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Synthesis, Structural Characterization and Biological Evaluation of Rhenium(I) Tricarbonyl Complexes with β‐Carboline Ligands.
DOI: 10.1002/slct.201701961 Full Papers
1
z
2 Inorganic Chemistry
3
4 Synthesis, Structural Characterization and Biological
5
Evaluation of Rhenium(I) Tricarbonyl Complexes with
6
7 b-Carboline Ligands.
8
9
Iva´n Maisuls,[a,b] Ezequiel Wolcan,[a] Oscar E. Piro,[c] Eduardo E. Castellano,[d]
10
Gabriela Petroselli,[e] Rosa Erra-Balsells,[e] Franco M. Cabrerizo,*[b] and Gustavo T. Ruiz*[a]
11
12
13
14 Two b-carboline rhenium(I) complexes, fac-[Re(CO) with TD-DFT calculations using several hybrid functionals.
3
15 (dppz)(nHo)]OSCF and fac-[Re(CO)(nHo)Cl] where dppz= Cellular uptake and cytotoxic effect of both complexes against
3 3 3 2
16 dipyrido[3,2-a:2’,3’-c] phenazine and nHo=9H-pyrido[3,4-b] human lung carcinoma (A549) cells were evaluated. For
17 indole (norharmane), have been synthesized. These complexes comparative purpose, two related fac-[Re(CO)(L)(nHo)]+ com-
3
18 were fully characterized by structural X-ray diffraction, 1H and plexes (L=bpy and phen) were included in the biological
19 13CNMR, UV-vis absorption and FT-IR spectroscopy and mass studies. The anti-proliferative effect of the compounds was
20 spectrometry. Ground state geometry optimization was carried rationalizedintermsofthedifferentextensionoftheligandsp-
21 out in vacuo with the PBE0 hybrid functional using the system.
22 LanL2DZ basis set. The characterization was complemented
23
24 Introduction
in intracellular domains by conventional and/or time-resolved
25
Rhenium(I) complexes comprise a group of compounds emission microscopy. This is appropriate to elucidate their
26
showing quite interesting physicochemical features, i.e., rich cellulardistributionand,potentially,theirmechanismofaction.
27
excited-state behavior,[1] thermal and photochemical stability,[2] Rhenium(I) tri-carbonyl complexes, fac-[Re(CO)(L)(L)]
28 3 1 2
large Stokes shift and long luminescence lifetimes.[3] These (where L and L are different mono or bidentate ligands),
29 1 2
properties make them appealing candidates for diverse representasubgroupofRe(I)complexeshavinga-Re(CO) core
30 3
applications in broad research areas such as photo-induced initsarchitecture.Thiscoremakesthemquiterobustfromthe
31
electron transfer,[4] solar energy conversion,[5] catalysis,[6] oncol- chemical point of view. Moreover, fac-[Re(CO)(L)(L)] com-
32 3 1 2
ogy[7]andnuclearmedicine,[8]amongothers. plexesrepresentversatilestartingmaterialsthatcanbechemi-
33
In particular, due to their luminescent properties, Re(I) callymodifiedatease(thatisin1–3stepsynthesis)introducing
34
complexes are used as biological labelling reagents[9] and also specific ligands to fine-tune their physical or chemical proper-
35
as non-covalent luminescent molecular probes for bio-mole- ties.[2,11] Therefore, rhenium organometallic compounds based
36
cules and cell imaging.[10] As such, they can be easily followed onthe-Re(CO) coredeservetobefurtherinvestigated.
