Syn hesis,
S uc u e,
P ope ies
And
Biological
Beha iou
O
The
Complex
[Ru
i
(HL)
CI]
2HO
(H4L-
1,2-Cyclohexanediammine e aace ic
Acid)
Rosa io
A.
Vilaplana,"
A.
Cas i lei as
b
and
F ancisco
Gonzb.lez-Vilchez
aDepa amen o
de
Quimica
Ino gdnica,
Secci6n
de
Quimica
Bioino gdnica,
Facul ad
de
Quimica,
Ap do.
Co eos
553,
E-41071
Se illa,
Spain.
hDepa amen o
de
Quhnica
Ino gdnica,
Facul ad
de
Fa macia,
Uni e sidad
de
San iago
de
Compos ela,
E-
15
782
San iago
de
Compos ela,
Spain
GRAPHICAL
ABSTRACT
The
oc ahed al
complex
[Ru(Hzcd a)CI2]’2H20
con ains
Ru(IV)
su ounded
by
wo
ni ogen
a oms,
N(I)
and
N(2),
and
wo
chlo ide
ions
c/s
o
each
o he ,
all
in
he
equa o ial
plane.
Two
oxygen
a oms,
O(11)
and
O(21)
a e
loca ed
in
ans
axial
oc ahed al
posi ions.
The
complex
shows
ema kable
in
i o
and
in
i o
ac i i y
agains
di e en
ca cinomas.
Cll
OI
1
o
whom
co espondence
should
be
add essed;
phone:
+34
95
4557159;
ax:
+34
95
4557081;
e-mail:
[email p o ec ed]
275
Vol.
2,
Nos.
3-4,
2004
Syn hesis,
S uc u e,
P ope ies
and
Biological
Beha iou
O
he
Complex
ABSTRACT
The
highly
wa e -soluble
u henium
complex
[Ru(H2L)CI2]’2H20,
in
which
H4L
is
he
seques e ing
ligand
ans-l,2-cyclohexanediammine e aace ic
acid
(cd a)
has
been
syn hesized,
s uc u ally
cha ac e ized
and
i s
p ope ies
s udied.
The
X- ay
c ys allog aphic
s udy
shows
ha
he
chela ing
coo dina ed
ligand
is
e aden a e
while
he
u henium
en i onmen
is
oc ahed al
and
sligh ly
dis o ed,
wi h
wo
chlo ide
anions
coo dina ed
in
cis
posi ions.
Po en iome ic,
conduc ime ic
and
in a ed
s udies
con i m
he
p esence
o
wo
ee
ca boxylic
g oups,
while
elec onic
and
ol amme ic
s udies
show
ha
he
cen al
ion
is
Ru(IV).
The
es ing
o
he
cy o oxic
ac i i y
o
his
complex
agains
h ee
di e en
human
cance
cell
lines
indica es
ha
[Ru(H2L)CIz].2HzO
shows
a
ema kable
and
selec i e
an ip oli e a i e
e ec
agains
he
human
u e ine
neck
ca cinoma
HeLa
and
he
malign
adenoca cinoma
ADLD,
showing
only
a
disc e e
u nou
cell
inhibi ion
ac i i y
agains
colon
adenoca cinoma
HT-29.
The
impo an
an ip o i e a i e
beha iou
o
complex
agains
he
human
adenoca cinoma
ADLD,
indica es
ha
[Ru(HL)CI].2HzO
migh
be
conside ed
as
po en ial
an ineoplas ic
compound.
INTRODUCTION
Me al-based
an i umou
d ugs
cons i u e
in
ou
days
a
b oad
esea ch
a ea
o
inc easing
in e es /1-4/.
Conc e ely,
cispla in,
cis-
[P (N
H3)2C12],
ca bopla in
[cis-diammine-
I,
-cyclobu anedica boxyla o-
pla inum(II)]
and
oxalipla in
[ ans-(R,R)-l,2-diamminecyclohexaneoxala opla inum
(II)],
a e
cu en ly
being
used
clinically
/5-10/.
Howe e ,
he
p oblem
o
bo h
acqui ed
and
inhe en
esis ance
o
umou
cells
p esen s
a
main
limi a ion
o
he
mo e
widesp ead
clinical
use
o
pla inum
complexes/3,7,9/.
In
he
hope
o
o e coming
hese
limi a ions,
o he
pla inum-based
an i umou
d ugs
ha e
been
syn hesized
and
es ed
o
an i umou
ac i i y/11-15/.
Fu he mo e,
new
an icance
d ugs
con aining
ansi ion
me al
ions
o he
han
pla inum
/16/ha e
been
also
assayed.
Possible
ad an ages
may
in ol e
di e en
coo dina ion
geome ies,
se e al
me al-ion
oxida ion
s a es
and
biological
a ge s
o he
han
DNA.
In
he
design
o
hese
new
d ugs,
u henium
complexes
ha e
aised
g ea
in e es /17-24/.
As
an
example,
he
an i umou
ac i i y
o
he
highly
wa e
soluble
complex
H[Ru(H2L)CI]-4H20
(H4L:
1,2-
p opylenediammine-N,N,N’,N’- e aace ic
acid,
pd a)
has
been
e alua ed
in
i o
and
in
i o/23,25/.
This
complex
apidly
binds
o
se um
p o eins
p oducing
s able
adduc s
in
which
he
co e
Ru(lII)(pd a)
is
p obably
bound
o
his idines
on
he
p o ein
su ace/26-28/.
On
he
o he
hand,
he
complex
damages
nuclea
DNA,
inhibi s
DNA
ecogni ion
and
s imula es
NADPH
oxidase
and
a
espi a o y
bu s
in
phagocy ic
neu ophils
and
elici s
phospho yla ion
o
y osine
esidues/25,29/.
