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Synthesis, characterization, kinetic investigation and biological evaluation of Re(i) di- and tricarbonyl complexes with tertiary phosphine ligands.
Volume 49
Number 1
7 January 2020
Dalton
Pages 1-242
Transactions
An international journal of inorganic chemistry
rsc.li/dalton
ISSN 1477-9226
PAPER
Marietjie Schutte-Smith et al.
Synthesis, characterization, kinetic investigation and
biological evaluation of Re(I ) di- and tricarbonyl complexes
with tertiary phosphine ligands
Dalton
Transactions
PAPER
Synthesis, characterization, kinetic investigation
and biological evaluation of Re( ) di- and
I
Citethis:DaltonTrans.,2020,49,35
tricarbonyl complexes with tertiary phosphine
†
ligands
VerityLindyGantsho,aMazzarineDotou, bMartaJakubaszek, b,cBrunoGoud, c
GillesGasser, bHendrikGideonVisseraandMarietjieSchutte-Smith *a
Rhenium(I)di-andtri-carbonylcomplexesoftheformfac-[Re(CO)
3
(L,L’-Bid)X]and[Re(CO)
2
(L,L’-Bid)X
2
],
whereX=aqua(H O),methanol(CH OH),triphenylphosphine(PPh ),1,3,5-triaza-7-phosphaadamantane
2 3 3
(PTA), tricyclohexylphosphine (PCy ) and L,L’-Bid = O,O’ bidentate ligands (tropolone = TropH and
3
3-hydroxyflavone=FlavH)andN,Obidentateligands(8-hydroxyquinoline=QuinH,5,7-chloro-8-hydro-
xyquinoline = diCl-QuinH and quinoline-2,4-dicarboxylic acid = QuinH ), were synthesized and un-
2
ambiguouslycharacterizedby1H-,13C-and31P-NMR,IR,UV/Visandmicro-analysis.Thecrystalstructures
of four complexes, namely fac-[Re(CO) (QuinH)(H O)]·H O (5), fac-[Re(CO) (Quin)(PPh )] (11), fac-
3 2 2 3 3
[Re(CO) (diCl-Quin)(PPh )](12)and[Re(CO) (Trop)(PPh ) ]·2C H CH (20)wereobtained.Re–Pbonding
3 3 2 32 6 5 3
distancesfor11and12are2.4948(8)and2.4908(8)Å,respectively,indicatingtheeffectoftheelectron-
withdrawingsubstituentsofthediCl-Quin−ligand.Thesecond-orderrateconstantsforthesubstitutions
of methanol at 25.1 °C in fac-[Re(CO) (L,L’-Bid)(CH OH)] (L,L’-Bid = Trop, Flav and QuinH) type com-
3 3
plexesbydifferententeringphosphineligands(PPh ,PCy ,andPTA)variedbetween7.23(7)×10−5and
3 3
1.32(3) × 10−3 M−1 s−1 and were found to depend on the coordinated bidentate ligand (in general k
1
(QuinH) < k (Trop) < k (Flav)). The toxicityof fac-[Re(CO) (QuinH)(PTA)], fac-[Re(CO) (Trop)(PTA)], fac- 1 1 3 3
[Re(CO) (Trop)(PPh )]andfac-[Re(CO) (Flav)(PPh )]onthecervicalcancerHeLaandepithelialRPE-1cell
3 3 3 3
Received14thOctober2019, lines wasthen evaluated. Complex fac-[Re(CO) (Flav)(PPh )] (16) and fac-[Re(CO) (Trop)(PPh )] (13) dis-
3 3 3 3
Accepted7thNovember2019
playedthehighestcytotoxicitywithIC valuesof12.21±0.17µMand13.35±0.94µM,respectivelyin
50
DOI:10.1039/c9dt04025k HeLa cells. Interestingly, a small selectivity towards cancer over non-cancerous cells was observed for
rsc.li/dalton thesecompounds(IC 50 =18.41±3.16µMand>25µMinRPE-1cells).
Introduction used to mimic Technetium-99m, the widely used PET radio
isotope.1–10Ontopofthis,rhenium(I)complexesareseriously
Rhenium(I) complexes increasingly exhibit interesting pro- investigated by seveal groups for its chemotherapeutic
pertiesinthefightagainstcancer,especiallyduetotheirmul-
properties.1–5
The use of phosphine ligands coordinated to
tiple potential applications. Rhenium-186 is investigated for technetium and rhenium isthe driving force for imaging and
potential application as a radiation therapy agent, while therapy in nuclear medicine.6–11 Due to its π-acceptor and σ-
Rhenium-188 has properties that could be exploited in PET. donor properties, phosphines can be used as reducing agents
−
Furthermore, it has been shown that cold rhenium can be towards the [MO ] (M = Tc, Re) salts, as well as chelating
4
agents to stabilize the metal in intermediate to low oxidation
states.12–14
The chemistry has been well-developed and
two cationic complexes anchored by phosphines have been
aUniversityoftheFreeState,DepartmentofChemistry,NelsonMandelaDrive,
introduced for myocardial perfusion imaging purposes:
Bloemfontein,SouthAfrica.E-mail:schuttem@ufs.ac.za
bChimieParisTech,PSLUniversity,CNRS,InstituteofChemistryforLifeandHealth [99mTcO 2 (P 53 ) 2 ]+(Myoview)and[99mTc-Q 12 ]+(TechneScanQ 12 ).15,16
Sciences,LaboratoryforInorganicChemicalBiology,Paris,France The use of fac-[M(CO) (H O) ]+ (M = Tc, Re) for the pro-
3 2 3
cInstitutCurie,PSLUniversity,CNRSUMR144,Paris,France
ductionofradiopharmaceuticalsfortherapeutic(Re)anddiag-
†Electronic supplementary information (ESI) available: All single crystal X-ray nostic (Tc) purposes is well-established.8,17 The three water
data.CCDC1947424(5),1950181(11),1950222(12)and1947425(20).ForESI
ligands can easily be replaced with innovative ligand systems.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9dt04025k This opens an opportunity for the formation of metal com-
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plexes with target tissue specificity and high in vivo stability, Bid = O,O′ bidentate ligands (tropolone = TropH and 3-hydro-
amongst other factors that are necessary in radiophamarma- xyflavone=FlavH)andN,Obidentateligands(8-hydroxyquino-
ceuticaldesign.18 line=QuinH,5,7-chloro-8-hydroxyquinoline=diCl-QuinHand
Preparing water-soluble, organometallic transition metal quinoline-2,4-dicarboxylic acid = QuinH ). The substitution
2
complexes have received attention for applications in various kinetics of selected compounds and their cell toxicity is also
areasofresearch.19–21Watersolubilityofmetalcomplexesisa
investigated in order to see if a parallel between substitution
desired feature in radiopharmacy and nuclear medicine reactivity and cell toxicity can be drawn. The latter is of par-
because such compounds have better in vivo characteristics ticular interest since there is a surge in the interest of using
(e.g.,clearanceofthedrugfromthebodyisfaster).Significant rhenium complexes as anticancerorantibacterial compounds
progress has been made over the years on synthesizing
orasphotodynamictherapyphotosensitizers.32–41
water-soluble complexes for diagnostic and therapeutic
purposes.22,23 Water solubility is generally achieved by using
a variety of water-soluble ligands. 1,3,5-Triaza-7-phospha- Results and discussion
adamantane(PTA)isoneofthemonodentatephosphineligands
Complexsynthesis
used in this studyand was specifically chosen due to its high
water solubility. Becauseofthewatersolubility, high-oxidative The preparation of the rhenium starting synthon, fac-
stability and low steric requirements of PTA, investigations [NEt 4 ] 2 [Re(CO) 3 (Br) 3 ] (1), was performed according to a pro-
have confirmed that ligand substitution with fac- cedure described by Alberto et al.4 The CO stretching fre-
[NEt ] [ReBr (CO) ] is relatively easy and can be useful in the quencyof1featuresasignalat1846and1996cm
−1usingKBr
42 3 3
designofinnovativeradiopharmaceuticals.24 asreference.