37 3
Thecombinationoftransitionmetalswithbioactiveligands
38
offers the possibility of designing novel compounds that may
39 [a] I.Maisuls,Prof.E.Wolcan,Prof.G.T.Ruiz
INIFTA optimizeorincreasetheintrinsicchemical,photochemicaland/
40
UNLP(CCTLaPlata-CONICET),Diag.113y64,C.C.16,Suc.4,(B1906ZAA) or pharmacological properties of the free ligands. In this
41 LaPlata,Argentina
context, we have undertaken the search of novel complexes
42 E-mail:gruiz@inifta.unlp.edu.ar
based on the combination of both -Re(CO) core and a group
43 [b] I.Maisuls,Prof.F.M.Cabrerizo 3
IIB-INTECH–UNSAM-CONICET of alkaloids called b-carbolines (bCs) as ligands. From the
44
I.MarinoKm8,2.CC164,(7130)Chascomffls,BuenosAires,Argentina chemicalpoint ofview,bCsderivefrom9H-pyrido[3,4-b]indole
45 E-mail:fcabrerizo@intech.gov.ar
or norharmane (nHo, Scheme1(a)). The interest in these
46 [c] Dr.O.E.Piro
alkaloids arises from their biological and biochemical role. In
47 InstitutoIFLP(CCTLaPlata-CONICET)yDepto.deF(cid:3)sica
FCE-UNLP,C.C.67 fact, bCs were found to be active compounds in several
48
(1900)LaPlata,Argentina biochemical and pharmacological[12] processes. Morever, bCs
49 [d] Dr.E.E.Castellano
have also shown quite unique and interesting photochemi-
50 InstitutodeF(cid:3)sicadeS¼oCarlos
cal,[13] photophysical and/or photosensitizing properties.[14] In
51 USP,C.P.369
13560S¼oCarlos,Brazil consequence,theuseofthesealkaloidsindifferentapplications
52
[e] Dr.G.Petroselli,Prof.R.Erra-Balsells in the biomedical fields, such as photodynamic therapy, has
53 CIHIDECAR-CONICET,DepartamentodeQu(cid:3)micaOrg(cid:4)nica,FCEyN been described.[15] Recently, we have synthesized and fully
54 UBA
characterizedtwonovel-Re(CO) complexeswithpolypyridines
55 Pabell(cid:5)nII,3erP.,CiudadUniversitaria,(1428)BuenosAires,Argentina 3
and nHo as ligands.[16] Briefly, nHo binds to the metal center
56 Supporting information for this article is available on the WWW under
https://doi.org/10.1002/slct.201701961 through the pyridine nitrogen atom. Such a kind of coordina-
57
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HRESI-MSandUV-MALDI-MS
1
2
Mass spectrometry (MS) analysis was performed to determine
3
the structure of rhenium complexes. FigureS1a shows the
4
HRESI mass spectrum in positive ion mode of Re(CO)(nHo)Cl
5 3 2
complex(MW=642.08).Theintactmolecularionwasobserved
6
as sodiated adduct [M+Na]+. Contributions from 187Re and
7
185Re (62.6 and 37.4% natural abundance, respectively) can be
8
observed at m/z values of 665.035 and 663.034. Structure
9
diagnosissignalswereobtainedbyMALDI-MSwhenDCTBand
10
nHo were used as matrices, FiguresS1b and S1c. In negative
11
ionmode,theintactmolecularion[M](cid:2)asanionradicalspecies
12
was detected at m/z=642.53 when LDI-MS was used and at
13
m/z=642.73 when MALDI-MS was used (matrix, nHo), Fig-
14
ureS2.
15
The HRESI mass spectrum in positive ion mode of the
16
cationic organometallic complex [Re(CO)(dppz)(nHo)]+ (MW=
17 3
720.74) is shown in FigureS3a. The intact molecular ion was
18
observed as cation [M]+ at m/z values of 721.098 and 719.095
19
(contributions from 187Re and 185Re, respectively). Additionally,
20
theintactmolecularionforthecomplexwasdetectedascation
21
[M]+ byMALDI-MSwhenDCTBandnHowereusedasmatrices
22
and alsowhen nomatrixwas added (LDI-MS) (FiguresS3band
23
S3c)
24
Scheme1.Schematicstructureof(a)norharmane,(b)dppz,(c)fac-[Re(CO)
3
25 (dppz)(nHo)]+,(d)fac-[Re(CO)(nHo)Cl],(e)fac-[Re(CO)(bpy)(nHo)]+and(f)
3 2 3
26 fac-[Re(CO) 3 (phen)(nHo)]+.CarbonshavebeennumberedfortheNMR StructuralcharacterizationbyX-raydiffraction
analysis.
