Future Medicinal Chemistry,
Год журнала:
2023,
Номер
15(22), С. 2065 - 2086
Опубликована: Ноя. 1, 2023
Background:
VEGFR-2
is
a
key
regulator
of
cancer
cell
proliferation,
migration
and
angiogenesis.
Aim:
Development
thieno[2,3-d]pyrimidine
derivatives
as
potential
anti-cancer
agents
targeting
VEGFR-2.
Methods:
Seven
in
vitro
nine
silico
studies
were
conducted.
Results:
Compound
10d
demonstrated
strong
anticancer
potential,
boosting
apoptosis
based
on
inhibition.
It
arrested
the
S
phase
cycle
upregulated
apoptotic
factors.
Docking
molecular
dynamics
simulation
confirm
stability
VEGFR-2–10d
complex
suggest
that
these
compounds
have
good
binding
affinities
to
In
addition,
drug-likeness
was
confirmed.
Conclusion:
Thieno[2,3-d]pyrimidines,
particularly
compound
10d,
has
effects
may
contribute
development
new
therapies.
Biomolecules,
Год журнала:
2024,
Номер
14(2), С. 218 - 218
Опубликована: Фев. 12, 2024
Considering
the
pivotal
role
of
angiogenesis
in
solid
tumor
progression,
we
developed
a
novel
series
quinazoline–thiazole
hybrids
(SA01–SA07)
as
antiproliferative
and
anti-angiogenic
agents.
Four
out
seven
compounds
displayed
superior
activity
(IC50
=1.83-4.24
µM)
on
HepG2
cells
compared
to
sorafenib
=
6.28
µM).
The
affinity
towards
VEGFR2
kinase
domain
was
assessed
through
silico
prediction
by
molecular
docking,
dynamics
studies,
MM-PBSA.
high
degree
similarity
regarding
binding
pose
within
active
site
VEGFR2,
with
different
orientation
4-substituted-thiazole
moieties
allosteric
pocket.
Molecular
MM-PBSA
evaluations
identified
SA05
hybrid
forming
most
stable
complex
sorafenib.
impact
vascular
cell
proliferation
EA.hy926
cells.
Six
(SA01–SA05,
SA07)
anti-proliferative
0.79–5.85
6.62
toxicity
evaluated
BJ
Further
studies
effect
promising
compounds,
SA04
SA05,
assessment
EA.hy296
motility
using
wound
healing
assay
ovo
potential
CAM
sorafenib,
led
confirmation
potential.
PLoS ONE,
Год журнала:
2025,
Номер
20(1), С. e0316146 - e0316146
Опубликована: Янв. 27, 2025
This
study
presents
T-1-NBAB
,
a
new
compound
derived
from
the
natural
xanthine
alkaloid
theobromine,
aimed
at
inhibiting
VEGFR-2,
crucial
protein
in
angiogenesis.
’s
potential
to
interacts
with
and
inhibit
VEGFR-2
was
indicated
using
silico
techniques
like
molecular
docking,
MD
simulations,
MM-GBSA,
PLIP,
essential
dynamics,
bi-dimensional
projection
experiments.
DFT
experiments
utilized
also
structural
electrostatic
properties
of
.
Computational
analysis
performed
predict
ADME-Tox
profiles
After
semisynthesis,
vitro
results
showed
that
effectively
inhibits
an
IC
50
0.115
μM,
compared
sorafenib’s
0.0591
μM.
In
tests
demonstrated
significant
activity
against
breast
cancer
cell
lines
MCF7
T47D,
values
16.88
μM
61.17
respectively,
high
selectivity.
Importantly,
induced
early
late
apoptosis
cells,
indicating
its
as
strong
anticancer
agent.
Additionally,
reduced
migration
healing
abilities
suggesting
it
could
be
promising
anti-angiogenic
Overall,
these
findings
suggest
is
lead
for
further
research
treatment
cancer.
Abstract
In
this
work
novel
2,4‐dioxothiazolidine‐derived
compounds
targeting
VEGFR‐2
were
designed
and
synthesized.
Such
evaluated
for
their
anti‐proliferative
inhibitory
abilities.
Compound
17
specifically
demonstrated
the
strongest
activity
against
HCT‐116
cell
line,
with
an
IC
50
value
of
10.09
μM.
Additionally,
15
,
18
19
revealed
good
effects
values
12.46,
16.87,
12.35
μM,
respectively.
potent
anti‐VEGFR‐2
efficacy,
0.068
which
was
comparable
to
sorafenib
(IC
0.058
μM).
induced
apoptosis
in
cancer
cells
caused
G0‐G1
phase
cycle
arrest.