Ano he
in e es ing
ligand
is
he
po en ial
hexaden a e
seques e ing
agen
ans-l,2-
cyclohexanediammine e aace ic
acid
(cd a),
in
which
he
e hylenediammine
g oup
o
ed a
has
been
eplaced
by
he
he e ocyclic
moie y
ans-l,2-cyclohexanediammine.
The
ligand
cd a
is
widely
used
nowadays
in
a ied
applica ions,
i.e.,
as
de oxi ie
o
hea y
me als
ha
con amina e
pa ien s/30/,
o
use
in
endodon ics
/31/,
o
ex ac ion
o
pec in
polyme s
/32/
and
o
sepa a ion
and
quan i a ion
by
se e al
echniques
o
276
Rosa io
A.
Vilaplana
e
al.
Bio&o ganic
Chem& y
and
Applica ions
ino ganic
ions
and
anionic
me al
complexes/33/.
Al hough
he
me al
complexes
o med
by
cd a
a e
known
om
ime
ago/34/,
ecen
li e a u e
has
shown
new
syn hesis
p ocedu es
and
impo an
p ope ies
o
new
isola ed
complexes.
Conc e ely,
hose
o med
by
cd a
wi h
Cu(ll)
and
Ni(ll)
ha e
been
s udied
by
X- ay
pho oelec on
spec oscopy
and
X- ay
c ys al
di ac ion
s udies
/35,36/
and
in e es ing
esul s
on
he
s uc u e,
elec ochemis y,
kine ics,
pKa
alues
and
in luence
o
chela e
e ec s
on
he
wa e -exchange
mechanisms
o
complexes
cd a/Fe(lll)/Fe(ll)/
ha e
been
epo ed
/37,38/.
Resea ch
on
he
o ma ion
cons an s
and
dissocia ion
kine ic
o
cd a/lan hanide(lll)/
complexes
/39,40/
as
well
as
solu ion
s udies
and
de e mina ion
o
he
c ys al
s uc u es
o
cd a
complexes
o med
wi h
he
i alen
ions
o
AI,
Ga,
In
and
Sc
/41/ha e
been
also
published.
The
esea ch
de eloped
so
a
on
pla inum-g oup
me al
complexes
o med
wi h
cd a
conce ns
i s
he
he
X- ay
c ys allog aphic
s udy
o
he
dip o ona ed
ligand
and
i s
complexes
wi h
[PdCI4]
2-
and
[P CI4]
2
sal s
/42a/.
Addi ionally,
he
eac ion
kine ic
p ocesses
in ol ed
in
he
o
ma ion
o
Pd(ll)
and
P (ll)
complexes
o
di e en
composi ion
wi h
amminepolyca boxyla e
ligands
(i.e.,
{(H6L)[Pd/P CI4]}
o
[Pd(H2L)])
we e
also
s udied/42b/.
Dini ogen
complexes
o med
be ween
Ru(ll)
and
cd a
we e
isola ed
and
cha ac e ized/42c/.
On
he
o he
hand,
p omising
esul s
we e
ob ained
in
he
i s
s udy
de eloped
on
he
an i umou
ac i i y
o
new
Pd(ll)(cd a)
complexes/42d/.
Di e en
Ru(lll)
complexes
such
as
[Ru(H4L)CI]
3-n
and
[Ru(HL)Ci]3"-I),
we e
syn hesized
and
cha ac e ized
by
analy ical
and
elec ochemical
echniques/43/.
Finally,
educ ion
o
molecula
ni ogen
o
ammonia
in
aqueous
solu ion
unde
ambien
condi ions
occu s
in
he
p esence
o
an
illumina ed
RuO2/P /CdS
sys em;
his
eac ion
is
ca alysed
by
se e al
Ru(ll)
complexes
as,
o
example,
[Ru(cd a)N]
2-/44/.
As
a
esul
o
he
a ac i e
esea ch
in
p og ess
on
biological
p ope ies
o
complexes
o med
by
Ru(lll)
wi h
amminepolyca boxylic
ligands,
as
well
as
he
absence
o
s uc u al
and
an i umou
ac i i y
o
Ru(cd a)
complexes,
we
p esen
in
his
pape
he
syn hesis,
cha ac e iza ion
by
chemical
and
spec oscopic
echniques,
x- ay
c ys al
s uc u e
and
biological
beha iou
o
he
wa e -soluble
complex
[Ru(HzL)CI].2H:O
(I),
in
which
he
ligand
cd a
(H4L)
is
ac ing
as
e aden a e
molecule/45/.
Ou
esul s
demons a e
ha
he
complex
con ains
Ru(IV)
and
shows
ac i i y
agains
se e al
in
i o
and
in
i o
umou s.
This
esea ch
open
a
new
way
o
he
medical
and
pha maceu ical
de elopmen
o
po en ial
an ineoplas ic
complexes
o med
by
he
chela ing
agen
cd a
wi h
pla inum
me als.
EXPERIMENTAL
X- ay
c ys allog aphy
A
p isma ic
yellow-ambe
c ys al
o
compound
was
moun ed
(glass
ibe )
on
an
En a
Nonius
CAD4
au oma ic
di ac ome e
/46/
and
2388
unique
e lec ions
we e
measu ed.
Cell
cons an s
and
o ien a ion
ma ix
o
da a
collec ion
we e
ob ained
by
leas -squa es
e inemen
o
he
20
alues
o
25
e lec ions.