27
Figure1 is an ORTEP[18] drawing of the Re(CO)(nHo)Cl
28 3 2
complex. Crystal data, data collection procedure, structure
29
30
tion arrangement has been referred as a good strategy for the
31
developmentofnovelsystemicdrugsbasedonbCspotentially
32
havingareducedneurotoxiceffects.[17]
33
Certainly,thesearchofnovel-Re(CO) complexescoordinat-
34 3
ing bCs represents an excellent alternative that deserve to be
35
furtherexplored.Inthiscontext,wereporthereinthesynthesis
36
and full characterization of two novel bC(cid:2)Re(I) complexes,
37
namely fac-[Re(CO)(dppz)(nHo)]+, where dppz=dipyrido[3,2-
38 3
a:2’,3’-c] phenazine, a known DNA intercalating molecule
39
(Scheme1(b)),andthefirstneutralRe(I)complexwithonlynHo
40
as ligands, fac-[Re(CO)(nHo)Cl] (Scheme1(c) and (d), respec-
41 3 2
tively).Moreover,asafirststepinthebiologicalevaluation,the
42
cytotoxicity activity of [Re(CO)(bpy)(nHo)]+ (Scheme1(e)),
43 3
[Re(CO)(phen)(nHo)]+ (Scheme1(f)), [Re(CO)(dppz)(nHo)]+
44 3 3
andRe(CO)(nHo)Clcomplexesagainsthumancarcinomalung
45 3 2 Figure1.Viewofdimericfac-[Re(CO)(nHo)Cl]complexshowingthedis-
cells(A549)aswellastheircellularuptakewasinvestigated. 3 2
46 placementellipsoidsofnon-Hatomsatthe30%probabilitylevel.Metal-
47 ligandbondsareindicatedbyfulllinesandintermolecularN(cid:2)H***Clbonds
48 Results and Discussion b ha y v d e a b sh e e e d n l l i a n b e e s l . le F d o . r S c e la le ri c t t y e , d in b t o h n e d fu le se n d gt h h e s t [ e A˚ ro ] c a y n c d lic an ri g n l g e s s o [8 n ] l a y ro th u e nd N- R a e to (I m ) s
49 ions:Re1;C(1A)-Re(1):1.980(15),C(1B)-Re(1):1.923(12),C(1C)-Re(1):1.873
Two Re(I) complexes with nHo as ligands, fac-[Re(CO)
50 3 (12),N(11A)-Re(1):2.281(14),N(12A)-Re(1):2.247(9),Re(1)-Cl(1):2.483(3).Re2;
(dppz)(nHo)]+ and fac-[Re(CO)(nHo)Cl], were obtained and
51 3 2 C(2A)-Re(2):1.900(13),C(2B)-Re(2):1.902(14),C(2C)-Re(2):1.882(19),N(21A)-
fully characterized by elemental analysis, FT-IR, NMR and by a Re(2):2.208(10),N(22A)-Re(2):2.164(12),Re(2)-Cl(2):2.495(3).
52
combination of mass spectrometry techniques. Also, the solid
53
state structure of the Re(CO)(nHo)Cl complex was solved by
54 3 2
X-raydiffractionmethods.
55
56
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determinationmethodsandrefinementresultsaresummarized best least-squares plane less than 0.024A˚]. The molecular
1
inTable1.Bonddistancesandanglesaroundthemetalionsare planes subtend dihedral angles of 59.8(2)8 (Re1) and 61.7(2)8
2
inTablesS1-S2. (Re2) with each other and the corresponding Re(I) ions lay
3
nearlyontotheirintersections.
4
As shown in Figure1, the pair of complexes is arranged in
5
Table1. CrystaldataandstructurerefinementresultsforRe(CO) 3 (nHo) 2 Cl. the lattice as dimeric units linked through NH***Cl bonds
6
7
Empiricalformula C
25
H
16
ClN
4
O
3
Re [N***Cl distances of 3.29 and 3.26A˚ and (N(cid:2)H***Cl) angles of
Formulaweight 642.07 1358].