Byusingthe‘2+1’approach,thethreelabileaqualigands ThroughtheadditionofAgNO
3
inacidicwater(pH2.2),the
onfac-[M(CO) 3 (H 2 O) 3 ]+aresubstitutedbyaN,O/O,O′-bidentate three Br − of 1 could be replaced with H 2 O molecules forming
ligand and a monodentate ligand.25 For this study, the phos- fac-[Re(CO) 3 (H 2 O) 3 ]+ (2).4 The carbonyl ligands on 2 are
phineligandiscoordinatedtothemetalcentreasamonoden- stronglyboundtothemetalcentre,whilethethreewatermole-
tate ligand and,in turn,causesthe carbonylligand transto it cules are labile and are effortlessly displaced byother ligands
to become more labile, allowing it to be substituted by a
(Scheme1).5
second phosphine ligand, forming a Re(I) dicarbonyl species, Complexes 3–7 were obtained by adding various bidentate
whichwillpotentiallydisplayevenbetterinvivocharacteristics ligandsto 2, resulting intwo ofthe H 2 O ligandsbeing substi-
thantheRe(I)tricarbonylcomplex.Thisapproachisknownas tuted to produce fac-[Re(CO) 3 (L,L′-Bid)(H 2 O)] type complexes
the‘2+1+1’approach.26 where L,L′-Bidisthe bidentateligand. Thekineticbehaviorof
ReactivitystudiesofRe(I)tricarbonylcomplexeshaveadual complexes 5–7 upon the introduction of a phosphine mono-
purpose. Firstly, it serves as a model for Tc(I) complexes and dentate ligand was performed in methanol. A relatively quick
secondly it assists in predicting in vivo behavior. It is well- substitutionoccursbetweentheH 2 Omoleculeon5–7andthe
known that metal complexes undergo changes when they
methanol,producing8–10(Scheme1).
come into contact with nucleophiles like thiocyanate in The carbonyl ligand trans to the coordinated phosphine
blood.27–29 Information on the type of mechanism (dissocia- ligand can be substituted with a second phosphine through
tive vs. associative) provides important information in the the addition of excess phosphine ligand in toluene as solvent
design of new complexes, as recently discussed in detail.30 at 80 °C to produce 20 (Scheme 2). All complexes could be
This analytical tool can give sufficient information about the characterizedbyinfraredaswellas1H,13Cand31PNMRspec-
invivometalstabilityandreactivity,aswellastherateofdistri- trometry and micro-analysis of which characteristic spectro-
bution and clearance from the body. For that reason, this scopic details are given in the Experimental section
study aims at elucidating the mechanism of substitution for (Scheme3).
Re(I) tricarbonyl complexes with various phosphine ligands,
enablinghencefurthercharacterizationofpotentialradiophar-
maceuticals. The formation of the Re(I) dicarbonyl complexes
occurs at high temperatures, thus limiting kinetic investi-
gations for the substitution of the carbonyl due to equipment
restrictions, as reported by Manicum et al.31 They concluded
that the removal of a CO ligand from Re(I) tricarbonyl com-
plexes, similar to those used in this study, only takes place at
hightemperatures.
We report here the synthesis of a range of Re(I) di- and tri-
carbonyl complexes of the form fac-[Re(CO) (L,L′-Bid)X] and
3
[Re(CO) (L,L′-Bid)X ], where X = aqua (H O), methanol
2 2 2
(CH 3 OH), triphenylphosphine (PPh 3 ), 1,3,5-triaza-7-phospha- Scheme1 Synthesis of fac-[Re(CO) 3 (H 2 O) 3 ]+ (2), fac-[Re(CO) 3 (L,L’-Bid)
adamantane(PTA)andtricyclohexylphosphine(PCy 3 )andL,L′- (H 2 O)](3–7)andfac-[Re(CO) 3 (L,L’-Bid)(CH 3 OH)](8–10).
36 | DaltonTrans.,2020,49,35–46 Thisjournalis©TheRoyalSocietyofChemistry2020
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Scheme2 Synthesis of fac-[Re(CO) (L,L’-Bid)(P)] (11–19) and [Re
3
(CO) (Trop)(PPh ) ]·2CH (20).
2 32 7 8
Scheme3 Representationofthecomplexessynthesized.
X-Raycrystallography
Detailed structural information of these complexes were
obtained from crystallographic analyses. Slow evaporation of
thesolvent (water/methanol/toluene)fromcomplexes5,11,12
and 20 resulted in single crystals, yielding the subsequent
molecular structures (Fig. 1). All the crystallographic data,
including anisotropic displacement parameters, all bond dis-
tancesandangles,atomicandhydrogencoordinatesaregiven
inthe ESI,†whileselected bonddistancesand anglesare pre-
sented in Table 1. Hydrogen bonding interaction and π–π Fig.1 Molecularrepresentationofthecrystalstructuresof5,11,12and
20.Somehydrogenatomsareomittedforclarity.Ellipsoidsaredrawnat interactiondataisalsopresentedintheESI.†
50%probability.
Complex 5 crystalized in the monoclinic C2/c space group.
The Re(I) metal centre is coordinated to three facial carbonyl
ligands, a quinoline-2-carboxylato-4-carboxylic acid bidentate
Table1 Asummaryofselectedbonddistances(Å)andbiteangles(°)of
ligandintheequatorialplaneandanaqualigandintheaxial thecrystalstructuresof5,11,12and20
position. Two Re(I) units and two solvent water molecules are
foundintheasymmetricunit.Asignificantdeviationfromthe Complex
predicted 90° angles for octahedral complexes is seen in the
(5)a (11) (12) (20)
bond angles of 5, making the complex distorted. This is
evident from the following angles: O04–Re1–O08 (81.76(10)°, Re1–C01(Å) 1.915(3)/1.912(4) 1.920(3) 1.924(3) 1.883(3)
76.89(9)°) and N1–Re1–O04 (75.31(9)°, 75.26(9)°). All other R R e e 1 1 – – C C 0 0 3 2 ( ( Å Å ) ) 1 1 . . 9 9 1 0 1 0 ( ( 4 4 ) ) / / 1 1 . . 9 9 0 0 8 1 ( ( 4 4 ) ) 1 1 . . 9 9 5 1 4 2 ( ( 3 3 ) ) 1 1 . . 9 9 5 0 2 8 ( ( 3 3 ) ) — 1.887(3)
bond lengths and angles for 5 compare well with those of Re1–X(Å) 2.228(3)/2.204(3) 2.189(3) 2.184(2) 2.158(2)
similar structures.42,43 The structure of 5 is stabilized by one Re1–O04(Å) 2.145(2)/2.142(2) 2.130(2) 2.149(2) 2.155(2)
intermolecular π–π interaction between the two rings of the R R e e 1 1 – – P P 2 1 ( ( Å Å ) ) — — — 2.4948(8) — 2.4908(8) 2 2 . . 4 4 2 3 3 0 9 2 ( ( 8 8 ) )
bidentateligandandfourteeninter-andintramolecularhydro- Re1–O8(Å) 2.203(3)/2.185(3) — — —
gen interactions. The bidentate ligand (plane through N1, X–Re1–Y(°) 75.31(9)/75.26(9) 76.08(9) 75.62(8) 72.96(7)
O04,C04,C05,C06,C07,C08,C09,C10,C12,C13,C14)twists X = N1 (5, 11, 12) and O03 (20). aTwo molecules in the asymmetric
significantlyfromtheplanethroughRe1,C02,O02,C03,O03, unit(moleculeA/moleculeB).
N1,O04 withadihedral angleof 16.41(9)° and27.99(7)° for A
andBrespectively(Fig.2).
The basic structures of 11 and 12 are verysimilar. In both, A slight distortion in the octahedral geometry can be seen
the Re(I) metal centre is coordinated to three facial carbonyl in both structures with bond angles C01–Re1–O04 (97.38(10)°)
ligands, an 8-hydroxyquinolinato (11)/5,7-dichloro-8-hydroxy- andC02–Re1–N1(98.00(10)°)in11andC01–Re1–O04(99.52(10)°)
quinolinato(12)bidentateligandintheequatorialplaneanda and C02–Re1–N1 (96.96(11)°) in 12 which deviates sig-
triphenylphosphineligandintheaxialposition. nificantlyfromthepredictedninetydegrees.TheRe–CObond
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bite angle(O04–Re1–O03) of72.96(7)° which is comparable to
similar structures.50 Complex 20 contains one weak (3.882(6)
Å)intramolecularπ–πinteractionbetweenthebidentateligand
and the phenyl ring from the monodentate triphenyl-
phosphine ligand. The tropolonato bidentate ligand bends
slightlytowardsoneofthePPh ligandswithadihedralangle
3
of 8.46(7)° between the planes through Re1, C01, O01, C02,
O02,O03,O04andO03,O04,C1,C2,C3,C4,C5,C6,C7.