In ensi ies
o
3123
e lec ions
wi hin
he
ange
2
<20
<50
we e
measu ed
and
collec ed
a
293
K
using
monoch oma ic
MoK,
adia ion
(2
0.71073
A)
and
he
a/20
scan
echnique.
In ensi ies
we e
co ec ed
o
Lo en z
and
pola iza ion
e ec s/47/and
2388
{(1>2o->(I)}
we e
conside ed
as
obse ed.
A
semiempi ical
277
Vol.
2,
Nos.
3-4,
2004
Syn hesis,
S uc u e,
P ope ies
and
Biological
Beha iou
O
he
Complex
abso p ion
co ec ion
(q-scans)
was
made/48/.
The
s uc u e
was
sol ed
by
he
Pa e son
me hod/49/
and
subsequen
di e ence
Fou ie
maps,
and
e ined
on
F
by
a
ull
ma ix
leas -squa es
p ocedu e
using
aniso opic
displacemen
pa ame e s/50/.
All
hyd ogen
a oms
we e
loca ed
in
di e ence
map
and
included
as
ixed
con ibu ions
iding
on
a ached
a oms
wi h
iso opic
he mal
pa ame e s
1.2
imes
hose
o
hei
ca ie .a oms.
The
H
a oms
o
wo
wa e
molecules,
O(1)
and
O(2),
we e
no
loca ed.
The e o e,
he
con ibu ion
o
he
densi y
o
a
diso de ed
wa e
molecule
was
sub ac ed
om
he
measu ed
s uc u e
ac o s
wi h
use
o
he
SQUEEZE
op ion
/51/.
Subsequen
e inemen
hen
con e ged
wi h
R
ac o s
and
pa ame e
e o s
signi ican ly
be e
han
o
all
a emp s
o
model
he
sol en
diso de .
The
Flack
x
pa ame e
(absolu e
s uc u e
pa ame e )
was
calcula ed
o
be
0.05(6)
o
he
p esen
s uc u e
and
0.95(6)
o
he
in e ed
s uc u e,
hus
p o iding
s ong
e idence
ha
he
absolu e
s uc u e
has
been
assigned
co ec ly/52/.
C i e ia
o
a
sa is ac o y
comple e
analysis
we e
he
a ios
o
ms
shi
o
s anda d
de ia ion
less
han
0.001
and
no
signi ican
ea u es
in
inal
di e ence
maps.
A omic
sca e ing
ac o s,
om
"In e na ional
Tables
o
C ys allog aphy"/53/.
Molecula
g aphics,
om
PLATON
/51/and
SCHAKAL/54/.
Chemicals
Hyd a ed
u henium
(III)
chlo ide
(Sigma)
was
dissol ed
in
e hanol
and
e luxed
o
30
min.
A e
concen a ion
o
d yness,
he
compound
was
s o ed
unde
CaCI_
(RuCI3).
The
ligand
cd a
was
used
as
pu chased
(Sigma).
All
o he
chemicals
and
sol en s
we e
analy ical
g ade
eagen
p oduc s.
Analy ical,
po en iome ic
and
conduc ime ic
s udies
Elemen al
mic oanalyses
we e
pe o med
a
he
Mic oanaly ical
Labo a o y
o
he
Ba celona
Uni e si y.
Me al
con en
was
de e mined
by
a omic
abso p ion
spec oscopy
using
a
Pe kin
Elme
2380
model,
a
10
mA
and
349.9
im.
Hyd a ion
wa e
molecules
we e
de e mined
by
he mal
analysis.
Po en iome ic
and
conduc ime ic
s udies
we e
ca ied
ou
wi h
a
C ison
Mic oTT
2022
i ime e ,
p o ided
wi h
au obu e e
Mic obu
2030.
Aqueous
solu ions
o
he
complex
(50-100
mg/100
ml)
we e
i a ed
agains
a
30
mM
NaOH
solu ion.
Elec ical
conduc ime y
o
he
same
solu ion
was
pe o med
on
a
C ison
525
conduc ime e .
Elec onic
and
in a ed
spec oscopy
The
elec onic
spec a
o
solu ions
we e
eco ded
on
a
Jasco
V550
spec ome e
in e aced
wi h
a
PC.
IR
spec a
we e
eco ded
on
an
FT-IR
Jasco
300E
ins umen
in
he
200-4000
cm
-
ange,
using
ei he
Nujol
mulls
suppo ed
be ween
polye hylene
pla es
o
KB
pelle s.
Vol ammme ic
s udies
Cyclic
oi amme y
measu emen s
we e
ca ied
ou
using
a
P ince on
Applied
Resea ch
analyse .
A
278
Rosa io
A.
l,71al)lana
e
aL
Bioinol2,anic
Chem& y
and
Applica ions
glassy
ca bon
elec ode
was
used
as
wo king
elec ode
on
aqueous
solu ions
(NaCIO4
0.15
M)
o
complex
a
concen a ions
anging
be ween
1.0
and
6.0
mM.
Po en ials
we e
measu ed
agains
a
sa u a ed
(NaC1)
calomel
elec ode
(SCE)
as
e e ence
elec ode.
Vol ammog ams
(CV)
we e
ob ained
a
po en ial
alues
be ween
+1.5
and
-1.5
V.
Scan
a e
was
equal
o
50
m
V/s.
Biological
in
i o
and
in
i o
assays
Complex
was
dissol ed
in
a
mixed
1:1
DMSO:H20
solu ion
and
used
as
concen a ed
s ock
solu ion
om
which
dilu ed
solu ions
(I/10
dil / ion
ac o )
we e
p epa ed
and
added
o
g owing
cul u e
medium
o
each
one
o
he
cellula
ypes
included
in
he
s udy.