8 Temperature 293(2)K
9 Wavelength 0.71073A˚
10 Crystalsystem Monoclinic Spectroscopiccharacterization
Spacegroup Pc
11 Unitcelldimensions a=11.2840(3)A˚ FT-IR absorption spectra of the complexes showed intense
12 b=10.4360(2)A˚
bandsinthe2100–1800cm(cid:2)1region,whichareconsistentwith
13 c=29.8590(8)A˚
both the facial configuration of the carbonyl ligands and with
b=91.828(1)8
14
Volume 3514.4(2)A˚3 their Cs symmetry.[19] Absorption bands were attributed to the
15
Z 4 A’1, A’’ and A’2 stretching modes of CO ligands in the
16 Absorptioncoefficient 3.557mm(cid:2)1
complexes according to our previous report on similar
17 F(000) 1240
Crystalsize 0.211x0.068x0.060mm3 complexes with nHo.[16] Absorption band at 3200–3300cm(cid:2)1
18
#-rangefordatacollection 1.36to25.258. region was assigned to N(cid:2)H peak of nHo ligands which has
19
Indexranges -13(cid:3)h(cid:3)13,0(cid:3)k(cid:3)12,(cid:2)35(cid:3)l(cid:3)35 alsobeenreportedforothermetal-nHocomplexes.[16,20]
20 Reflectionscollected 21612 1H- and 13C-NMR spectra showed the expected signals for
21 Independentreflections 11152[R(int)=0.0827]
both nHo and dppz ligands. However, all signals were slightly
Observedreflections[I>2s(I)] 9691
22
Completenessto#=25.258 98.0% shifted, with respect to the free ligands, due to their
23
Refinementmethod Full-matrixleast-squaresonF2 coordination with Re atom. It is noteworthy that 13C-NMR
24 Data/restraints/parameters 11152/2/613
spectrumofbothcomplexesshowedasignalathighfields,i.e.,
25 Goodness-of-fitonF2 1.058
26 FinalRindicesa[I>2s(I)] R1=0.0441,wR2=0.1230 d ~ 197.5ppm (Re(CO) 3 (nHo) 2 Cl) and d ~ 196.4 ([Re(CO) 3
Rindices(alldata) R1=0.0484,wR2=0.1246 (dppz)(nHo)]+)whichwereassignedtothecarbonylligands.
27
Absolutestructureparameter -0.02(1) The UV-vis absorption spectrum of Re(CO)(nHo)Cl in
28 Largestdiff.peakandhole 0.759and(cid:2)1.321e.A˚(cid:2)3 3 2
MeOH solution consists of three different absorption bands,
29
aR =SjjF j-jFjj/SjF j,wR =[Sw(jF j2-jFj2)2/Sw(jF j2)2]1/2 bluelineinFigure2.Thefirstband,showingthehighestmolar
1 o c o 2 o c o
30
31
32
There are two closely related but independent Re(I)
33
complexes per asymmetric unit. Assuming that the Re(cid:2)Cl
34
bonds define the axis, the molecules can be seen as an
35
incompletefour-bladedpropeller-likestructurelackingthetwo
36
trans blades which are replaced by CO groups. It can be
37
envisagedthatforaright-screwrotationalongtheRe(cid:2)Clbond,
38
Re1 complex has one of its NH group on the front and the
39
other one on the rear edges of the blades, while in Re2
40
complex both NH groups are on the front blades edges.
41
Rhenium(I) ions are in slightly distorted octahedral environ-
42
ments, fac-coordinated to three carbonyl groups [Re(cid:2)C bond
43
distancesintherange from1.87(1)to1.98(2)A˚ (Re1)andfrom
44
1.88(2) to 1.90(1) A˚ (Re2); C(cid:2)Re-C bond angles in the 89.3(5)-
45
92.1(5)8 (Re1) and 89.8(5)-92.2(6)8 (Re2) intervals; C(cid:2)O lengths
46
from 1.08(2) to 1.20(1) A˚ (Re1) and from 1.14(1) to 1.16(2) A˚
47
(Re2); Re-C(cid:2)O angles are in the 177(1)-179(1)8 and 175(1)-178
48
(1)8rangesforRe1andRe2,respectively].
49
Twoothercis-positionsareoccupiedbytwonHomolecules
50
acting as mono-dentate ligand through their pyridine N-atoms
51
along their electron lone-pair lobes [Re(cid:2)N bond distances of
52
2.28(1) and 2.247(9) A˚ (Re1) and 2.21(1) and 2.16(1) A˚ (Re2)].
53
Thesix-foldcoordinationiscompletedbyachlorineion[Re(cid:2)Cl Figure2.AbsorptionspectraofmethanolicsolutionofRe(CO) 3 (nHo) 2 Cl(blue
54 distancesof2.483(3)A˚ forRe1and2.495(3)A˚ forRe2]. solidline),[Re(CO) 3 (dppz)(nHo)]O 3 SCF 3 (redsolidline),nHo(lightbluedotted
55 line),nHoH+(bluedottedline)anddppz(reddottedline).
As expected from extended p-bonding delocalization, the
56
nHoligandsareplanar[rmsdeviationofnon-Hatomsfromthe
57
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absorptioncoefficient,e(e~5.7x104M(cid:2)1cm(cid:2)1),iscenteredat Polarizable Continuum Model the differences in SCF energies
1
l =241nm. A less intense band (e ~ 2.8 x 104 M(cid:2)1 cm(cid:2)1) betweenRe1andRe2werelowerthan0.6Kcal/mol.