The Re–CO bond distances in the equatorial plane (Re1–
C01 and Re1–C02) of 11, 12 and 5 are all considered to be
within the predicted range of ∼1.90 Å for similar
complexes.44,45 The Re–CO bond distances in the axial plane
Fig.2 Illustration of the out-of-plane bending and/or twisting of the (Re1–C03)of11,12and5areslightlylongerthantheequator-
bidentateligandin5(moleculeAandB),11,12and20. ialRe–CObonddistances,whichispossiblyattributabletothe
transinfluenceoftheligandoppositetoit.51TheRe–CObond
distances in the equatorial plane of 20 are slightly shorter
distances are comparable to other similar structures, with (1.883(3) and 1.887(3) Å, respectively). The Re1–N1 bond dis-
Re1–C02, Re1–C01 and Re1–C03 reported as 1.917(3) Å, tancesare consideredtobewithinnormalrangeof∼2.20Å.42
1.910(3) Å and 1.952(3) Å, respectively for 11, and 1.924(3) Å, The Re1–O04 bond distances of the functionalized hydroxy-
1.908(3) Å and 1.952(3) Å, respectively for 12, all of which are quinolinatoligands12and5areslightlylongercomparedtothat
considered within normal range.44–46 Both bidentate ligands, ofthestandard8-hydroxyquinolinatoin11butarestillwithin
8-hydroxyquinolinato and 5,7-dichloro-8-hydroxyquinolinato range of similar structures. The Re1–O03 and Re1–O04 bond
show a minimally constrained bite angle (O04–Re1–N1) of distances of 20, 2.1578(19) and 2.1548(18) Å, respectively, are
76.05(8)° and 75.62(8)°, respectively, which is comparable to slightlylongerthanthatofsimilarstructures,rangingbetween
similarstructures.47 2.12–2.14Å.46TheRe1–P1of11and12fallwithinthenormal
Both crystal structures 11 and 12 are stabilized by four π–π rangeof∼2.50ÅbuttheRe1–P1andRe1–P2of20areslightly
interactions, three ofwhich are intramolecularand oneweaker shorter, and range from ∼2.42 Å to ∼2.43 Å, which could be
intermolecular in nature (see ESI†). Interactions between the attributed to the stabilizing effect of the phosphine ligands.47
central ring of the bidentate ligand and the phenyl ring from The bite angles of the quinolone ligands in 5, 11 and 12 are
the triphenylphosphine ligand contribute to the π-interactions well within range of similar structures (75.26(9)°–76.08(9)°) as
of these molecules. Two hydrogen bonding interactions are well asthat ofthe tropolonato ligand20(72.96(7)°).50 The out
present in 11, one intermolecular (H33–O04) and the other ofplanebendofthebidentateligandof11,12and20ismuch
intramolecular (H22–O04), contributing to the packing of the smallercomparedtothatof5,evidentfromFig.2.
molecule. Contrary to 11, structure 12 display three additional
Kineticexperiments
inter- and intramolecular hydrogen interactions as a result of
the chloride atomsattached tothe bidentateligand. Structures Thesubstitutionkineticsof8,9and10withPPh 3 ,PCy 3 andPTA
11 and 12 have a slight out of plane bend of the bidentate asenteringligands,respectivelywerestudiedatvarioustempera-
ligand (N1, O04, C1, C2, C3, C4, C5, C6, C7, C8, C9) from the tures.Allreactionswereperformedunderpseudofirst-ordercon-
planethroughRe1,C01,O01,C02,O02,N1,O04withadihedral ditionswiththeenteringligandinlargeexcessineachcase.The
angleof6.2(2)°and 9.25(7)°for11and12respectively(Fig.2). rates of the reactions increase linearly with an increase of the
20 crystalized in the triclinic P ˉ 1 space group. The Re(I) concentrationoftheenteringligandandtimeversusabsorbance
metalcentreiscoordinatedtotwocarbonylligands,atropolo- spectraofallthereactionsstudiedrevealsisosbesticpoints,indi-
nato bidentate ligand in the equatorial plane and two tri- cating one-step reactions. Based on this a general mechanism,
phenylphosphineligandscoordinatedasmonodentateligands illustratedinScheme4,couldbepresented.
in the axial position. Two toluene solvent molecules complete Thereactionratecanbedenotedas:
theasymmetricunit;oneofthesearedisorderedovertwoposi- Rate¼k
1
½ReðL;L′BidÞ(cid:2)½L(cid:2)(cid:3)k(cid:3)1 ½ReðL;L′BidÞðLÞ(cid:2)
tions in a 41.4:58.6 ratio. There is a slight distortion in the
octahedral geometry around the rhenium atom that can be where k 1 represents the forward reaction and k−1 the reverse
seen in the bond angles C01–Re1–O04 (98.15(9)°) and C02– reaction. [Re(L,L′-Bid)] is fac-[Re(L,L′-Bid)(CO) 3 (CH 3 OH)] and
Re1–O03 (102.93(10)°), which deviates significantly from the
predicted 90°. Re–CO bond distances are comparable to
others, withRe1–C01and Re1–C02 reported as1.883(3) Åand
1.887(3)Årespectively,allofwhichareconsiderednormal.48,49
The Re1–O03 and Re1–O04 distance of 2.1578(19) Å and
2.1548(18) Å, respectively compare well with similar struc- Scheme4 Schematic representation of the predicted mechanism for
tures.50Thetropolonatoligandshowsaminimallyconstrained themethanolsubstitutionreactionoffac-[Re(CO) (L,L’-Bid)(CH OH)].
3 3
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Table2 Asummaryofthekineticdataforthesubstitutionkineticsof8,
9and10withPTA,PPh andPCy atdifferenttemperatures
3 3
fac-[Re(CO) (Trop)(CH OH)]andPTA
3 3
15.1°C 25.1°C 35.1°C 45.1°C
k (M−1s−1) 0.108(4) 0.331(6) 0.934(2) 2.423(6)
1
K
1 03
(M
k−
−1
1
(
)
s−1)
1
0
5
.0
1
7
3
1
(
4
5
(
9
8
)
)
1
0
5
.2
6
1
8
1
(
(
3
3
6
)
) 1
0
5
.6
3
0
8
7
(
(
2
8
1
)
) 1
1
4
.6
4
8
2
(
(
4
3
)
4)
1 ‡
ΔH ðkJmol(cid:3)1Þ 72(2)
‡
ðk1 Þ
ΔS ðJK(cid:3)1mol(cid:3)1Þ −12(6)
ðk1 Þ
fac-[Re(CO) (Trop)(CH OH)]andPPh
3 3 3
15.1°C 25.1°C 35.1°C 45.1°C
k (M−1s−1) 0.1476(8) 0.4189(3) 1.1401(6) 3.3082(4)
1
K
1 03
(M
k−
−1
1
(
)
s−1)
5
0
7
.0
9
2
7
5
(
4
3
6
3
(
)
5)
5
0
7
.0
9
7
3
2
(
3
5
(
6
7
)
)
6
0
0
.1
3
8
2
9
(
(
6
2
4
)
) 7
0
6
.4
2
3
2
4
(
(
1
6
0
)
5) 1 ‡
ΔH ðkJmol(cid:3)1Þ 70(1)
‡
ðk1 Þ
ΔS ðJK(cid:3)1mol(cid:3)1Þ −16(5)
ðk1 Þ
Fig.3 (a)AtypicalUV/Visspectrumofthemethanolsubstitutionreac- fac-[Re(CO) 3 (Trop)(CH 3 OH)]andPCy 3
tion between fac-[Re(CO) (Flav)(CH OH)] and PCy at 25.1 °C. [Re] = 2 × 10−4 M,[PCy ] =0.01 3 0 M. (b) A 3 fit ofabsorban 3 ce vs. time for this 15.1°C 25.1°C 35.1°C 45.1°C 3
t
r r
e
e e
m
a a c c
p
t t i i
e
o o
r
n n
at
a
u
b t
re
e λ
s
tw
.
= e 4 e 3 n 0n fa m c- , [ Δ Re t ( = CO 28 ) 3 . ( 2 Fl s a . v) ( ( c C ) H A 3 O pl H ot )] of an k o d bs P vs C . y [ 3 PC a y t 3 ] v fo ar r io th u e s 1
K
k 1 0
1
3 (
(
M
‡ M
k− − −1 1
1
(
)
s s − − 1 1 ) ) 0 0
1
. .
4
0 0
7
0 1
(
2 9
5
8 4
)
6 (7 (2 ) ) 0 0
1
. .
5
0 0
9
0 4
(
6 2
2
7 7
)
9 (6 9 ) (8)
1
0 0
7
. . 0 0
7
1 9
(
7 7
8
3 9
)
( ( 8 3 ) )
2
0 0
0
. . 0 2
3
4 1
(
3 5
4
7 (
)
4 ( ) 5)
ΔH ðkJmol(cid:3)1Þ 67(2)
‡
ðk1 Þ
ΔS ðJK(cid:3)1mol(cid:3)1Þ −61(7)
[Re(L,L′-Bid)(L)]istheproductofsubstitution,fac-[Re(L,L′-Bid)
ðk1 Þ
fac-[Re(CO) (Flav)(CH OH)]andPTA
(CO) (L)]andListheenteringphosphineligand. 3 3
3
Thethreecomplexeswere selectedtocompare theeffectof 5.1°C 15.1°C 25.1°C 35.1°C
bidentate donor ligands on reaction rates. PicoH (pyridine-2-
k (M−1s−1) 0.524(3) 1.0102(6) 2.1207(6) 4.9872(4) c
la
a
t
r
o
b
-
o
4-
x
c
y
a
la
rb
to
o
-
x
4
y
-
l
c
i
a
c
rb
a
o
c
x
id
yl
)
ic
d
a
is
c
p
id
la
)
y
an
si
d
m
Q
il
u
a
i
r
n
it
H
y
(
i
q
n
u
s
in
tr
o
u
l
c
in
tu
e
r
-2
e
-c
a
a
n
r
d
bo
f
x
o
y
r
- 1
K
1 0
1
3
( ‡ M
k−
−1 1
(
)
s−1)
3
0
7
.1
0
4
1
1
(
6
2
(
1
8
)
)
4
0
2
.2
6
3
2
7
(
(
3
2
6
)
) 4
0
9
.4
4
2
3
9
(
(
4
4
6
)
) 5
0
8
.8
4
5
7
3
(
(
5
8
4
)
)
thisreason,werethoughttodisplaycompellingkineticeffects ΔH
‡
ðk1 Þ
ðkJmol(cid:3)1Þ 51(3)
suitable for comparison. The kinetic data for PicoH was pre- ΔS ðJK(cid:3)1mol (cid:3)1Þ −67(12)
ðk1 Þ
viouslyinvestigatedbySchutteetal.andwillbereferredtofor
comparison purposes.45 Fig. 3a illustrates a typical UV/Vis fac-[Re(CO) 3 (Flav)(CH 3 OH)]andPPh 3
spectrum for the reaction between the phosphine ligand and 5.1°C 15.1°C 25.1°C 35.1°C
k (M−1s−1) 1.373(9) 3.709(6) 10.758(5) 29.972(4)
1
K
1 03
(M
k−
−1
1
(
)
s−1) 0
3
.