The
in
i o
assays
we e
done
agains
h ee
di e en
human
cance
cell
cul u es:
malignan
melanoma
(ADLD),
u e ine
neck
ca cinoma
(HeLa)
and
colon
adenoca cinoma
(HT-29).
Fo
de e mina ion
o
pla ing
e iciency
and
colo ime ic
eading,
we
p epa ed
pla es
o
24
and
96
wells,
espec i ely,
ha
we e
hen
inocula ed
wi h
5,000
o
30,000
cells/well.
A e
24
h
om
he
inocula ion,
di e en
concen a ions
o
he
es ing
p oduc
we e
added
o
he
cance
cells.
A e
48
h
o
he
named
addi ion,
he
cells
we e
washed
and
hen
ixed.
Finally,
he
colo ing
and
eading
o
he
pla es
we e
ca ied
ou .
In
all
cases
we
de e mined
he
numbe
o
cells
a
he
beginning
(To ),
jus
be o e
he
addi ion
o
he
es ing
p oduc s
(To)
and
48
h
la e
(T
con ols
and
T
es s),
acco ding
o
Scheme
1.
The
an i umou
ac i i y
o
was
es ed
in
i o
agains
Eh lich
asci ic
umou
(EAT),
he
in ape i oneally-implan ed
P388
lymphocy ic
leukemia
and
he
sub enal
capsule
( ansplan ed
human
mamma y
ca cinoma)
MX-I
xenog a .
The
expe imen s
we e
pe o med
acco ding
o
he
NIH
p o ocols
a
ONI
Cen e,
Mad id,
Spain.
CD2F
emale
mice
wi h
weigh s
wi hin
a
3
g
alue
ange
and
a
minimum
weigh
o
18
g
we e
used
o
all
expe imen s
excep
o
MX-1
ca cinoma,
whe e
a hymic
swiss
mice
we e
used
(4
g
alue
ange
and
weigh
o
17
g).
The
es
g oups
was
o med
by
6
animals
and
con ol
g oup
by
12.
Syn hesis
o
he
complex
[RuV(HL)CI].2HO
[1]
Solid
cd a
(228
mg,
1.0
mmol)
was
added
o
a
clea
solu ion
o
RuCI3
(0.230
mg,
1.1
e ool)
dissol ed
in
a
50
ml
o
HCI
0.1
M,
while
s i ing.
The
deep
ed
mix u e
was
in oduced
in o
a
sealed
p essu e
eac o
and
hea ed
o
16
h
a
120C
in
elec ic
o en.
A e
cooling,
he
pink- ed
ob ained
solu ion
was
slowly
concen a ed
o
abou
5
ml
by
e apo a ion
a
oom
empe a u e.
Yellow-ambe
p isma ic
c ys als
sui able
o
X- ay
di ac ion
s udies
we e
eco e ed
and
he
solid
analysed.
Two
hyd a ion
wa e
molecules
pe
mol
o
compound
we e
ound
by
he mal
analysis.
Anal.
(%),
Calc.
o
C4H2008N2CI2Ru’2H20:
C,
30.4;
H,
4.5;
N,
5.1;
CI,
12.8;
Ru,
18.3.
Found:
C,
30.6;
H,
4.1;
N,
5.3;
CI,
12.2;
Ru,
17.9.
RESULTS
AND
DISCUSSION
X- ay
s uc u e
Table
p esen s
a
summa y
o
he
ele an
c ys al
da a
and
e inemen
esul s
o
complex
I.
The
279

Vol.
2,
Nos.
3-4,
2004
Syn hesis,
S uc u e,
P ope ies
and
Biological
Beha iou
O
he
Complex
Table
1
C ys al
da a
and
s uc u e
e inemen
o
[Ru(H2cd a)Cl2].2H20
Iden i ica
ion
code
Empi ical
o mula
Fo mula
weigh
Tempe a u e
Waeleng
h
C ys al
sys em,
space
g oup
Uni
cell
dimensions
Volume
Z,
Calcula ed
densi y
bso p
ion
coe icien
F
(000)
C ys al
size
T..he a
ange
o
da a
collec ion
Limi ing
indices
Re lec ions
collec ed
/
unique
Comple eness
o
he a
27.44
?cbso p
ion
co ec ion
Max..
and
ain.
ansmission
Re inemen
me hod
Da a
/
es ain s
/
pa ame e s
Goodness-o - i
on
Final
R
indices
[I>2sigma(1)]
R
ndices
(all
da a)
_bsolu e
s uc u e
pa ame e
La ges
di .
peak
and
hole
udc a
Cl4
H24
C12
.|2
O10
Ru
552.32
293
(2)
K
0.71073
A
Hexagonal,
P6(5)
(No.
170)
a
13.
567
(2)
A
b
13.
567
(2)
A
c
22.
286(6)
A
3552.5(12)
A^3
alpha
90
deg.
be a
90
deg.
gamma
120
deg.
6,
i.
549
.Mg/m"
3
0.
935
mm"-I
1680
0.40
x
0.34
x
0.20
mm
1.73
o
27.44
deg.
-14<=h<=0,
0<=k<=17,
0<=!<=28
3123
/
2779
[R(in )
0.0103]
i00.0
%
Psi
.-scans
0.8350
and
0.7061
Full-ma ix
leas -squa es
on
2779
/
!
/
271
0.943
R1
0.0498,
wR2
0.0518
R1
0.0498,
wR2
0.0518
0.05(6)
0.515
and
-0.380
e.A-3
molecula
s uc u e
ob ained
by
X- ay
di ac ion
analysis
is
shown
in
Fig.
along
wi h
he
numbe ing
o
a oms
in
he
molecule.
