| dc.description | The
discovery
of
new
bioactive
compounds
in
nature
is
an
active
area
of
research.
Marine-‐derived
biologically
active
natural
products
continue
to
be
a
source
of
potential
therapeutic
compounds
as
well
as
a
motivation
to
develop
new
synthetic
strategies
to
construct
them.
We
report
the
identification
and
characterization
of
a
group
of
more
than
40
phospholipids
and
free
fatty
acids
from
the
Caribbean
sponge
Asteropus
niger
using
mass
spectrometry,
circular
dichroism
(CD),
magnetic
resonance
studies,
and
chain
length
correlations
to
determine
the
structures.
Some
of
these
fatty
acids
were
unprecedented
in
nature,
such
as
the
(2R,5Z,9Z,13Z)-‐2-‐methoxyoctadeca-‐5,9,13-‐trienoic
acid,
(2R,5Z,9Z)-‐2-‐
methoxy-‐25-‐methylhexacosa-‐5,9-‐dienoic
acid,
(2R,5Z,9Z)-‐2-‐methoxy-‐24-‐methylhexacosa-‐5,9-‐
dienoic
acid,
(2R,5Z,9Z)-‐2-‐methoxyoctacosa-‐5,9-‐dienoic
acid,
(2R,5Z,9Z)-‐2-‐methoxy-‐26-‐
methylheptacosa-‐5,9-‐dienoic
acid,
and
the
(2R,5Z,9Z)-‐2-‐methoxy-‐27-‐methyloctacosa-‐5,9-‐dienoic
acid.
An
improved
synthetic
methodology
for
the
preparation
of
the
2-‐methoxylated
unsaturated
fatty
acids
was
used
to
prepare
two
2-‐methoxylated
Δ5,9-‐diunsatruated
fatty
acids,
namely
the
(5Z,9Z)-‐(±)-‐2-‐methoxy-‐5,9-‐eicosadienoic
acid
and
the
(±)-‐2-‐methoxy-‐5,9-‐
eicosadiynoic
acid,
in
seven
and
eight
steps
with
overall
yields
of
6%
and
11%,
respectively.
Five
2-‐methoxylated
monounsaturated
fatty
acids
were
prepared,
including
the
(5Z)-‐(±)-‐2-‐methoxy-‐
5-‐eicosenoic
acid,
(±)-‐2-‐methoxy-‐5-‐eicosynoic
acid,
(±)-‐2-‐methoxy-‐9-‐eicosynoic
acid,
(6Z)-‐(±)-‐2-‐
methoxy-‐6-‐octadecenoic
acid,
and
the
(±)-‐2-‐methoxy-‐6-‐octadecynoic
acid
in
seven
to
eight
steps
with
overall
yields
between
6-‐20%.
With
the
synthesis
of
the
(5Z,9Z)-‐(±)-‐2-‐methoxy-‐5,9-‐
eicosadienoic
acid
we
were
able
to
corroborate
the
structure
of
the
natural
compound
by
gas chromatographic
co-‐injection
of
the
methyl
ester
with
the
whole
fatty
acid
methyl
ester
(FAME)
mixture
from
the
sponge
A.
niger.
The
inhibition
of
the
relaxation
of
Topoisomerase
IB
(TopIB)
by
a
mixture
of
2-‐
methoxylated
fatty
acids
mainly
composed
of
the
(2R,5Z,9Z)-‐2-‐methoxy-‐25-‐methylhexacosa-‐5,9-‐
dienoic
acid
and
(2R,5Z,9Z)-‐2-‐methoxy-‐24-‐methylhexacosa-‐5,9-‐dienoic
acid,
isolated
from
A.
niger,
was
studied
displaying
inhibitory
concentrations
at
an
EC50
of
~4.3
μM
for
the
human
TopIB
and
an
EC50
of
~11.7
μM
for
the
Leishmania
TopIB
(LdTopIB).
These
results
are
compared
to
short-‐chain
fatty
acids,
such
as
the
(±)-‐2-‐methoxy-‐5,9-‐eicosadienoic
acid,
and
the
(±)-‐2-‐
methoxy-‐6-‐octadecenoic
acid,
that
only
inhibited
the
LdTopIB
at
concentrations
of
22-‐31
μM
and
89-‐90
μM,
respectively,
while
neither
of
the
latter
acids
significantly
inhibited
hTopIB
(EC50
>
100
μM).
These
short-‐chain
acids
were
toxic
against
L.
infantum
promastigotes
(EC50
=
237-‐250
μM),
as
compared
to
the
very
long-‐chain
2-‐methoxylated
unsaturated
fatty
acids
(EC50
~
776
μM).
The
antibacterial
activity
of
the
2-‐methoxylated
unsaturated
fatty
acids
against
multi-‐
drug
resistant
bacteria
was
studied
and
the
(±)-‐2-‐methoxy-‐6-‐octadecynoic
acid
inhibited
the
methicillin-‐resistant
S.
aureus
(MRSA)
with
an
IC50
of
17
μg/ml.
The
long-‐chain
C20
2-‐
methoxylated
fatty
acids
did
not
inhibit
the
studied
bacterial
strains.
Our
results
indicated
that
the
formation
of
micelles
was
responsible
for
their
antibacterial
activity.
It
was
found
that
2-‐
methoxylation
reduces
the
concentration
where
micelles
are
formed
as
compared
to
the
corresponding
non-‐methoxylated
fatty
acids. | |