7
0
9
3
2
6
(
2
6
5
7
(
)
6)
3
0
8
.0
7
9
1
5
(
8
2
2
1
(
)
5)
4
0
5
.2
1
3
2
8
(
4
1
(
5
8
)
)
4
0
5
.6
6
5
2
7
(
8
5
(
6
7
)
)
1 ‡
ΔH ðkJmol(cid:3)1Þ 56(4)
‡
ðk1 Þ
ΔS ðJK(cid:3)1mol(cid:3)1Þ −39(13)
ðk1 Þ
fac-[Re(CO) (Flav)(CH OH)]andPCy
3 3 3
15.1°C 25.1°C 35.1°C 45.1°C
k (M−1s−1) 1.246(2) 2.153(4) 4.524(7) 8.997(2)
1
K
1 03
(M
k−
−1
1
(
)
s−1) 0
2
.
1
5
0
9
1
3
(
(
2
7
5
)
)
1
1
.
6
3
3
2
1
(
(
3
3
)
7)
2
1
.
7
5
6
6
7
(
(
8
5
)
5)
4
1
.
8
9
3
1
2
(
(
5
1
)
8)
1 ‡
ΔH ðkJmol(cid:3)1Þ 49(2)
‡
ðk1 Þ
ΔS ðJK(cid:3)1mol(cid:3)1Þ −74(9)
ðk1 Þ
fac-[Re(CO) (QuinH)(CH OH)]andPTA
3 3
25.1°C
Fig.4 (a)Aplotofligandconcentrationvs.k obs forfac-[Re(CO) 3 (Trop) 103k (M−1s−1) 8.209(8)
v (C s. H k 3 o O bs H f ) o ], r [ f R a e c ] -[ = Re 2 (C × O 10 ) 3 − (F 4 la M v) a (C t2 H 5 3 . O 1 H °C )] . , ( [ b R ) e A ]= pl 2 ot × o 1 f 0 l − ig 4 a M nd at co 25 n . c 1 e ° n C tr . ation 1 K 0 1 3 (M k 1 − −1 1 ( ) s−1) 2 0 8 .0 1 2 ( 9 3 ( 9 4 ) )
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fac-[Re(Flav)(CO) (CH OH)] in methanol. The time vs. absor- electron delocalization. From the abovementioned findings, it
3 3
bance datawas fitted to single exponentials (Fig. 3b) confirm- can be concluded that the influence of the bidentate ligands
ingfirst-orderbehavior.Thek valueswereobtainedforeach areasfollows:k (PicoH)<k (QuinH)<k (Trop)<k (Flav).
obs 1 1 1 1
complexandplottedagainstligandconcentrationsatdifferent From this data it can be observed that the first order rate
temperatures(Fig.3c).Fig.4(aandb)illustratesasummaryof constants, k , generally decrease for PPh > DMAP > PTA >
1 3
the reaction plots of fac-[Re(CO) (Trop)(CH OH)] (9) and fac- PCy > Py, however, this does not coincide for an associative
3 3 3
[Re(CO) (Flav)(CH OH)](10)withdifferententeringligands. activated mechanism since the pK of PCy (9.7)52 is larger
3 3 a 3
Three neutral Re(I) tricarbonyl complexes were selected for than that of DMAP (9.6),53 PPh
3
(7.64),54 PTA (6.0)55 and Py
thisstudy,oneofwhichcontainedaN,O-bidentateligandand (5.25).56 Interestingly Schutte et al. did not observe a trend in
twowithO,O′-bidentateligands.Anaxialmethanolligandwas k values for the monodentate ligands and pK either, which
1 a
available for substitution by monodentate entering ligands. further suggests that association does not play an important
Theratedataforthemethanolsubstitutionreactionsbetween roleinthereactionmechanism.
the three complexes with various phosphine ligands (PTA, Negative ΔS ‡ values normally point towards associative be-
PPh and PCy ) are summarized in Table 2. The kinetic data havior, but our recent work on the substitution reactions of
3 3
obtainedbySchutteetal.45isincludedinTable3forcompari- fac-[Re(Trop)(CO) (CH OH)] under various pressures, strongly
3 3
sonreasons. suggests dissociative behavior for the substitution of methanol
The values of the second order rate constants, k , for the byvariousenteringligands.30 Here, rather large positive values
1
complex with a N,O-bidentate ligand is much smaller than fortheactivationvolumes(+10–14cm3mol −1)ofreactionswith
thosewithO,O′-bidentateligands.Thisisnotexplainablewith variousenteringligandsunderdifferentpressureswasreported,
the current knowledge at hand. The results obtained are con- pointingstronglytoadissociativeactivatedmechanism.
gruent with those obtained by Schutte et al.44,45 who further TheO,O′bidentateligands(TropandFlav)seemtoprovide
established that k fac-[Re(Flav)(CO) (OH )] > k fac-[Re more stable substitution products. In terms of the Flav com-
1 3 2 1
(TropBr )(CO) (OH )], and attributed it to the electron with- plexes fac-[Re(CO) (Flav)(PTA)] had the highest value (4943(46)
3 3 2 3
drawing effects of the bromido substituents on the TropBr M −1). The stability constants, K , of the O,O′ bidentates (Trop
3 1
backbone.Thisisinaccordancewiththevaluesobtainedfrom andFlav-complexes)areingeneralhigherthanthosereported
thisstudywherethek valueobtainedforthereactionbetween fortheN,O-bidentateligands,whichinturnsfavoursthemfor
1
fac-[Re(Flav)(CO) (CH OH)] and PTA is more than 6 times useinfuturedrugdesign.
3 3
faster than the reaction between fac-[Re(Trop)(CO) (CH OH)]
3 3
Cytotoxicity
andPTA.Thek valueobtainedforfac-[Re(Flav)(CO) (CH OH)]
1 3 3
and PPh is approximately 25 times faster than the similar ColdReorganometalliccompoundshavebeenwidelyexplored
3
reaction with fac-[Re(Trop)(CO) (CH OH)] and 5 times faster as luminescent probes for cell imaging.57–62 In addition, as
3 3
than fac-[Re(Flav)(CO) (CH OH)] and PTA. From the results mentioned in the introduction, several rhenium compounds
3 3
obtained in this study, as well as those obtained by Schutte have been established which display cytotoxicity equal to or
et al.44,45 k (QuinH) > k (PicoH), this could be attributed to exceedingthatofcisplatin.32,37,38,63–76
1 1
Table3 Rateconstantsofmethanolsubstitutionreactionsbetweenvariousfac-[Re(CO) (L,L’-Bid)(CH OH)]complexeswithdifferentmonodentate
3 3
ligandsat25.1°C
[Re(Trop)] [Re(Flav)] [Re(QuinH)] [Re(PicoH)]
PTA k (M−1s−1) 0.331(6) 2.1207(6) 8.209(8)×10−3
k
K
1 −1
(M
(s−
−
1
1
)
) 1
2
5
.1
6
1
8
(
(
3
3
)
6
×
)
10−4
4
4
9
.2
4
9
3
(
(
4
4
)
6
×
)
10−4
2
2
8
.9
1
(
(
4
3
)
9
×
)
10−5
1
PPh k (M−1s−1) 0.4189(3) 10.758(5)
3
K
k 1 −1
(M
(s−
−
1
1
)
) 5
7
7
.2
9
3
3
(
(
7
5
)
6
×
)
10−5
4
2
5
.3
1
8
2
4
(
(
1
8
5
)
)
×10−4
1
PCy k (M−1s−1) 0.006799(8) 2.153(4)
3
K
k 1 −1
(M
(s−
−
1
1
)
) 1
4
5
.2
9
7
(
(
2
6
)
)×10−5
1
1
6
.3
1
2
8
(
(
3
3
)
7
×
)
10−3
1
Pya k (M−1s−1) 1.38(8) 0.00331(2) 0.00164(8)
K
k 1 −1
(M
(s−
−
1
1
)
) 4
0
6
.3
0
0
0
(
(
1
1
)
0
×
0)
10−3
6
0
5
.0
(
5
9
(
)
7)×10−3
2
0
1
.0
(
3
2
(
)
2)×10−3
1
DMAPa k (M−1s−1) 5.10(2) 0.00652(9) 0.00321(4)
K
k 1 −1
(M
(s−
−
1
1
)
) 3
0
2
.1
0
6
0
(4
0
)
(8
×
0
1
0
0
0
−
)
3
2
0
6
.0
0
2
(
(
3
3
0
)
)
×10−3
2
0
9
.1
(
1
3
(
)
1)×10−3
1
aKineticdataobtainedbySchutteetal.