The
e aden a e
chela ing
ligand
(cd a)
con ains
wo
ee
ca boxylic
g oups
and
is
bonded
o
he
cen al
ion
by
wo
ni ogen
a oms,
N(l)
and
N(2),
and
wo
chlo ide
anions
cis
o
each
o he ,
sha ing
he
equa o ial
plane
wi h
he
ni ogen
a oms.
The
emaining
coo dina ion
posi ions
a e
occupied
by
wo
oxygen
a oms,
O(11)
and
O(21),
om
coo dina ed
ca boxyla e
g oups,
si ua ed
in
ans
axial
oc ahed al
posi ions
ha
comple e
in
his
way
he
oc ahed al
coo dina ion
sphe e
a ound
u henium
a om.
280
Rosa io
A.
Vilaplana
e
al.
.Bioino ganic
Chemis y
and
Applica ions
CI1
O12
O11
Rul
Cl2
N2
O
22,
N1
Fig.
1"
O14
0,13
View
o
he
molecula
s uc u e
o
complex
showing
he
oc ahed al
en i onmen
o
he
u henium
cen al
ion.
Table
2
p esen s
selec ed
bonds
leng hs
and
angles
o
complex
1.
As
expec ed,
he
chlo ide
coo dina ed
ions
a e
loca ed
much
u he
om
he
u henium
a om
(2.37
A)
han
he
wo
ni ogen
a oms
(2.11
/
and
2.13
A).
A
possible
explana ion
is
ela ed
o
he
no able
nucleophilic
cha ac e
o
he
chela ing
ligand
ha
induces
a
no able
inc easing
o
he
dis ance
Ru-CI.
Fu he mo e,
he
bulky
chela ing
ligand
migh
be
he
o igin
o
he
sligh
educ ion
obse ed
in
he
CI-Ru-CI
angle
alue
(91.4),
in
compa ison
wi h
he
same
angle
in
cispla in
(91.9).
These
wo
e ec s
ha e
also
been
ound
in
simila
complexes
wi h
o he
aminopolyca boxylic
ligands,
i.e.,
Ru(ed a)CI2
[22]
and
Ru(pd a)Cb,
[23].
Clea ly,
he
dis ance
Ru-O(I
1)
is
sho e
(2.03
/)
han
he
dis ance
Ru-O(21)
(2.07
/).
As
a
consequence,
he
oc ahed al
con igu a ion
a ound
u henium
a om
is
sligh ly
dis o ed
(Fig.
I)
wi h
angles
281
Vol.
2,
Nos.
3-4,
2004
Syn hesis,
S uc u e,
P ope ies
and
Biological
Beha iou
O
he
Complex
Table
2
Selec ed
bond
leng hs
[A]
and
angles
[deg]
o
[Ru(H2cd a)Cl2].2H20
Ru
(I)
-O(II)
2.
028
(3)
Ru
(i)
-O
(21)
2.070
(3)
Ru
(i)
-I.,
(I)
2.108
(2)
Ru
(i)
-l.I
(2)
2.
128
(2)
Ru
(!)
-CI
(2)
2.3658(9)
Ru
(I)
-el
(I)
2.3723(8)
0
(ll)-Ru
(I)-O
(21)
o
(11)
-Ru
(I)
- ,
(i)
o
(21)
- u
([)
-u
O
(II)
-Ru
(l)
-I.-|
(’2)
0
(21
-Ru
!
-n
(2)
I-
(i)
-Ru
(i)
-l,I
(2)
o
(I
l
-Ru
(I)
-cl.
(2)
O
(2.)
-Ru
(I)
-CI
{2)
I.i
(I)
-Ru
(I)
-el
(2)
I.I
(2)
-Ru
(I)
-CI
(2)
O
(ll)-Ru
(1)-Cl
(i)
O(21)-Ru
(i)
-CI
(i)
I..I
()-Ru
()-Cl
()
II(2)-Ru
(1)-Cl
(I)
C1
(2)
-Ru
(1)-CI
(1)
173.48
(8)
80.72(9)
94.89(8)
95.57
79.14(i0)
84.54(8)
93.05(7)
91.97(7)
92.69(7)
170.39(8)
91.83(6)
92.21(6)
171.69(8)
92.57(6)
9.1.39(3)
signi ican ly
educed
om
ideal
oc ahed al
alues,
i.e.,
N(I)-Ru-N(2),
84.5;
O(1
I)-Ru-N(I),
80.7
and
0(2
I)-Ru-N(2),
79.1
.
I
is
impo an
o
ema k
ha
he
nonbonding
CI...C1
dis ance
(bi e)
in
compound
(3.35
A),
is
di ec ly
co ela ed
wi h
he
dis ance
be ween
adjacen
o
p oximal
coo dina ion
si es
in
biological
a ge s
such
as
DNA.
This
bi e
dis ance
is
iden ical
o
ha
o
cispla in,
and
co esponds
o
he
sepa a ion
be ween
wo
app op ia e
DNA-nucleobase
dono
a oms,
his
ac
enabling
c oss-linking
o ma ion
a e
in e ac ion
o
complex
wi h
DNA
inside
he
cell/29/.
in
he
packing,
he
molecules
o
complex
a e
assembled
in
a
3D-ne wo k
by
in e molecula
hyd ogen
bonding
ha
in ol es
wo
pai s
o
oxygen
a oms,
O(13)...O(24),
2.65
/l
and
O(23)...O(14z),
2.67
A
(symme y
ans o ma ions;
1:
x-y+
1,
x,
z-l/6
and
2:
y,
-x+y+
1,
z+
1/6),
as
ound
in
simila
cd a
complexes
/42a/,
i.e.,
he
hyd oxyl
g oups
o
he
non-coo dina ed
ca boxylic
moie y
ac
as
hyd ogen-a om
dono s
while
he
ca bonyl
g oups
a e
he
hyd ogen-a om
accep o s
in
hese
associa ions
(Fig.