2 max
appears at l =308nm. There are two successive absorption
3 max
bands appearing as shoulders of the latter band at l ~ 348
4 max TD-DFTcalculations
and365nm(e~1.2x104and8.0x103M(cid:2)1cm(cid:2)1,respectively).
5
When comparing the absorption spectra of the complex with TD-DFT calculations were performed on the optimized struc-
6
those recorded for free neutral (nHo) and protonated (nHoH+) turesofRe1andRe2conformers.Atthebeginning,therelative
7
norharmane (light blue and blue dotted lines, respectively in performance of several hybrid functionals (see experimental
8
Figure2),[16,21] it is evident that, despite other electronic section) was assayed by their ability to reproduce the
9
transitions,bothnHo-likeandnHoH+-likebC’sringscontribute, experimental absorption spectrum in MeOH of both Re1 and
10
atleastinpart,totheoverallabsorptionofRe(CO)(nHo)Cl. Re2. The results of the simulations are shown in FiguresS4a-g
11 3 2
This is in agreement with TD-DFT calculations discussed incomparisonwiththeexperimentalabsorptions.Itisobserved
12
below. In addition, absorbance observed at l > 300nm also that the M06 functional gives the best agreement with the
13
suggeststhepresenceofnewchargetransfertransitionsbands experimentalabsorptionspectrumofRe(CO)(nHo)ClinMeOH,
14 3 2
due to the coordination of nHo with the metal center (vide Figure3.
15
infra).
16
The UV-vis absorption spectrum of [Re(CO)(dppz)(nHo)]
17 3
OSCF in MeOH solutions, red line in Figure2, consist in one
18 3 3
intensebandcenteredinl =280nm(e~6.4x104M(cid:2)1cm(cid:2)1)
19 max
andseveraloverlappingbandsin325–425nmregion(e~1.5x
20
104 M(cid:2)1 cm(cid:2)1), i.e. corresponding to typical vibronic compo-
21
nentsofdppz(reddottedlineinFigure2)andnHoligands.
22
23
24 TheoreticalcalculationsonRe(CO) (nHo) Cl
3 2
25
DFTand TD-DFTcalculations have shed light on the nature of
26
the absorption bands of fac-[Re(CO)(L)(L)] complexes. They
27 3 1 2
are comprised of a set of IL, MLCT and LMCT electronic
28
transitions.[11c,22] In particular, these methods have been em-
29
ployed recently to unravel the character of the electronic
30
transitions in [Re(CO)(bpy)(nHo)]+.[16] Since the replacement of
31 3
bpy by nHo could deeply modify the electronic structure not
32
only of complex but also of each nHo ligand, TD-DFT
33
calculations on Re(CO)(nHo)Cl complex were performed in
34 3 2
order to get a deeper understanding of its experimental
35
absorptionspectrum.Further,sincetheX-raystructurerevealed Figure3.ComparisonoftheobservedUV-visabsorptionspectrumofRe(CO) 3
36 (nHo)ClinMeOH(blackcurve)withTD-DFTcalculatedelectronictransitions
that there are two un-equivalent complexes per asymmetric 2
37 (verticallines)andsimulatedspectraforRe1(dashedbluecurve)andRe2
unit (vide supra) ground state geometry optimization was (dashedredcurve)undertheM06/6-311G/6-311G*/LanL2TZ(f)leveloftheory.
38
previously performed on two conformers of Re(CO)(nHo)Cl
39 3 2
(namedasRe1andRe2inFigure1).
40
41
Electronic transitions resultscalculated at thesamelevel of
42 Groundstategeometryoptimization
theory for Re1 and Re2 in MeOH are summarized in TablesS3
43
Additional structural information was obtained by DFT calcu- andS4.
44
lations on two Re1 and Re2 conformers. X-ray crystallographic The most relevant MOs which are responsible for the
45
data was usedas referencein order to control the precision of electronic transitions in the absorption spectrum of Re(CO)
46 3
theoretical values obtained. TablesS1-S2 show the calculations (nHo)Cl complex in the 230–400nm wavelength range are:
47 2
results of selected bond distances and angles for Re1 and Re2. HOMO, LUMO, and a set of MOs H-10 through H-1 and L+1
48
Bond lengths and angles differed only by 0.1-0.2A˚ and 38 or throughL+6.