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Table4 ObtainedIC values(inµM)after48h Quin complexes and in general also more cytotoxic. This
50
initial data would suggest that cytotoxicity might not comple-
HeLa RPE-1 tely be ascribed to the formation of adducts withDNA or pro-
fac-[Re(CO) (Quin)(PTA)] 44.31±1.44 >100 teinsforthesetypesofcomplexes.
3
fac-[Re(CO) (Trop)(PTA)] >100 >100
3
fac-[Re(CO) (Trop)(PPh )] 13.35±0.94 >25
3 3
fac-[Re(CO) (Flav)(PPh )] 12.21±0.17 18.41±3.16
3 3 Experimental section
Cisplatin 8.02±0.57 39.07±0.45
Generalproceduresandinstrumentation
The UV/vis spectra were performed on a Varian Cary 50 Conc
Rhenium complexes containing water or methanol are
UV/Visible Spectrophotometer, equipped with a Julabo
prone to substitution (as illustrated by this study). The cyto-
F-12 mV temperature cell regulator (accurate to 0.1 °C) in a
toxicityobserved is assumed to be related to the formation of
1.000±0.001cmquartzcuvettecell.
adducts with DNA or proteins. Due to poor solubility, in this
The infrared spectra of the complexes were recorded on a
study, cytotoxicity was investigated only for the fac-[Re
Bruker Tensor 27 Standard System spectrophotometer with a
(CO) (QuinH)(PTA)], fac-[Re(CO) (Trop)(PTA)], fac-[Re
3 3 laser range of 4000–370 cm −1, coupled to a computer. The IR
(CO) (Trop)(PPh )] and fac-[Re(CO) (Flav)(PPh )] complexes.
3 3 3 3
spectrometer was equipped with a temperature cell regulator,
HeLa (Human cervix adenocarcinoma) and RPE-1 (Human
accuratewithin0.3°C.Solidsampleswereanalysedaspotass-
retinalpigmentedepithelial)celllineswereusedtodetermine
iumbromide(KBr)pelletsandthedatawerecollectedatroom
the potential of our compounds. Cytotoxicity was assessed by
temperature.
fluorometric cell viability assay using resazurin. Worthy of
All 1H and 13C NMR spectra were performed on a Bruker
note, the highest concentration tested for fac-[Re(CO) (Trop)
3 300 MHz nuclear magnetic resonance spectrometer operating
(PPh )] was 25 µM due to its poor solubility in cell media.
3 at 300 MHz using deuterated solvents. All 31P NMR spectra
Cisplatin was used as a positive control. As can be seen in
were performed on a Bruker 400 MHz nuclear magnetic reso-
Table 4, complex fac-Re(CO) (Trop)(PPh ) (IC value 13.35 ±
3 3 50
nance spectrometer operating at 400 MHz using deuterated
0.94 µM) and fac-[Re(CO) (Flav)(PPh )] (IC value 12.21 ± 3 3 50
solvents. Chemical shifts are reported in parts per million
0.17 µM) were found to be the most cytotoxic compounds in
(ppm)usingTMS(tetramethylsilane)asaninternalstandard. HeLa cell line with IC values comparable to the ones of cis-
50
platin. This could possibly relate to the higher stability of
Synthesis
these complexes as suggested by the kinetic studies.
Interestingly, the IC 50 values of fac-Re(CO) 3 (Trop)(PPh 3 ) and Synthesis of fac-[NEt 4 ] 2 [Re(CO) 3 (Br) 3 ] (ReAA) (1). (NEt 4 )Br
fac-[Re(CO) (Flav)(PPh )]onRPE-1cellswereallhigherthanon (5.06 g; 0.024 mol) was ground into a fine powder and dried
3 3
HeLa cells, showing an interesting selectivity between cancer- under vacuum overnight. Under dry nitrogen atmosphere
ous and non-cancerous cells (IC 50 value >25 µM and 18.41 ± 2,5,8-trioxanone diglyme (150 ml) was added to the (NEt 4 )Br
3.16µM,respectively). andheatedto80°Cfor1hour.[Re(CO) 5 Br](5.02g;0.012mol)
was added to the mixture and stirred for 24 hours at 120 °C.
Aftercoolingdownthereactionwasfilteredandtheprecipitate
Conclusion was washed with cold dichloromethane, followed by cold
ethanol. The white product was left to dry overnight. (Yield:
The kinetic studies add on to the growing body of work on 8.61g;90%)IR(KBr,cm
−1):ν
=1996,1846.
co
these complexes wherein it was found that complexes with Synthesis of fac-[NEt ] [Re(CO) (H O) ] (2). ReAA (100 mg;
42 3 2 3
bidentateligandslikeFlavandTrophavehighersecondorder 0.129 mmol) was dissolved in water (10 ml) at pH 2.2. AgNO
3
rate constants in general and that the mechanism of substi- (66.4 mg; 0.387 mmol) was added to the solution and it was
tution is probably dissociative in nature. Furthermore, higher stirred at room temperature for 24 hours. AgBr (precipitate)
stabilityconstantswerefoundfortheFlavandTropcomplexes wasfilteredoffandweighed(73.2mg).Bidentateligandswere
coordinatedtoaphosphineligandinthesixthposition. addedtothefac-[NEt ] [Re(CO) (H O) ]filtrate.
42 3 2 3
Only fac-[Re(CO) (QuinH)(PTA)], fac-[Re(CO) (Trop)(PTA)], Synthesis of fac-[Re(CO) (Quin)(H O)] (3). 8-Hydroxy-
3 3 3 2
fac-[Re(CO) (Trop)(PPh )] and fac-[Re(CO) (Flav)(PPh )] com- quinoline (18.7 mg; 0.129 mmol) was added to the filtrate
3 3 3 3
plexes were used for biological studies due to solubility. and it was stirred at room temperature for 36 hours. The
Compelling IC results were obtained for fac-[Re(CO) (Trop) solution was yellow and a bright yellow precipitate, fac-
50 3
(PPh )] and fac-[Re(CO) (Flav)(PPh )]. These compounds dis- [Re(CO) (Quin)(H O)],wasfilteredoff,driedandweighed.(Yield=
3 3 3 3 2
played the highest cytotoxicity of the series of compounds in 45.2mg;81%)IR(KBr,cm −1):ν =2021,1887.UV/Vis:λ =
co max
tested HeLa cells. Very interestingly, they had a smaller effect 265nm,ε=4000M −1cm −1.1HNMR(300MHz,methanol-d4):
on non-cancerous cells, showing selectivity against malignant δ = 8.90 (dd, 1H, J = 1.2 Hz, 7.8 Hz), 8.63 (dd, 1H, J = 1.4 Hz,
cellline.Thedatapoolistoosmalltoeffectivelyrelatekinetic 7.6 Hz), 7.85 (d, 1H, J = 7.4 Hz), 7.61 (d, 1H, J = 8.5 Hz), 7.58
datatocytotoxicityvalues,butitisinterestingtonotethatthe (d,1H,J=7.4Hz),7.12(d,1H,J=1.2Hz,8.4Hz),1.8(s,2H).
FlavandTropphosphinecomplexesweremorestablethanthe 13C NMR (300 MHz, methanol-d4): δ = 161.2, 160.5, 159.3,
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143.2,135.1,128.2,125.3,122.6,120.4.Anal.calc.C,33.33,H, tate, fac-[Re(CO) (QuinH)(CH OH)], was dried and weighed.