2).
In
addi ion,
he
wo
wa e
molecules
loca ed
be ween
neighbou ing
molecula
uni s
a e
also
H-bonded
o
oxygen
ca boxyla o
g oups
{O(1)...O(213),
2.89/l
and
O(2)...O(113),
2.87
A
(symme y
ans o ma ions;
3:
y,
-x+y,
z+l/6)}.
This
H-
bonded
pa e n
can
be
desc ibed
as
a
ne wo k
o
sup amolecula
helices.
In
he
c
di ec ion
he
packing
gene a es
a
six old
sc ew
axis
and
pa allel
channels
(Fig.
3),
wi h
ca i ies
o
adius
2.15
A.
These
channels
a e
hyd ophilic
because
he
oxygen
a oms
o
ca boxylic
moie ies
and
hose
o
wa e
molecules
poin
owa ds
he
ca i ies.
282
Rosa io
A.
Vilaplana
e
al.
Bioino ganic
Chemis ),
and
Applica ions
Fig.
2:
Packing
d awing
iew
o
showing
he
assembling
o
molecules
in
a
3D-ne wo k
by
in ennolecula
hyd ogen
bonding
in ol ing
wo
pai s
o
oxygen
a oms.
283
VoL
2.
Nos.
3-4,
2004
Syn hesis,
S uc u e,
P ope ies
and
Biological
Beha iou
()./’ he
Complex
The
in
i o
an i umou
ac i i y
o
complex
agains
EAT
and
P388
umou s
was
e alua ed
a
se e al
ea men
doses
in
he
ange
20--240
mg/kg
body
weigh .
The
he apeu ic
ac i i y
o
he
complex
was
ob ained
om
he
T/C
pe cen age
which
is
desc ibed
as
T/C%
(100)
x
mean
li e
span
o
ea ed
mice/mean
li e
span
o
un ea ed
mice;
u nou
ee
su i o s
we e
excluded.
The
minimum
alue
o
T/C
o
mode a e
ac i i y
is
120
(EAT
and
P388
umou s);
i
T/C
>
125
he
complex
is
conside ed
a
candida e
o
u he
an i umou
assays.
T/C
alues
equi ed
o
ac i i y
in
MX-1
xenog a
umou mus
be lowe
han
20
(T/C
<20).
Fo
EAT,
a
T/C
(%)
o
350
was
ob ained
(25
mg/kg)
and
he
comple e
emission
o
he
u nou
obse ed
a
a
dose
o
50
mg/kg.
The
oxic
.dose
(LDs0)
was
equal
o
100
mg/kg.
In
he
case
o
he
lymphocy ic
leukemia
P388,
a
T/C(%)
alue
o
140
was
ob ained
(60-120
mg/kg)
while
in
MX-I
xenog a
ca cinoma,
his
pa ame e
was
equal
o
16
a
a
dose
o
240
mg/kg.
These
esul s
e idence
a
no able
and
speci ic
an ip oli e a i e
e ec
o
complex
[Ru(HzL)CI2]’2H20
agains
he
human
umou
cell
lines
ADLD
and
HeLa,
wi h
selec i e
and
impo an
cy o oxic
p ope ies
in
bo h
cases.
The
in
i o
an i umou
ac i i y
is
also
ema kable
in
he
s udied
u nou s.
A
u he
in es iga ion
o
he
an ineoplas ic
ac i i y
o
his
new
po en ial
u henium
d ug
agains
o he
ypes
o
u nou
is
ad isable.
ACKNOWLEDGEMENTS
We
g ea ly
app ecia e
inancial
suppo
om
MCYT,
Spain
(G an s
PPQ2000-0035-P4
and
BQU2001-
2455)
and
EC
(COST
Chemis y
P ojec s
D20/005
and
D20/009).
The
au ho s
a e
g a e ul
o
P o .
A.
Ce illa
and
V.
Folgado,
om
Valencia
Uni e si y
(Spain),
o
he
help
p o ided
in
he
cyclo ol amme ic
s udy.
REFERENCES
1.
N.
Fa ell,
in:
Pla inum-based
D ugs’
in
Cance
Chemo he apy,
L.R.
Kelland
and
N.
Fa ell
(Eds.),
Humana
P ess,
To owa,
N.J.,
2000;
p.
321.
2.
E.R.
Jamieson
and
S.J.
Lippa d,
Chem..
Re .,
99,
2467
(1999).
3.
M.J.
Bloemink
and
J.
Reedijk,
in:
Me al
lons
in
Biological
Sys ems,
A.
Sigel
and
H.
Sigel
(Eds.),
ol.
32,
Dekke ,
New
Yo k,
1995;
Chap e
19.
4.
J.
Reedijk,
PNAS,
100,
3611
(2003).
5.
J.
Reedijk,
Cu .
Opin.
Chem.
Biol.,
3,
236
(1999).
6.
Z.J.
Guo
and
P.J.
Sadle
Angew.
Chem.
In .
Edi .,
38,
1513
(1999).
7.
E.
Wong
and
C.M.
Giandomenico,
Chem.
Re .,
99,
2451
(1999).
8.
G.
Giaccone,
D ugs,
59,
Suppl.
4-9
(2000).
9.
S.L.
B uhn,
J.H.
Toney
and
S.J.
Lippa d,
P og.
lno g.
Chem.,
38,
477
(1990).
A.