Furthermore,
it
upregulated
BAX
levels
(5.1‐fold)
downregulated
Bcl‐2
(4.2‐fold),
indicating
its
pro‐apoptotic
effects.
also
increased
caspase‐8
caspase‐9
by
3.3‐fold
4.7‐fold,
respectively,
compared
control.
The
computational
studies
provided
insights
into
kinetic,
structural
properties,
binding
mode
VEGFR‐2‐
complex.
DFT
calculations
elucidated
compound
′s
electronic
while
ADMET
toxicity
tests
suggested
acceptable
degrees
drug‐likeness
potential
synthesized
compounds.
Our
findings
suggest
that
holds
promise
as
a
apoptotic
inhibitor
may
guide
future
efforts
developing
new
anticancer
drugs.
RSC Advances,
Год журнала:
2023,
Номер
13(51), С. 35853 - 35876
Опубликована: Янв. 1, 2023
This
work
presents
the
synthesis
and
in
vitro,
silico
analyses
of
new
thiadiazole
derivatives
that
are
designed
to
mimic
pharmacophoric
characteristics
vascular
endothelial
growth
factor
receptor-2
(VEGFR-2)
inhibitors.
A
comprehensive
evaluation
inhibitory
properties
synthesized
against
cancer
cell
lines
MCF-7
HepG2
identified
several
auspicious
candidates.
Among
them,
compound
14
showed
remarkably
low
IC50
values
0.04
μM
0.18
HepG2,
respectively.
VEGFR-2
revealed
a
promising
value
nanomolar
range
(103
nM).
Further
examination
cycle
has
ability
stop
progression
cells
via
G0-G1
phase
arrest.
Interestingly,
also
demonstrated
noteworthy
pro-apoptotic
effect
cells,
with
notable
increases
early
apoptosis
(16.53%)
late
(29.57%),
along
slight
increase
population
necrotic
(5.95%).
Furthermore,
significant
drop
cells'
migrate
heal
wounds.
Additionally,
promoted
by
boosting
BAX
(6-fold)
while
lowering
Bcl-2
(6.2-fold).
The
binding
affinities
candidates
their
target
were
confirmed
computational
investigations,
including
molecular
docking,
principal
component
analysis
trajectories
(PCAT),
dynamics
(MD)
simulations.
14's
stability
reactivity
investigated
using
density
functional
theory
(DFT).
These
thorough
results
highlight
potential
as
lead
contender
for
additional
research
creation
anticancer
drugs
VEGFR-2.
establishes
foundation
future
therapeutic
developments
anticancer-
angiogenesis-related
scientific
fields.
Journal of Chemistry,
Год журнала:
2024,
Номер
2024, С. 1 - 25
Опубликована: Март 1, 2024
A
new
nicotinamide
derivative,
(E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazone)ethyl)phenyl)nicotinamide,
was
designed
as
a
VEGFR-2
inhibitor.
Utilizing
the
density
functional
theory
(DFT)
calculations,
three-dimensional
structure
of
compound
determined,
shedding
light
on
its
stability
and
reactivity.
Molecular
docking
revealed
capability
to
inhibit
VEGFR-2,
which
further
supported
by
molecular
dynamics
(MD)
simulations
confirming
binding
target
protein.
In
addition,
mechanics-generalized
born
surface
area
(MM-GBSA),
protein-ligand
interactions
profiler
(PLIP),
essential
studies
provided
validation
compound’s
precise
with
optimal
energy.
Then,
“compound
10”
synthesized
subjected
in
vitro
assays.
Compound
10
inhibited
an
IC50
value
105.4
±
0.896
nM,
comparing
sorafenib’s
61.65
0.934
nM.
Besides,
it
exhibited
cytotoxicity
against
HepG2
MCF-7
cancer
cell
lines,
values
35.78
0.863
μM
57.62
0.871,
5.95
0.917
8.45
0.912
μM.
Furthermore,
demonstrated
lower
level
toxicity
towards
Vero
127.3
Likewise,
induced
apoptosis
lines
through
flow
cytometric
analysis
addition
increase
levels
caspase-3
caspase-9.
Moreover,
hindered
migration
healing
abilities
cells.
conclusion,
our
study
positions
promising
candidate
for
chemical
modifications
biological
evaluations.
Medicinal Chemistry,
Год журнала:
2024,
Номер
20(9), С. 876 - 899
Опубликована: Май 27, 2024
Vascular
endothelial
growth
factor
receptor-2
(VEGFR-2)
is
a
critical
protein
involved
in
tumor
progression,
making
it
an
attractive
target
for
cancer
therapy.
