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Synthesis of Camphor-Derived Bis(pyrazolylpyridine) Rhodium(III) Complexes: Structure-Reactivity Relationships and Biological Activity.
Article
CiteThis:Inorg.Chem.2019,58,307−319 pubs.acs.org/IC
Synthesis of Camphor-Derived Bis(pyrazolylpyridine) Rhodium(III)
−
Complexes: Structure Reactivity Relationships and Biological
Activity
Angelina Petrovic,
́†
Milan M. Milutinovic,
́†,∇
Edward T. Petri,
#
Marko Z
̌
ivanovic,
́†
Nevena Milivojevic,
́†
Ralph Puchta,
‡,§,∥
Andreas Scheurer,
‡
Jana Korzekwa,
‡
Olivera R. Klisuric,
́⊥
and Jovana Bogojeski
*,†
† ́
Faculty of Science, University of Kragujevac, Radoja Domanovica 12, 34000 Kragujevac, Serbia
‡ §
Inorganic Chemistry, Department of Chemistry and Pharmacy, Computer Chemistry Center, Department of Chemistry and
Pharmacy, and ∥ Zentralinstitut für Scientific Computing, University of Erlangen-Nürnberg, 91058 Erlangen, Germany
⊥ #
Faculty of Science, Department of Physics and Faculty of Science, Department of Biology and Ecology, University of Novi Sad,
́
Trg Dositeja Obradovica 4, 21000 Novi Sad, Serbia
∇
Department of Organic Chemistry, University of Paderborn, Warburgerstraße 100, 33098 Paderborn, Germany
*
S Supporting Information
ABSTRACT: Two novel rhodium(III) complexes, namely, [RhIII(X)Cl ] (X = 2 2,6-bis((4S,7R)-
3
7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine or 2,6-bis((4S,7R)-1,7,8,8-tet-
ramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine), were synthesized from camphor
derivatives ofabis(pyrazolylpyridine),tridentatenitrogen-donorchelatesystem,giving[RhIII(H L*)-
2
Cl ] (1a) and [RhIII(Me L*)Cl ] (1b). A rhodium(III) terpyridine (terpy) ligand complex,
3 2 3
[RhIII(terpy)Cl ] (1c), was also synthesized. By single-crystal X-ray analysis, 1b crystallizes in an
3
orthorhombicP2 2 2 system,withtwomoleculesintheasymmetricunit.Tridentatecoordinationby
1 1 1
theN,N,N-donorlocalizesthecentralnitrogenatomclosetotherhodium(III)center.Compounds1a
and 1b were reactive toward L-methionine (L-Met), guanosine-5′-monophosphate (5′-GMP), and
glutathione(GSH),withanorderofreactivityof5′-GMP>GSH>L-Met.Theorderofreactivityof
theRhIIIcomplexeswas:1b>1a>1c.TheRhIIIcomplexesshowedaffinityforcalfthymusDNAand
bovineserumalbuminbyUV−visandemissionspectralstudies.Furthermore,1bshowedsignificantin
vitro cytotoxicity against human epithelial colorectal carcinoma cells. Since the RhIII complexes have
similar coordination modes, stability differences were evaluated by density functional theory (DFT)
calculations (B3LYP(CPCM)/LANL2DZp). With (H L*) and (terpy) as model ligands, DFT calculations suggest that both
2
tridentateligandsystemshavesimilarstability.Inaddition,moleculardockingsuggeststhatalltestcompoundshaveaffinityfor
the minor groove of DNA, while 1b and 1c have potential for DNA intercalation.
■
INTRODUCTION Transition-metal complexes have been synthesized with
pyridine-containing tridentate triamine ligands, for use in
Transition-metal complexes have a range of applications in
supramolecular chemistry,1 catalytic chemistry,2 and as catalytic reactions or as potential antitumor agents, etc.
medicinal agents.3 In chemical biology, transition-metal Tridentate triamine ligands have advantages, including ready
complexes were investigated as
inhibitors,4−9
imaging
availability, relatively low cost, and low toxicity.28 Various
agents,10−12 biological probes,13,14 or catalysts with unique metal complexes with camphor-based pyridine ligands have
also been used for asymmetric catalytsis29 and tested for
properties. Over the last century, platinum-based complexes
havebeenusedasanticancer drugs.15,16 However, sideeffects, biomolecular interactions or antitumor
activity.30−33
such as cell-acquired resistance and high toxicity,17 have Previously, we synthesizeda RhIIIcomplex with a tridentate
prompted investigation of other metal complexes.18,19 Despite nitrogen-donor pincer-type ligand that displayed promising
their variable oxidation states, the anticancer properties of properties and biomolecular reactivity.20 Thus, we sought to
rhodium complexes have not been extensively explored.20,21 expand our investigation of RhIII complexes to pincer-type
However, kinetically inert transition-metal complexes could ligands with diverse substituent patterns on the pyrazolyl
serve as scaffolds for pharmacological agents due to their moiety,creatingdifferencesinspaceconfigurationandelectron
inertness, stability, unique geometries, and structural diver- density distribution that could influence biomolecular
sity.22 Recently, such metal complexes were shown to have interaction potential or cytotoxicity.