Eas man,
in:
30
Yea s
o
Cispla in:
Chemis y
and
Biochemis y
o
a
Leading
An icance
D ug,
B.
Lippe
(Ed.),
Ve lag
Hel e ica
Chimica
Ac a,
ZU ich,
1999,
p.
111.
10.
290

Rosa io
A.
l/ilaplana
e
al.
Bioino ganic
ChemisOT
and
Applica ions
11.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
28.
29.
32.
33.
34.
J.A.R.
Na a o,
J.M.
Salas,
M.A.
Rome o,
R.
Vilaplana,
F.
Gonzilez-Vilchez
and
R.
Fau 6,
J.
Med.
Chem.,
41,332
(1998).
M.
Galanski,
M.
Be ge
and
B.K.
Kepple ,
Me al-Based
D ugs,
7,
349
(2000).
A.
Zenke ,
M.
Galanski,
T.L.
Be eu e ,
B.K.
Kepple
and
W.
Lindne ,
J.
Biol.
Ino g.
Chem.,
5,
’498
(2000).
B.
Desoize
and
C.
Madoule ,
C i .
Re .
Oncol.
Hema o .,
42,
317
(2002).
N.
Fa ell,
Y.
Qu,
L.
Feng
and
B.
Van
Hou en,
Biochemis y
29,
9522
(1990).
K.
Akdi,
R.
Vilaplana,
S.
Kamah,
J.A.R.
Na a o,
.J.M.
Salas
and
F.
Gonzilez-
Vilchez,
J.
Ino g.
Biochem.,
90,
51
(2002)
and
e .
he ein.
B.K.
Kepple ,
New
J.
Chem.,
14,
389
(1990).
M.J.
Cla ke,
F.
Zhu
and
D.R.
F asca,
Chem.
Re .
99,
2511
(1999).
G.
Sa a,
A.
Be gamo,
S.
Zo ze ,
B.
Ga a,
C.
Casa sa,
M.
Cocchie o,
A.
Fu lani,
V.
Sca cia,
B.
Se li,
E.
lengo,
E.
Alessio
and
G.
Mes oni,
Eu .
J.
Cance ,
38,
427
(2002).
M.J.
Cla ke,
Coo d.
Chem.
Re .,
236,
209
(2003).
F.
Gonzb.lez-Vilchez
and
R.
Vilaplana,
Re .
Biol.
Cel.,
53,
194
(1986).
R.
Vilaplana,
M.G.
Basallo e,
C.
Ruiz,
E.
Gu ie ez-Puebla
and
F.
Gonzlez-
Vilchez,
J.
Chem.
Soc.,
Chem.
Com in.,
100
(1991
).
R.
Vilaplana,
M.A.
Rome o,
M.
Qui 6s,
J.M.
Salas
and
F.
Gonzilez-Vilchez,
Me al-Based
D ugs,
2,
211
(1995).
S.R.
G gu ic-Sipka,
R.A.
Vilaplana,
J.M.
P ez,
M.A.
Fue es,
C.
Alonso,
Y.
Al a ez,
T.J.
Sabo
and
F.
Gonzlez-Vilchez,
J.
Ino g.
Biochem.,
97,
215
(2003).
R.
Vilaplana,
F.
Gonzilez-Vilchez,
F.
Delmani,
J.
To eblanca,
J.
Mo eno
and
G.
Ga cia-He dugo,
J.
Biol.
Ino g.
Chem.,
(submi ed).
F.
Gonzlez-Vilchez,
R.
Vilaplana,
G.
Biasco
and
L.
Messo i,
J.
Ino g.
Biochem.,
71,
45
(1998).
E.
Gallo i,
C.
Ve o i,
E.
Alessio,
F.
Gonzilez-Vilchez,
R.
Vilaplana,
P.
O ioli,
A.
Casini
and
L.
Messo i,
A ch.
Biochem.
Biophys.,
376,
156
(2000).
L.
Messo i,
F.
Gonzilez-Vilchez,
R.
Vilaplana,
E.
Piccioli,
E.
Alessio
and
B.K.
Kepple ,
Me al-Based
D ugs,
7,
335
(2000).
M.
Ca ballo,
R.
Vilaplana,
G.
Mi quez,
M.
Conde,
F.J.
Bedoya,
F.
Gonzilez-
Vilchez
and
F.
Sob ino,
Biochem.
J.,
328,
559
(1997).
D.J.
Snchez,
M.
G6 nez,
J.L.
Domingo
and
J.M.
Liobe ,
J.
Appl.
Toxicol.,
15,
285
(1995).
M.D.
Sousa-Ne o,
J.G.
Passa inho,
J.R.
Ca alho,
A.M.
C uz,
J.D.
P6co a
and
P.C.
Saquy,
B az.
Den .
J.,
13,
123
(2002).
C.
Rihouey,
C.
Mo an
I.
Bo isso a,
A.
Jauneau,
M.
Dema y
and
M.
Ja is,
Ca bohyd a e
Polyme s,
28,
159
(1995).
A.i.
Valle,
M.J.
Gonzilez
and
M.L.
Ma ina,
J.
Ch oma .,
607,
207
(1992);
E.A.
Gau ie ,
R.T.
Ge a ,
R.E.
Se an
and
D.A.
Ba is oni,
J.
Ch oma .,
706,
115
(1995);
M.C.
B eadmo e,
M.
Mack
and
P.R.
,ddad,
Anal.
Chem.,
71,
1826
(1999).
G.
Schwa zenbach
and
H.
Acke mann,
Hel .
Chim.
Ac a,
32,
1682
(1949);
J.H.
Holloway
and
C.N.