49
less showing a good agreement between data obtained by By using the AOMIX program, five contributions to those
50
crystal structures and those obtained by computational MOs were considered from a Mulliken population analysis: (i)
51
chemistry. Self consistent field (SFC) energies in vacuo of both Re atom, (ii) the three carbonyls, (iii) nHo1 molecule, (iv) nHo2
52
Re1andRe2conformersdifferedbyonly0.16Kcal/mol.Though moleculeand(v)Clatom.Thecalculated%compositionsofall
53
a systematic study varying the angles between the two nHo fragments at each MO for Re1 and Re2 in MeOH are shown in
54
ligands in both Re(CO)(nHo)Cl conformers was not carried TablesS5 and S6. In the 300–400nm region, the most relevant
55 3 2
out,sincekT~0.6Kcal/molat298K,afreerotationofthenHo electronictransitionsareH!L,H-1!L+1,H!L+1,H-3!L,H-
56
coordinated ligands in solution is highly probable. Under the 4!L, H-3!L+1 and H-4!L+1. Figures4 and S5 show the
57
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 Figure4.SpatialplotsofmostrepresentativeMOsinRe1conformerofthe
17 Re(CO)(nHo)ClcomplexinMeOH(isovalue=0.02).
3 2
Figure5.CellviabilityofA549cellswithincreasingconcentrationsofthe
18
fourinvestigatedcomplexesandnHoascontrol.
19
20
spatial plots of H-1, H, L and L+1 MOs for Re1 and Re2 in
21
MeOH,whichgiveinsighttotheelectronictransitions. Table2. IC 50 oftheReI-nHocomplexesandnHoinA549cells.
22
For Re1, Figure4, it is observed that in MeOH H is a MO Complex IC value(mM)
23 50
mostly centered on the Re atom (~ 43%) with smaller
24 Re(CO)(nHo)Cl 85(cid:4)1
contributions from the three CO and nHo2 (~ 20–23%) and 3 2
25 [Re(CO) 3 (bpy)(nHo)]+ 88(cid:4)1
from nHo1 and Cl (~ 6–8%). H-1 is a MO mostly centered on [Re(CO)(phen)(nHo)]+ 65(cid:4)1
26 3
nHo1 (~ 58%) with smaller contribution from the Re atom (~ [Re(CO)(dppz)(nHo)]+ 10(cid:4)1
3
27 21%), the three CO and Cl (each ~ 9%) and nHo2 (~ 3%). H-3 nHo >250
28
(not shown) is a MO which is widespread between the Re
29
atom,nHo1andnHo2withlessercontributionsfromthethree
30
COandCl.H-4(notshown)isaMOmostlycenteredontheRe ligand. IC values show that the cytotoxic activity of the
31 50
atom(~49%)withsmallercontributionsfromthethreeCOand investigated ReI-nHo complexes increases with the size of the
32
nHo1 (~ 22 and 17%, respectively) and from Cl (~ 9%). On the ancillary or extension of the p-system of the ligands: IC dppz <
33 50
other hand, L and L+1 are MOs centered on nHo2 and nHo1, IC phen < IC bpy < IC nHo. This accounts for the impact the
34 50 50 50
respectively.Therefore,alltheelectronictransitionsinMeOHin chemicalstructureoftheligandshasontheoverallcytotoxicity
35
the300–400nmregionareMLLCT andMLLCT of the investigated rhenium complexes, as it was shown for
36 (Re(CO)3!nHo1) (Re(CO)3!
. ruthenium[23]andplatinum[24]complexes.
37 nHo2)
Thehighenergypartofthespectrum,i.e.,below300nm,is Thehighestcytotoxicity of[Re(CO)(dppz)(nHo)]+ mightbe
38 3
more complex and the main electronic transitions does not associated to the intrinsic intercalative property of the dppz
39
seem to be “pure” excitations but a mixture of nearly all of ligand with DNA (nuclear and/or mitochondrial)[25] and/or also
40
them. However, they appear to be a composition of IL , with the differential cell penetration, which can enhance the
41 (nHo)
LLCT and MLLCT transitions. This is a distinct toxicity. In fact, this complex shows a quite similar cytotoxic
42 (Cl!nHo) (Re(CO)3!nHo)
feature when compared to the [Re(CO)(bpy)(nHo)]+ complex, effect (IC =10mM) to the one described for cisplatin (IC =
43 3 50 50
where neat p!p* electronic transitions centered in bpy and 8.0mM) against the same cell line.[20] Therefore, is important to
44
nHo fragments, respectively, were obtained by TD-DFT calcu- emphasize that [Re(CO)(dppz)(nHo)]+ might represent an
45 3
lations.[16] attractivealternativeasapotentialantitumordrug.