3 3
1.86,N,3.24.Found:C,33.17,H,1.87N,3.26%. (Yield=24.4mg;78%)IR(KBr,cm
−1):ν
=2044,2008UV/Vis:
co
Synthesis of fac-[Re(CO) (diCl-Quin)(H O)] (4). 5,7-Dichloro- λ =367nm,ε=3650M −1cm −1.1HNMR(300MHz,metha-
3 2 max
8-hydroxyquinoline (27.6 mg; 0.129 mmol) was added to the nol-d4):δ=11.32(s,1H),9.87(s,1H),8.82(d,1H,J=4.6Hz),
filtrate and it was stirred at room temperature for 36 hours. 7.82–7.85 (m, 3H), 3.62 (s, 1H), 3.45 (d, 2H, J = 6.2 Hz). 13C
The solution was yellow and a light yellow precipitate, fac-[Re NMR (300 MHz, methanol-d4): δ = 175.3, 168.2, 147.8, 142.3,
(CO) (diCl-Quin)(H O)], was filtered off, dried and weighed. 140.9, 135.7, 133.2, 128.1, 125.5, 116.7, 45.2. Anal. calc. C,
3 2
(Yield = 57.4 mg; 88%) IR (KBr, cm −1): ν = 2025, 1875. UV/ 34.68,H,2.13,N,2.70.Found:C,34.52,H,2.14,N,2.74%.
co
Vis: λ = 279 nm, ε = 4100 M −1 cm −1. 1H NMR (300 MHz, Synthesis of fac-[Re(CO) (Trop)(CH OH)] (9). fac-[Re
max 3 3
methanol-d4):δ=9.72(dd,1H,J=1.7Hz.8.2Hz),9.65(d,1H, (CO) (Trop)(H O)] (50 mg; 0.122 mmol) was dissolved in
3 2
J=5.4 Hz),8.64(t,1H,J=3.2Hz,4.6 Hz),8.23(s,1H), 3.2(s, methanol (4 ml) and stirred at room temperature for 6 hours.
1H).13CNMR(300MHz,methanol-d4):δ=154.7,151.2,148.7, Thesolventwasevaporatedfromthesolution.Ayellowprecipi-
136.8,134.3,132.8,131.0,125.4,122.8.Anal.calc.C,28.75,H, tate, fac-[Re(CO) (Trop)(CH OH)], was dried and weighed.
3 3
1.21,N,2.79.Found:C,28.91,H,1.19,N,2.80%. (Yield = 49.6 mg, 94%) IR (KBr, cm −1): ν = 2034, 1877. UV/
co
Synthesis of fac-[Re(CO) (QuinH)(H O)]·H O (5). Quinoline- Vis: λ = 345 nm, ε = 3100 M −1 cm −1. 1H NMR (300 MHz,
3 2 2 max
2,4-dicarboxylic acid (28.3 mg; 0.129 mmol) was added to the methanol-d4):δ=7.21(dt,2H,J=1.5Hz,8.2Hz),6.87(dt,2H,
filtrate and it was stirred at room temperature for 36 hours. J=1.4Hz,5.5Hz),5.26(q,1H,J=8.2Hz),3.25(d,1H,J=5.2
The solution was orange and a bright orange precipitate, fac- Hz), 3.14 (d, 2H, J = 4.8 Hz). 13C NMR (300 MHz, methanol-
[Re(CO) (QuinH)(H O)], was filtered off, dried and weighed. d4):δ=185.7,132.3,132.1,128.6,126.3,110.9,50.1.Anal.calc.
3 2
(Yield=60.7mg;92%)IR(KBr,cm
−1):ν
=2023,1994UV/Vis: C,31.20,H,2.14.Found:C,31.05,H,2.16%.
co
λ =362nm,ε=3675M −1cm −1.1HNMR(300MHz,metha- Synthesis of fac-[Re(CO) (Flav)(CH OH)] (10). fac-[Re
max 3 3
nol-d4):δ=10.98(s,1H),8.54(s,1H),8.32(d,1H,J=5.4Hz), (CO) (Flav)(H O)](45mg;0.086mmol)wasdissolvedinmetha-
3 2
7.84–7.87(m,3H),2.21(s,2H).13CNMR(300MHz,methanol- nol (3 ml) and stirred at room temperature for 6 hours. The
d4): δ = 174.5, 168.9, 145.2, 141.6, 133.4, 131.2, 130.9, 128.7, solventwasevaporatedfromthesolution.Ayellowprecipitate,
125.1, 117.3. Anal. calc. C, 32.19, H, 1.93, N, 2.68. Found: C, fac-[Re(CO) (Flav)(CH OH)], was dried and weighed. (Yield = 3 3
32.15,H,1.92,N,2.66%. 44.5mg;95%)IR(KBr,cm −1):ν =2003,1978.UV/Vis:λ =
co max
Synthesis of fac-[Re(CO) (Trop)(H O)] (6). Tropolone 325nm,ε=4255M −1cm −1.1HNMR(300MHz,methanol-d4):
3 2
(47.5 mg; 0.389 mmol) was added to the filtrate and it was δ=8.21(dd,2H,J=1.2Hz,4.4Hz),7.73–7.75(m,2H),7.71(t,
stirred at room temperature for 36 hours. The solution was 1H, J = 7.4 Hz), 7.59 (d, 1H, J = 8.2 Hz), 7.48 (dd, 1H, J = 1.4
yellow and a bright yellow precipitate, fac-[Re(CO) (Trop) Hz, 9.2 Hz), 7.33 (d, 1H, J = 5.8 Hz), 7.05 (d, 1H, J = 6.2 Hz),
3
(H O)], was filtered off, dried and weighed. (Yield = 148 mg; 4.32(s, 1H), 3.44(s, 1H),3.18 (d, 2H,J=6.4 Hz),2.53(s, 1H).
2 93%)IR (KBr,cm −1):ν =2021, 1869. UV/Vis:λ = 343nm, 13C NMR (300 MHz, methanol-d4): δ = 158.2, 156.9, 152.3,
co max
ε=3120M −1cm −1.1HNMR(300MHz,methanol-d4):δ=6.44 143.2, 137.6, 135.1, 132.8, 129.8, 128.1, 127.6, 126.7, 122.5,
(dt, 2H, J = 1.8 Hz, 8.5 Hz), 6.21 (dt, 2H, J = 1.4 Hz, 5.8 Hz), 121.8, 119.7, 45.7. Anal. calc. C, 42.30, H, 2.43. Found: C,
5.45 (q, 1H, J = 7.6 Hz), 3.87 (d, 1H, J = 4.8 Hz), 1.82 (s, 1H). 42.51,H,2.41%.
13C NMR (300 MHz, methanol-d4): δ = 188.3, 134.4, 134.2, Synthesis of fac-[Re(CO) (Quin)(PPh )] (11). fac-[Re
3 3
128.2, 127.8, 113.7, 82.8. Anal. calc. C, 29.34, H, 1.72. Found: (CO) (Quin)(H O)] (10 mg; 0.023 mmol) was dissolved in
3 2
C,29.17,H,1.71%. methanol (2 ml). PPh (6.32 mg; 0.0231 mmol) was dissolved
3
Synthesis of fac-[Re(CO) (Flav)(H O)] (7). 3-Hydroxyflavone in methanol (2 ml) separately and the two solutions were
3 2
(31.3 mg; 0.129 mmol) was added to the filtrate and it was added together. The mixture was stirred at room temperature
stirred at room temperature for 36 hours. The solution was for 6 hours. The solution was left to crystalize. Brown crystals
yellow and a light yellow precipitate, fac-[Re(CO) (Flav)(H O)], wereobtainedandsuitableforcollectionontheX-raydiffract-
3 2
was filtered off, dried and weighed. (Yield = 60.3 mg; 88%) IR ometer. (Yield = 13.5 mg; 88%) IR (KBr, cm −1): ν = 2015,
co
(KBr,cm −1):ν =1998,1943.UV/Vis:λ =320nm,ε=4280 1911, 1886. UV/Vis: λ = 435 nm, ε = 3560 M −1 cm −1. 31P
co max max
M −1cm −1.1HNMR(300MHz,methanol-d4):δ=8.33(dd,2H, NMR (400 MHz, toluene-d8): δ = 29 Hz. 1H NMR (300 MHz,
J = 1.2 Hz, 4.4 Hz), 7.95–7.98 (m, 2H), 7.82 (t, 1H, J = 7.4 Hz), methanol-d4):δ=9.22(dd,1H,J=1.2,7.1Hz);8.56(d,1H,J=
7.63 (d, 1H, J = 8.2 Hz), 7.29 (dd, 1H, J = 1.4 Hz, 9.2 Hz), 7.21 4.2Hz),8.15(m,9H,PPh ),7.97(m,6H,PPh ),7.72(tt,1H,J=
3 3
(d,1H,J=5.8Hz),7.10(d,1H,J=6.2Hz),4.98(s,1H),3.21(s, 1.5,7.2Hz),7.64(dd,2H,J=1.7,6.4Hz).13CNMR(300MHz,
1H).13CNMR(300MHz,methanol-d4):δ=155.2,151.7,142.5, methanol-d4): δ = 165.4, 152.7, 138.2, 136.6, 135.8, 128.1,
139.8, 135.3, 134.2, 132.9, 131.5, 129.8, 127.3, 126.8, 124.4, 127.2, 126.8, 124.4, 121.7, 119.6. Anal. calc. C, 53.25, H, 3.13,
121.6, 118.1, 72.3. Anal. calc. C, 41.14, H, 2.11. Found: C, N,2.07,P,4.58.Found:C,52.99,H,3.15,N,2.09,P,4.55%.