Reilley,
Anal,
Chem.,
32,
249
(1960);
D.
W igh ,
J.H.
Holloway
and
C.N.
Reilley,
Anal,
Chem.,
37,
384
291
Vol.
2,
Nos.
3-4,
2004
Syn hesis,
S uc u e,
P ope ies
and.Biological
Beha iou
O
he
Complex
(1965);
J.D.
Ca
and
D.G.
Swa z age ,
Anal
Chem.,
43,
1520
(1971);
E.
Ca mona
and
F.
Gonzb.lez,
Anal.
Qui e.,
72,
768,
773
(1976).
35.
D.
A zey,
D.
De ilippo,
A.
Rossi
and
R.
Camini i,
Spec ochim.
Ac a
(A),
49,
1779
(1993).
36.
J.D.
Ma in,
J.M.
Te ce o,
A.
Ma illa,
J.
Nicl6s,
A.
Busno
and
S.
Fe e ,
Polyhed on,
!5,
439
(1996).
37.
S.
Seibig
and
R.
an
Eldik,
ho g.
Chim.
Ac a,
279,
37
(1998);
Eu .
J.
Ino g.
Chem.,
447
(1999).
38.
T.
Schneppensiepe ,
S.
Seibig,
A.
Zahl,
P.
T egloan
and
R.
an
Eldik,
Ino g.
Chem.,
40,
3670
(2001).
39.
K.Y.
Choi,
K.S.
Kim
and
C.P.
Hong,
Bull.
Ko .
Chem.
So .,
15,
782
(1994).
40.
E.
Szilagyi
and
E.
B ueche ,
J.
Chem.
Soc.
Dal on
T ans.,
13,
2229
(2000).
41.
S.P.
Pe osyan s
and
A.B.
llyukhin,
Russ.
J.
Ino g.
Chem.,
47,
712
(2002).
42.
a)
E.N.
Duesle ,
R.E.
Tapsco ,
M.G.
Basallo e
and
F.
Gonzb.lez-Vilchez,
Ac a
C ys .,
41C,
678
(1985);
b)
M.G.
Basallo e,
R.
Vilaplana
and
F.
Gonz.lez-
Vlchez,
Polyhed on,
13,
1853
(1994).
c)
J.M.
L6pez-
Alcalb.,
M.C.
Pue a
and
F.
Gonzilez-Vlchez,
Re .
Chim.
Mink ale,
21,257
(1984);
d)
F.
Gonzilez-
Vilchez,
M.G.
Basallo e,
J.
Beni ez
and
R.
Vilaplana,
Re .
Esp.
Oncol.,
29,
609
(1982).
43.
M.M.
Taqui
Khan,
A.
Kuma
and
Z.
Shi in,
J.
Chem.
Res.
Mp.,
4,
1001
(1986).
44.
M.M.
Taqui
Khan,
R.C.
Bha dwaj,
C.
Bha dwaj
and
N.N.
Rao,
J.
Pho ochem.
Pho obiol.
A-Chemis y,
68,
137
(1992).
45.
T.V.
Filippo a,
T.N.
Polyona,
A.L.
II’inskii,
M.A.
Po ai-Koshi s
and
N.A.
Eze skaya,
Zh.
Neo g.
Khim.,
26,
1418
(1981);
A
p elimina y
communica ion
on
he
s uc u e
o
his
complex
was
p e iously
published:
R.
Vilaplana,
F.
Gonzilez-
V lchez,
E.
Gu ie ez-Puebla
and
C.
Ruiz-Vale o,
Ino g.
Chim.
Ac a,
224,
15
(1994).
46.
B.V.
Nonius,
CAD4
Exp ess
So wa e,.
Ve .
5.1/1.2.
En a Nonius,
Del ,
The
Ne he lands
(1994).
47.
M.
K e schma ,
GENHKL
P og am
o
he
educ ion
o
CAD4
Di ac ome e
da a,
Uni e si y
o
Tuebingen,
Ge many
(1997).
48.
A.C.T.
No h,
D.C.
Phillips
and
F.S.
Ma hews,
Ac a
C ys .
24A,
351
(1968).
49.
G.M.
Sheld ick,
Ac a
C ys .,
46A,
467
(1990).
50.
G.M.
Sheld ick,
SHELXL-97,
P og am
o
he
Re inemen
o
C ys al
S uc u es,
Uni e si y
o
51.
54.
Goe ingen,
Ge many
(1997).
A.L.
Spek,
PLATON,
A
Mul ipu pose
C ys allog aphic
Tool,
U ech
Uni e si y,
U ech ,
The
Ne he lands
(2002).
ll.D.
Flack,
Ac a
C ys .,
39A,
876
(1983).
In e na ional
Tables
o
C ys allog aphy,
Vol.
C,
Kluwe
Academic
Publishe s:
Do d ech ,
The
Ne he lands
(1995).
E.
Kelle ,
SCHAKAL-97,
A
compu e
p og am
o
he
g aphic
ep esen a ion
o
c ys allog aphic
models.
Uni e si y
o
F eibu g
i.
B .,
Ge many
(1997).
55.
J.
Fuji a,
K.
Nakamo o
and
M.
Kobayashi,
J.
Ame .
Chem.
Soc.,
78,
3963
(1958).
56.
P.C.
Kong
and
F.
Rochon,
Can.
J.
Chem.,
57,
526
(1979)
57.
B.
de
Kle k-Engels,
H.-W.
F hau and
K.
V ieze,
Ino g.
Chem.,
32,
5528
(1994).
58.
A.A.
Diaman is
and
J.V:
Dub awsky,
Ino g.
Chem.,
22,
1934
(1983).
molecula
and
292
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