46
ReI-nHo complexes with bpy, phen and nHo as ligands,
47
show moderated effect on A549 cells when comparing their
48 CytotoxicityandcellularuptakeofReI-nHocomplexes
cytotoxicity with related metal complexes based on nHo as
49
Cytotoxicity of four ReI-nHo complexes (Scheme1) against ligands, i.e., AgI-nHo and polypyridyl RuII-nHo complexes.[20,23a]
50
A549 cells was evaluated, Figure5. Data provided herein show Therefore,itwouldbeinterestingtostudythepotentialuseof
51
that the coordination of the -Re(CO) core to nHo ligand thesecomplexesasbiologicallabelsofintracellulardomains.
52 3
increases the toxicity of the bC moiety to A549 cells. All the Re(I)-complexescanbetaken upbydifferenttypesofcells.
53
investigated complexes are more toxic than free nHo (Table2). The efficiency of this process is closely related to their type of
54
Moreover, the intrinsic cytotoxicity of the complexes ligandsandnetcharge.[10c]Thus,tofurtherevaluatetheuptake
55
depends on the chemical nature of the accompanying ligand of this family of ReI-nHo complexes, A549 cells were co-
56
rather than on the net charge of the molecules or the nHo incubated in independent experiments and then visualized by
57
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fluorescence microscopy by making use of the intrinsic possible to estimate this parameter due to the high hydro-
1
luminescentproperties(FigureS6)ofthesecomplexes.Figure6 phobicityofthecomplexes.Thisresultleadsustoassumethat
2
theymightlocalizeintoanyhydrophobicintracellularcompart-
3
ments such as mitochondria, lysosomes or the Golgi body, as
4
seen in other related compounds.[26] In particular, the neutral
5
Re(CO)(nHo)Cl complex represents an excellent alternative to
6 3 2
Re(I) complexes reported in the literature for cellular imaging
7
orbiologicalprobes,sincemostofthemarepositively(cationic)
8
or negatively (anionic) charged.[10c,d] Nevertheless, further
9
studiesareneededtobringlightonthis.
10
11
12 Conclusions
13
TwoRe(I)complexeswithnHohavebeen obtained. Solidstate
14
Structural X-ray diffraction analysis of Re(CO)(nHo)Cl complex
15 3 2
revealed that there are two closely related but independent
16
Re(I) complexes per asymmetric unit in the crystal lattice. The
17
molecules of each complex differed in the orientation of both
18
NH groups of the nHo ligands. The pair of complexes is
19
arranged inthelatticeasdimericunitslinked throughNH***Cl
20
bonds.GroundstategeometryoptimizationbyDFTcalculations
21 Figure6.Phasecontrast(left),fluorescence(center)andmergedimages
showed thatin solutionthe nHo ligands may rotate freely.TD-
22 (right)of(a)nHo(control)(b)Re(CO) 3 (nHo) 2 Cland(c)[Re(CO) 3 (dppz)(nHo)]+ DFTcalculationsestablishedthatthemostimportantelectronic
ofsuspendedA549cells.
23
transitions present in the spectrum of the Re(CO)(nHo)Cl
24 3 2
complexareMLLCT alongwithamixtureofIL
25 (Re(CO)3!nHo1,nHo2) (nHo)
shows, as a representative example, images of A549 cells andLLCT transitions.
