Journal of Synthetic Organic Chemistry Japan,
Journal Year:
2024,
Volume and Issue:
82(1), P. 50 - 62
Published: Jan. 1, 2024
Covalent
drugs
render
potent
and
durable
activity
by
chemical
modification
of
the
endogenous
target
protein
under
live
cell
conditions.
To
maximize
pharmacological
efficay
while
alleviating
risk
toxicity
arising
from
non-specific
off-target
reactions,
current
covalent
drug
discovery
focuses
on
development
targeted
inhibitors
(TCIs).
In
design
TCIs,
an
electrophilic
reactive
group
(warhead)
is
strategically
incorporated
onto
a
reversible
ligand
to
facillitate
specific
engagement.
Various
aspects
warheads,
such
as
intrinsic
reactivity,
chemoselectivity,
reaction
mechanism,
reversibility
engagement,
would
affect
selectivity
TCIs.
While
targeting
cysteines
acrylamide-type
Michael
acceptors
have
been
most
successful
strategy
in
discovery,
wide
array
novel
warheads
devised
tested
for
designing
TCIs
recent
years.
This
review
provides
overview
chemistry
selective
proteins
conditions
its
applications
TCI
designs.
Coupling
of
photoswitching
with
dynamic
covalent
chemistry
enables
the
control
formation
and
cleavage
bonds
by
light
irradiation.
Peri-aryloxyanthraquinones
feature
an
exclusive
ability
to
switch
electrophilicity
interconversion
between
para-
ana-quinone
isomers,
which
was
used
for
first
time
implementation
a
C-O
bond.
Photogenerated
ana-isomers
undergo
concerted
oxa-Michael
addition
phenols
give
hitherto
unknown
4-hydroxy-10,10-diaryloxyanthracen-9-ones.
These
species
were
found
be
in
equilibrium
corresponding
ana-quinones,
thus
forming
system
new
type.
Withdrawal
colored
ana-quinones
from
equilibria
visible-light
irradiation
resulted
two
para-quinones
“locked”
aryloxy
groups.
Journal of Synthetic Organic Chemistry Japan,
Journal Year:
2024,
Volume and Issue:
82(1), P. 50 - 62
Published: Jan. 1, 2024
Covalent
drugs
render
potent
and
durable
activity
by
chemical
modification
of
the
endogenous
target
protein
under
live
cell
conditions.
To
maximize
pharmacological
efficay
while
alleviating
risk
toxicity
arising
from
non-specific
off-target
reactions,
current
covalent
drug
discovery
focuses
on
development
targeted
inhibitors
(TCIs).
In
design
TCIs,
an
electrophilic
reactive
group
(warhead)
is
strategically
incorporated
onto
a
reversible
ligand
to
facillitate
specific
engagement.
Various
aspects
warheads,
such
as
intrinsic
reactivity,
chemoselectivity,
reaction
mechanism,
reversibility
engagement,
would
affect
selectivity
TCIs.
While
targeting
cysteines
acrylamide-type
Michael
acceptors
have
been
most
successful
strategy
in
discovery,
wide
array
novel
warheads
devised
tested
for
designing
TCIs
recent
years.
This
review
provides
overview
chemistry
selective
proteins
conditions
its
applications
TCI
designs.