40.90,H,2.12%. Synthesis of fac-[Re(CO) (diCl-Quin)(PPh )] (12). fac-[Re
3 3
Synthesis of fac-[Re(CO) (QuinH)(CH OH)] (8). fac-[Re (CO) (diCl-Quin)(H O)] (40 mg; 0.079 mmol) was dissolved in
3 3 3 2
(CO) (QuinH)(H O)] (30 mg; 0.059 mmol) was dissolved in methanol(2ml).PPh (21.2mg;0.079mmol)wasdissolvedin
3 2 3
methanol (3 ml) and stirred at room temperature for 6 hours. methanol (2 ml) separately and the two solutions were added
Thesolventwasevaporatedfromthesolution.Ayellowprecipi- together. The mixture was stirred at room temperature for
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6hours.Thesolutionwaslefttocrystalize.Browncrystalswere (300 MHz, methanol-d4): δ = 184.7, 136.1, 135.8, 126.3, 124.7,
obtainedandweresuitableforcollectionontheX-raydiffract- 118.6, 80.5, 33.2, 26.9, 19.8. Anal. calc. C, 49.99, H, 5.84, P,
ometer. (Yield = 48.6 mg; 82%) IR (KBr, cm −1): ν = 2019, 4.60.Found:C,49.92,H,5.81,4.63%.
co
1925, 1873. UV/Vis: λ = 453 nm, ε = 4125 M −1 cm −1. 31P Synthesis of fac-[Re(CO) (Flav)(PPh )] (16). fac-[Re(CO) (Flav)
max 3 3 3
NMR (400 MHz, toluene-d8): δ = 32 Hz. 1H NMR (300 MHz, (H O)] (10 mg; 0.019 mmol) was dissolved in methanol (2 ml).
2
methanol-d4):δ=8.72(dd,1H,J=3.2,4.8Hz),8.54(d,1H,J= PPh (5.31 mg; 0.019 mmol) was dissolved in methanol (2 ml)
3
1.2 Hz), 7.92 (m, 9H, PPh ), 7.54 (s, 1H), 7.36 (m, 6H, PPh ). separately and the two solutions were added together. The
3 3
13C NMR (300 MHz, methanol-d4): δ = 154.7, 152.3, 149.8, mixturewasstirredat roomtemperature for6 hours.Thesolu-
140.7,135.6,133.2,132.9,128.6,124.1,118.7,116.3.Anal.calc. tion was left to crystalize. Yellow, thin, needle-like crystals,
C,48.33,H,2.57,N,1.88,P,4.15.Found:C,48.24,H,2.54,N, not suitable for X-ray diffractometry were obtained. (Yield =
1.89,P,4.13%. 14.2 mg; 78%) IR (KBr, cm −1): ν = 1998, 1975, 1862. UV/Vis:
co
Synthesis of fac-[Re(CO) (Trop)(PPh )] (13). fac-[Re λ =422nm,ε=4425M −1cm −1.31PNMR(400MHz,toluene-
3 3 max
(CO) (Trop)(H O)] (10 mg; 0.024 mmol) was dissolved in d8): δ = 23Hz.1H NMR(300MHz, methanol-d4): δ = 8.42(dd,
3 2
methanol(2ml).PPh (6.32mg;0.024mmol)wasdissolvedin 2H, J = 1.5 Hz, 5.4 Hz), 7.86 (m, 2H), 7.72 (t, 1H, J = 7.2 Hz),
3
methanol (2 ml) separately and the two solutions were added 7.68 (d, 1H, J = 7.2 Hz), 7.35 (m, 15H, PPh ), 7.16 (dd, 1H, J =
3
together. The mixture was stirred at room temperature for 1.8Hz,8.4Hz),7.13(d,1H,J=7.4Hz),7.06(d,1H,J=5.4Hz),
6 hours. The solution was left to crystalize. The crystals 4.76(s,1H).13CNMR(300MHz,methanol-d4):δ=157.4,153.8,
obtained were not suitable forcollection on the X-ray diffract- 141.7, 137.6, 137.4, 136.1, 134.0, 132.8, 132.2, 131.8, 129.7,
ometer. (Yield = 13.2 mg; 83%) IR (KBr, cm −1): ν = 2010, 128.3, 126.7, 126.4, 124.9, 122.1, 113.6, 70.6. Anal. calc. C,
co
1934, 1887. UV/Vis: λ = 344 nm, ε = 3980 M −1 cm −1. 31P 56.17,H,3.14,P,4.02.Found:C,56.24,H,3.16,P,3.99%.
max
NMR (400 MHz, toluene-d8): δ = 27 Hz. 1H NMR (300 MHz, Synthesis of fac-[Re(CO) (Flav)(PTA)] (17). fac-[Re(CO) (Flav)
3 3
methanol-d4):δ=7.76(m,9H,PPh ),7.36(m,6H,PPh ),6.23 (H O)](20mg;0.038mmol)wasdissolvedinmethanol(2ml).
3 3 2
(dt, 2H, J = 1.4 Hz, 7.3 Hz), 5.84 (dt, 2H, J = 1.7 Hz, 5.4 Hz), PTA (5.97 mg; 0.038 mmol) was dissolved in methanol (2 ml)
5.31 (q, 1H, J = 5.4 Hz), 5.12 (d, 1H, J = 5.3 Hz). 13C NMR separately and the two solutions were added together. The
(300 MHz, methanol-d4): δ = 184.7, 137.8, 136.5, 136.3, 135.4, mixture was stirred at room temperature for 6 hours. The
129.8,128.5,128.2,115.9,98.3.Anal.calc.C,51.45,H,3.08,P, product precipitated out and was recrystallized in methanol.
4.74.Found:C,50.97,H,3.11,P,4.76%. Thesolutionwaslefttocrystalize.Theyellowcrystalsobtained
Synthesisoffac-[Re(CO) (Trop)(PTA)](14).fac-[Re(CO) (Trop) were not suitable for collection on the X-ray diffractometer.
3 3
(H O)](20mg;0.049mmol)wasdissolvedinmethanol(2ml). (Yield = 20.7 mg; 82%) IR (KBr, cm −1): ν = 2019, 1943. UV/
2 co
PTA (7.66 mg; 0.049 mmol) was dissolved in methanol (2 ml) Vis: λ = 415 nm, ε = 4532 M −1 cm −1. 31P NMR (400 MHz,
max
separately and the two solutions were added together. The toluene-d8):δ=−55Hz.1HNMR(300MHz,methanol-d4):δ=
mixturewasstirredatroomtemperaturefor6hours.Thesolu- 8.26 (dd, 2H, J = 1.8 Hz, 6.2 Hz), 7.85 (m, 2H), 7.82 (t, 1H, J =
tion was left to crystalize. The orange crystals obtained were 7.5 Hz), 7.73 (d, 1H, J = 5.2 Hz), 7.27 (dd, 1H, J = 1.5 Hz, 8.5
notsuitableforcollectionontheX-raydiffractometer.(Yield= Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.18 (d, 1H, J = 5.4 Hz), 4.67 (s,
23.6mg;88%)IR(KBr,cm −1):ν =1982,1906.UV/Vis:λ = 1H), 4.21 (s, 6H, PTA), 2.66 (d, 6H, PTA, J = 5.3 Hz). 13C NMR
co max
354 nm, ε = 4145 M −1 cm −1. 31P NMR (400 MHz, toluene-d8): (300 MHz, methanol-d4): δ = 157.2, 154.6, 147.3, 138.1, 134.8,
δ=−60Hz.1HNMR(300MHz,methanol-d4):δ=6.11(dt,2H, 133.6, 132.3, 130.9, 128.5, 126.1, 125.7, 122.9, 120.6, 116.5,
J=1.2Hz,6.4Hz),5.89(dt,2H,J=1.8Hz,7.4Hz),5.36(q,1H, 78.8, 89.3, 51.6. Anal. calc. C, 43.31, H, 3.33, N, 6.31, P, 4.65.
J = 5.5 Hz), 4.28 (d, 1H, J = 1.8 Hz), 3.21 (s, 6H, PTA), 2.46 (d, Found:C,43.29,H,3.35,N,6.29,P,4.64%.
6H, PTA, J = 3.8 Hz). 13C NMR (300 MHz, methanol-d4): δ = Synthesisof fac-[Re(CO) (Flav)(PCy )] (18).fac-[Re(CO) (Flav)
3 3 3
186.3, 136.2, 133.1, 129.8, 125.9, 117.3, 93.4, 74.6, 52.8. Anal. (H O)](20mg;0.038mmol)wasdissolvedinmethanol(2ml).