26 (Cl!nHo)
stained with Re(CO)(nHo)Cl and [Re(CO)(dppz)(nHo)]+. Cells Data reported herein show that this group of complexes
27 3 2 3
are clearly stained by these types of rhenium(I) tri-carbonyl allowsforagreatdealofstructureandchemicalvariability,and
28
norharmane complexes. Visual inspection of the A549 cells canbefine-tunedtomeettherequirementsofawiderangeof
29
indicatedhealthycellmorphologyinalltestedsamples. biological applications (fluorescence markers and/or antitumor
30
As semi-quantitative test of cell viability, cells were co- drugs) that deserve to be further investigated. Moreover, their
31
incubated with the rhenium complexes and propidium iodide, relatively high hydrophobicity makes these complexes suitable
32
which is only taken up by dead or dying cells. Cell counting formicelle-baseddrugdelivery.[27]
33
showed no evidence of damage on treated cells with respect
34
to untreated cells as control, FigureS7. This evidences that
35 SupplementaryInformationAvailable
there is no cellular death during the time (1h) of the staining
36
protocol(seeExperimentalSection). Additional computational details. General experimental proce-
37
Cellswerealsoco-incubatedwithSYBRgreeninanattempt dures. Mass spectra (ESI, LDI and MALDI) of the complexes
38
to elucidate the intracellular localization of Re(CO)(nHo)Cl, (Figs. S1, S2 and S3). Comparison of the experimental UV-vis
39 3 2
Figure7. The absence of co-localization between both dyes absorption spectrum with TD-DFT calculated electronic tran-
40
suggeststhatthecomplexdonotaccumulateintothenucleus. sitions under different levels of theory (Figs. S4a-g). Spatial
41
plotsofMOsinRe2conformer(Fig.S5).Emissionspectraofthe
42
rhenium complexes (Fig. S6). Cells stained with Propidium
43
Iodide (Fig. S7). FTIR spectra of Re(CO)(nHo)Cl and [Re(CO)
44 3 2 3
(dppz)(nHo)]OSCF (Figs. S8a-b). 1HNMR and 13CNMR spectra
45 3 3
of Re(CO)(nHo)Cl and [Re(CO)(dppz)(nHo)]OSCF (Figs. S9
46 3 2 3 3 3
and S10). Bond lengths and angles (TablesS1 and S2). TD-DFT
47
calculations in MeOH (TablesS3 and S4). HOMOs and LUMOs
48
compositions (TablesS5 and S6). Full bond lengths and angles
49 Figure7.AttachedA549cellsstainedwithRe(CO)(nHo)Cl(Blue)andSYBR-
3 2 (TableS7). Atomic coordinates and isotropic displacement of
50 Green.
the non-H atoms (TableS8). Atomic anisotropic displacement
51
parameters (TableS9). Hydrogen coordinates and isotropic
52
displacementparameters(TableS10).
53
The cellular uptake characteristics of these complexes can
54
be estimated by their lipophilicities, which are commonly
55
referred to as the n-octan-1-ol/water partition coefficients,
56
expressed as log P .[23d] In the present study, it was not
57 o/w
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Acknowledgements Piro,M.P.Juliarena,G.T.Ruiz,E.Wolcan,M.R.F(cid:9)liz,DaltonTrans.2002,
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3 Cabrerizo,S.O.Angel,BMCRes.Notes2013,6,1–6;b)R.Cao,H.Chen,
2012-0423 and PICT 2012-0888), UBA X 0055BA and UNLP 11X/ W.Peng,Y.Ma,X.Hou,H.Guan,X.Liu,A.Xu,Eur.J.Med.Chem.2005,
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611 of Argentina and by FAPESP of Brazil. IM and GTR thank Dr. 40, 991–1001; c)M.G. Olmedo, L. Cerioni, M.M. Gonz(cid:4)lez, F.M.
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Croce (INIFTA, UNLP, Argentina) for their assistance in FT-IR Cabrerizo,V.A.Rapisarda,S.I.Volentini,FoodMicrobiol.2017,62,9–14;
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ANPCyT for research scholarships. E. W, O. E. P, G. P., R. E-B, F. M. [13] a)M.M. Gonzalez, M.L. Salum, Y. Gholipour, F.M. Cabrerizo, R. Erra-
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C. and G. T. R. are research members of CONICET. Authors also Balsells, Photochem. Photobiol. Sci. 2009, 8, 1139–1149; b)M.M.
10 Gonzalez, J. Arnbjerg, M.P. Denofrio, R. Erra-Balsells, P.R. Ogilby, F.M.
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13 Conflict of Interest
M.M. Gonzalez, E. Wolcan, M. Seifermann, R. Erra-Balsells, F.M.
14 Cabrerizo,Phys.Chem.Chem.Phys.2016,18,886–900.
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15 [14] a)M. Vignoni, R. Erra-Balsells, B. Epe, F.M. Cabrerizo, J. Photochem.
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17 Keywords: Antitumor agent · Bioinorganic chemistry ·
F.M. Cabrerizo, Org. Biomol. Chem. 2012, 10, 1807–1819; c)M.M.
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57
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