affinity both for DNA, their primary target, as well as various
proteins,23−27
suggesting potential use in the design of Received: August24, 2018
anticancer agents. Published: December19,2018
©2018AmericanChemicalSociety 307 DOI:10.1021/acs.inorgchem.8b02390
Inorg.Chem.2019,58,307−319
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Inorganic Chemistry Article
Therefore, in the present study we designed two new RhIII Synthesis and Characterization of [RhIII(H L*)Cl ] (1a) and
complexes ([RhIII(H 2 L*)Cl 3 ] and [RhIII(Me 2 L*)Cl 3 ]), where [RhIII(Me 2 L*)Cl 3 ] (1b). In general, a solution of 2 H 2 L*3 or Me 2 L*
H L* and Me L* are camphor derivatives of a previously (0.380 mmol; 1 equiv) in 20 mL of ethanol was slowly added to a
2 2 solution of 100 mg (0.380 mmol) of RhCl·xHO in 60 mL of
introduced bis(pyrazolylpyridine) ligand (Figure 1). For 3 2
ethanol. The mixture was stirred and refluxed overnight, affording a
yellow precipitate that was filtered and dried under vacuum. The
resultingyellowsolidwaspurifiedbyrecrystallization.Crystallization
of 1b was induced by slow diffusion of n-hexane into a dichloro-
methane solution of the1b complex.
Synthesisof[RhIII(HL*)Cl](1a).HL*(162.5mg)yielded1aasa
2 3 2
yellow solid(196 mg; 0.31mmol;81%).
1HNMR(500MHz,CDCN):δ=8.1(t,J =7.8Hz,para-Ar−
3 HH
CH,1H),7.82(d,J =7.8Hz,meta-Ar−CH,2H),6.94(brs,NH,
HH
2H), 3.35 (d, J = 3.9 Hz, HCCHCH, 2H), 2.41−2.37 (m,
HH 2 2
HCCHCH,2H),2.10−2.04(m,HCCHCH,2H),1.65−1.48(m,
2 2 2 2
HCCHCH and HCCHCH, 4H), 1.38 (s, CCH, 6H), 1.08 (s,
2 2 2 2 3
C(CH),6H), 0.89(s,C(CH),6H) ppm.
3 2 3 2
13CNMR(126MHz,CDCN):δ=158.9(ortho-Ar-C,2C),146.0
3
(HN−CCC,2C),139.2(para-Ar−CH,1C),135.4(HN−CCC,2C),
127.0(meta-Ar−CH,2C),121.0(HN−CCC,2C),63.2(CCH,2C),
3
52.1 (C(CH), 2C), 50.5 (HCCHCH, 2C), 36.3 (HCCHCH,
3 2 2 2 2 2
2C), 29.8(HCCHCH, 2C),25.0 (C(CH), 2C),21.6 (C(CH),
2 2 3 2 3 2
2C),11.2(CCH,2C) ppm.
3
Anal. Calcd for (C H ClNRh) C: 50.92; H: 5.22; N: 11.00.
27 33 3 5
Found: C: 51.26;H:5.93; N:11.14%.
ESI-MS: [M-Cl]+: Calcd: 599.64.09;Found: 599.18.
Synthesisof[RhIII(Me L*)Cl](1b).MeL*(173.1mg)yielded1b
2 3 2
asa yellow solid(189.5 mg;0.28mmol, 75%).
1HNMR(500MHz,CDCN):δ=8.14(dd,J =8.5Hz,meta-
3 HH
Ar−CH, 2H), 7.82 (t, J = 8.5 Hz, para-Ar−CH, 1H), 4.38 (s,
HH
NCH,6H),3.33(d,J =3.8Hz,HCCHCH,2H),2.31−2.05(m,
3 HH 2 2
Figure 1.Structuresof the investigatedRhIII complexes. HCCHCH,2H),2.05−1.91(m,HCCHCH,2H),1.52−1.33(m,
2 2 2 2
HCCHCH and HCCHCH, 4H), 1.41 (s, CCH, 6H), 1.08 (s,
2 2 2 2 3
C(CH),6H), 0.78(s,C(CH), 6H)ppm.
3 2 3 2
13C NMR (126 MHz, CDCN): δ = 159.9 (CHN−CCC, 2C),
comparison, a RhIII terpyridine (terpy) complex was also 151.9(ortho-Ar-C,2C),143.8 3 (CHN−CCC,2C),1 3 40.1(para-Ar−
synthesized and examined. Substitution reactions with CH,1C),128.9(CHN−CCC,2C) 3 ,119.5(meta-Ar−CH,2C),63.6
3
biomolecules were studied, and biomolecular interaction (CCH, 2C), 53.7 (C(CH), 2C), 47.8 (HCCHCH, 2C), 38.5
3 3 2 2 2
potential with calf thymus DNA (CT-DNA) and bovine (NCH,2C),32.6(HCCHCH,2C),26.7(HCCHCH,2C),19.6
3 2 2 2 2
serum albumin (BSA) were measured. New compounds were (C(CH),2C),18.3(C(CH),2C),10.0(CCH, 2C)ppm.