2
calc. C, 34.97, H, 3.30, N, 7.65, P, 5.64. Found: C, 35.07, H, PCy (10.7 mg;0.038mmol)wasdissolvedinmethanol(2 ml)
3
3.28,N,7.60,P,5.62%. separately and the two solutions were added together. The
Synthesis of fac-[Re(CO) (Trop)(PCy )] (15). fac-[Re mixture was stirred at room temperature for 6 hours. The
3 3
(CO) (Trop)(H O)] (30 mg; 0.073 mmol) was dissolved in yellow product precipitated out of solution and was filtered,
3 2
methanol(2ml).PCy (20.2mg;0.073mmol)wasdissolvedin driedandweighed.(Yield=30.2mg;71%)IR(KBr,cm
−1):ν
3 co
methanol (2 ml) separately and the two solutions were added = 2004, 1982. UV/Vis: λ = 456 nm, ε = 5530 M −1 cm −1. 31P
max
together. The mixture was stirred at room temperature for NMR (400 MHz, toluene-d8): δ = 57 Hz. 1H NMR (300 MHz,
6 hours. The solution was left to crystalize. The crystals methanol-d4): δ = 8.43 (dd, 2H, J = 2.1 Hz, 5.7 Hz), 7.98 (m,
obtained were not suitable forcollection on the X-ray diffract- 2H), 7.84 (t, 1H, J = 6.5 Hz), 7.72 (d, 1H, J = 7.3 Hz), 7.48 (dd,
ometer. (Yield = 40.3 mg; 82%) IR (KBr, cm −1): ν = 2011, 1H,J=1.8Hz,8.5Hz),7.26(d,1H,J=6.4Hz),7.18(d,1H,J=
co
1964, 1856. UV/Vis: λ = 362 nm, ε = 5130 M −1 cm −1. 31P 6.8Hz),5.18(s,1H),1.67(m,18H,PCy ),1.52(m,12H,PCy ).
max 3 3
NMR (400 MHz, toluene-d8): δ = 68 Hz. 1H NMR (300 MHz, 13C NMR (300 MHz, methanol-d4): δ = 154.8, 152.6, 141.2,
methanol-d4):δ=6.78(dt,2H,J=2.4Hz,7.2Hz),6.43(dt,2H, 137.7, 134.6, 134.1, 131.3, 130.5, 128.5, 127.4, 126.1, 122.8,
J=1.2Hz,6.8Hz),5.22(q,1H,J=6.8Hz),4.68(d,1H,J=1.5 121.9,116.5,78.5,32.4,29.6,27.1,22.7.Anal.calc.C,54.88,H,
Hz), 1.66 (m, 18H, PCy ), 1.48 (m, 12H, PCy ). 13C NMR 5.37,P,3.93.Found:C,54.74,H,5.34,P,3.96%.
3 3
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Synthesis of fac-[Re(CO) (QuinH)(PTA)] (19). fac-[Re(CO) Julabo F-12 temperature cell regulator (accuratewithin 0.1 °C)
3 3
(QuinH)(H O)](20mg;0.039mmol)wasdissolvedinmethanol was used for the kineticmeasurements. All the kineticexperi-
2
(2 ml). PTA (6.23 mg; 0.039 mmol) was dissolved in methanol mentsweredoneunderpseudofirst-orderconditions,withthe
(2 ml) separately and the two solutions were added together. ligandinexcess.ScientistMicomath,Version2.01983wasused
The mixture was stirred at room temperature for 6 hours. The tofitthedatatoselectedfunctions.Thecomputerleastsquare
solution was left to crystalize. The orange product precipitated fits of data is represented by the solid lines in the figures,
out of solution and was filtered, dried and weighed. (Yield = while the individual points representthe experimental values,
23.2 mg; 89%) IR (KBr, cm −1): ν = 2046, 1974. UV/Vis: λ = denotedbyselectedsymbols.
co max
442nm,ε=3870M −1cm −1.31PNMR(400MHz,toluene-d8):δ
= −67 Hz. 1H NMR (300MHz, methanol-d4): δ = 10.12 (s, 1H), Celllinesandcellculture
8.63 (s, 1H), 8.55 (d, 1H, J = 7.3 Hz), 7.72 (m, 3H), 3.27 (s, 6H TheHeLa(Homosapienscervixadenocarcinoma)celllinewas
(PTA)),2.58(d,6H,PTA,J=5.6Hz).13CNMR(300MHz,metha- cultured in DMEM (Gibco, Life Technologies, USA) sup-
nol-d4):δ=178.6,169.4,147.1,145.5,131.2,130.6,129.8,125.3, plementedwith10%offetalcalfserum(Gibco).RPE-1(Homo
123.8,114.9,86.4,41.2.Anal.calc.C,37.33,H,2.80,N,8.71,P, sapiens retinal pigmented epithelial) cell line was cultured in
4.81.Found:C,37.28,H,2.81,N,8.68,P,4.79%. DMEM/F-12 (Gibco) supplemented with 10% of fetal calf
Synthesis of fac-[Re(CO) (Trop)(PPh ) ]·2C H (20). fac- serum. Both cell lines were complemented with 100 U ml −1 2 32 7 8
[Re(CO) (Trop)(PPh )] (10 mg; 0.015 mmol) was dissolved in penicillin–streptomycin mixture (Gibco), and maintained in
3 3
toluene (2 ml). An excess of PPh (24.6 mg; 0.092 mmol) was humidifiedatmosphereat37°Cand5%ofCO .
3 2
dissolved in toluene (2 ml) separately and the two solutions
Cytotoxicity
were added together. The mixture was heated to 80 °C, whilst
stirred for 24 hours. The solvent was evaporated, orange crys- Cytotoxicity was assessed by fluorometric cell viability assay
tals, suitable for X-ray diffractometry were obtained. (Yield = using resazurin (ACROS Organics). HeLa and RPE-1 cells were
8.38mg;72%)IR(KBr,cm −1):ν =1919,1832.UV/Vis:λ = seededintriplicatesin96wellplatesatadensityof4000cells
co max
312 nm, ε = 6945 M −1 cm −1. 31P NMR (400 MHz, toluene-d8): per well in 100 µl, 24 h prior to treatment. Cells were then
δ = 26, −7 Hz. 1H NMR (300 MHz, methanol-d4): δ = 7.79 (m, treated with increasing concentration of compounds for 48 h.
12H, PPh ), 7.38 (m, 12H, PPh ), 7.10 (m, 10H, toluene), 6.45 After that time medium was replaced by fresh complete
3 3
(dt, 2H, J = 1.6 Hz, 7.5 Hz), 5.63 (dt, 2H, J = 1.5 Hz, 5.5 Hz), medium containing resazurin (0.2 mg ml −1 final concen-
5.22 (q, 1H, J = 5.2 Hz), 5.08 (d, 1H, J = 5.4 Hz), 2.44 (s, 6H, tration). After 4 h incubation at 37 °C, fluorescence signal of
toluene). 13C NMR (300 MHz, methanol-d4): δ = 185.3, 138.2, resorufin product was read by SpectraMax M5 microplate
137.3, 137.1, 134.5, 129.6, 128.9, 128.7, 128.2, 127.5, 124.6, reader (ex: 540 nm em: 590 nm). IC values were calculated
50
117.8, 95.2, 25.4. Anal. calc. C, 57.09, H, 4.14, P, 4.99. Found: usingGraphPadPrismsoftware.
C,57.02,H,4.18,P,5.02%.
X-raydatacollectionandrefinement Conflicts of interest
The reflection data used to determine the structures reported
here were collected on a Bruker X8 Apex II 4K diffractometer, Therearenoconflictstodeclare.
using graphite monochromated Mo-Kα radiation (with wave-
lengthλ=0.71073Å)andwithω-andφ-scansatatemperature
Acknowledgements
of100K. SAINT-Plus77 wasusedto doall thecellrefinements
and the data reduction was done with SAINT-Plus and
The authors thank the University of the Free State Research
XPREP.77 The multi-scan technique and software package
Fund (H. G. V.), the South African NRF (H. G. V.) and
SADABS78 was used to correct the absorption effects. The
the ERC (Consolidator Grant PhotoMedMet GA 681679
crystal structure was solved using the SIR-9779 package and
to G. G.). This work has received support under the
refined with WinGX80 and SHELXL-97.81 The graphical rep- program “Investissements d’ Avenir” launched by the French
resentations of the crystal structures were obtained using the
Government and implemented by the ANR with the reference
program DIAMOND.82 Unless otherwise stated, all the struc-
ANR-10-IDEX-0001-02PSL(G.G.).
tures are shown with thermal ellipsoids drawn at 50% prob-
ability level. All non-hydrogen atoms are refined anisotropi-
cally. Aromatic and hydroxyl hydrogen atoms were placed in References
geometricallyidealizedpositions(C–H=0.93andO–H=0.85)
and constrained to ride on their parent atoms (U (H) = 1 E. B. Bauer, A. A. Haase, R. M. Reich, D. C. Crans and
iso
1.5U (C)and1.5U (O)). F.E.Kühn,Coord.Chem.Rev.,2019,393,79.
eq eq
2 A.A.Haase,E.B.Bauer,F.E.KühnandD.C.Crans,Coord.
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Chem.Rev.,2019,394,135.
All reagents and chemicals were of analytical grade. AVarian 3 R.Alberto,R.SchibliandP.A.Schubiger,Polyhedron,1996,
Cary 50 Conc UV-Visible spectrophotometer equipped with a 15,1079.
44 | DaltonTrans.,2020,49,35–46 Thisjournalis©TheRoyalSocietyofChemistry2020
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