifs
that
embedded
in
a
number
of
molecules
with
interesting
biological
activities.
In
this
work,
we
developed
practical
and
general
synthetic
strategy
to
construct
medicinally
important
5-amino-1,2,3-triazole
moiety
on
DNA
by
coupling
DNA-conjugated
azides
monosubstituted
acetonitriles
via
azide-acetonitrile
"click"
reaction.
Under
mild
reaction
conditions,
displayed
broad
substrate
scope.
Most
substrates
gave
moderate-to-excellent
conversions.
Thus,
DNA-compatible
could
be
employed
DNA-encoded
library
(DEL)
construction
potentially
expand
the
chemical
space
libraries.
Journal of the American Chemical Society,
Journal Year:
2023,
Volume and Issue:
145(46), P. 25283 - 25292
Published: Oct. 19, 2023
DNA-encoded
chemical
library
(DEL)
has
been
extensively
used
for
lead
compound
discovery
decades
in
academia
and
industry.
Incorporating
an
electrophile
warhead
into
compounds
recently
permitted
the
of
covalent
ligands
that
selectively
react
with
a
particular
cysteine
residue.
However,
noncysteine
residues
remain
underexplored
as
modification
sites
DELs.
Herein,
we
report
design
utility
tyrosine-targeting
DELs
67
million
compounds.
Proteome-wide
reactivity
analysis
tyrosine-reactive
sulfonyl
fluoride
(SF)
probes
suggested
three
enzymes
(phosphoglycerate
mutase
1,
glutathione
s-transferase
dipeptidyl
peptidase
3)
models
tyrosine-targetable
proteins.
Enrichment
SF-functionalized
led
to
identification
series
inhibitors
model
enzymes.
In-depth
mechanistic
investigation
revealed
their
novel
modes
action
reactive
ligand-accessible
hotspots
Our
strategy
combining
activity-based
proteome
profiling
DEL
enrichment
(ABPP-CoDEL),
which
generated
selective
binders
against
variety
target
proteins,
illustrates
potential
use
this
methodology
further
drug
discovery.
ACS Pharmacology & Translational Science,
Journal Year:
2023,
Volume and Issue:
6(11), P. 1724 - 1733
Published: Oct. 12, 2023
DNA-encoded
libraries
(DEL)
have
emerged
as
an
important
drug
discovery
technical
platform
for
target-based
compound
library
selection.
The
success
rate
of
DEL
depends
on
both
the
chemical
diversity
combinatorial
and
accuracy
DNA
barcoding.
Therefore,
it
is
critical
that
chemistry
applied
to
construction
should
efficiently
transform
a
wide
range
substrates
while
preserving
integrity
tags.
Although
several
analytical
methods
been
developed
measure
damage
caused
by
reactions,
efficient
cost-effective
evaluation
criteria
detection
are
still
demanding.
Herein,
we
set
standards
evaluating
compatibility
development
at
laboratory
level.
Based
four
typical
models
three
different
formats,
evaluated
capabilities
methods,
including
ultraperformance
liquid
chromatography
(UPLC-MS),
electrophoresis,
quantitative
polymerase
chain
reaction
(qPCR),
Sanger
sequencing.
This
work
systematically
revealed
scope
capability
in
assessing
damages
transformation.
results,
recommended
UPLC-MS
qPCR
barcode
analysis
early-stage
DNA-compatible
chemistry.
Meanwhile,
identified
sequencing
was
unreliable
assess
this
application.
Organic Letters,
Journal Year:
2023,
Volume and Issue:
25(46), P. 8326 - 8331
Published: Nov. 9, 2023
Triazoles
are
privileged
structural
motifs
that
embedded
in
a
number
of
molecules
with
interesting
biological
activities.
In
this
work,
we
developed
practical
and
general
synthetic
strategy
to
construct
medicinally
important
5-amino-1,2,3-triazole
moiety
on
DNA
by
coupling
DNA-conjugated
azides
monosubstituted
acetonitriles
via
azide-acetonitrile
"click"
reaction.
Under
mild
reaction
conditions,
displayed
broad
substrate
scope.
Most
substrates
gave
moderate-to-excellent
conversions.
Thus,
DNA-compatible
could
be
employed
DNA-encoded
library
(DEL)
construction
potentially
expand
the
chemical
space
libraries.