3 2 3 2 3
testedforinvitrocytotoxicityusinga3-(4,5-dimethylthiazol-2- Anal. Calcd for (C H ClNRh) C: 52.39; H: 5.61; N: 10.53.
29 37 3 5
yl)-2,5-diphenyltetrazoliumbromide(MTT)assayandhuman Found: C: 52.26;H:5.53; N:10.01%.
epithelial colorectal carcinoma cells (HCT-116). density ESI-MS: [M-Cl]+: Calcd: 628.12; Found:628.14.
Instrumentation. NMR spectra were recorded on a 200 MHz
functional theory (DFT) calculations were conducted to
Varian Gemini-2000 and 500 MHz Bruker Avance spectrometer.
explorethesimilaritybetweenourbasicbis(pyrazolylpyridine)
NMRsignalswerereferencedtoresidualprotonorcarbonsignalsof
ligand system and the well-known terpyridine complex thedeuteratedsolvent(1Hand13CNMR)andarereportedinparts
a■nalogue.
per million relative to tetramethylsilane (TMS). Elemental analyses
(C, H,N) were performed by combustion and gas chromatographic
EXPERIMENTAL SECTION
analysis with an Elementar Vario MICRO elemental analyzer. pH
Chemicals and Solutions. Commercial chemicals were used measurementsweredoneusingaMettlerDelta350digitalpHmeter
without purification. L-Methionine (L-Met), glutathione (GSH), with resolution of ±0.01 mV and a combination glass electrode
guanosine-5′-monophosphate sodium salt (5′-GMP), 2,2′:6′,2″- calibratedusingstandardbuffersolutions(Sigma)atpH4,7,and9.
terpyridine (terpy), RhCl·xHO, N-2-hydroxyethylpiperazine-N′-2- UV−VisandkineticmeasurementswereconductedonaPerkinElmer
3 2
ethanesulfonicacid(HEPES), phosphate-buffered saline (PBS),CT- Lamda25and35double-beamspectrophotometerwiththermostated
DNA, ethidium bromide (EB), and BSA were from Sigma-Aldrich.
1.00cmquartzSuprasilcells.Temperaturewascontrolledto±0.1°C.
CT-DNAwasdissolvedintriple-distilleddeionizedwaterandstored Fluorescence was measured on an RF-1501 PC spectrofluorometer
at 4 °C for less than one week. The UV absorbance ratio (260 / (Shimadzu). Mass spectrometry was measured on a Waters
nm
280 )ofCT-DNAsolutionsinPBS(phosphate=0.01M,c(NaCl) QuadrupoleTOF Synapt2Gusing electrosprayionization (ESI).
nm
=0.137,c(KCl)=0.0027M,pH7.4)was1.8−1.9,indicatingalackof Solubility Measurements. The concentrations of saturated
protein contamination.34 Nucleophile stock solutions were freshy solutions of the studied RhIII complexes were determined by UV−
prepared before use. Dulbecco’s Modified Eagle Medium (DMEM) vis spectrometry. Therefore, the specific absorptivity of the
andPBSwereobtainedfromGIBCO,Invitrogen.Fetalbovineserum compounds in the water was determined first. This was measured
(FBS) and trypsin−ethylenediaminetetraacetic acid (EDTA) were using five dilution series (5, 10, 30, 40, 50 mM) of the studied
from PAA (The Cell Culture Company). Dimethyl sulfoxide complexes, and then the calibration curve was calculated using
(DMSO) and MTT were from SERVA. Doubly distilled deionized Lambert−Beerlaw.Theslopeofthecurvegavespecificabsorptivity.
waterwasusedforallexperiments.PreparationsofHL*andMeL* The required quantity of water solution was added to the 5 mL
2 2
ligands were according to published procedures.35 [Rh(terpy)Cl] volumetric flask. The solution was heated to 298 K. A previously
3
(1c) was prepared as published and characterized by standard weighedquantityofRhIIIcomplexwasaddedtothevolumetricflask,
analyticalmethods.36 untilthesaturationpointoccurred.Stirringwascontinuedupto7hat
308 DOI:10.1021/acs.inorgchem.8b02390
Inorg.Chem.2019,58,307−319
Inorganic Chemistry Article
298K.Thesamplewasfilteredthrough0.20μmmembranefilter.A observedflowtimeofDNA-containingsolutions(t)correctedforthe
measured quantity of filtered sample was transferred into another flow timeof bufferalone(t),η =(t− t)/t.
0 0 0
volumetric flask and made further dilutions. The absorbance was Protein Binding Studies. Protein fluorescence is due to natural
measured using UV−vis spectrophotometry. The same process was fluorophores such as tryptophan, tyrosine, and phenylalanine.
repeatedtwotimes. Changes in BSA fluorescence were used to monitor interaction with
KineticMeasurements.Thehydrolysisofcomplexes1a,1b,and metal complexes. Tryptophan fluorescence quenching experiments
1cwasstudiedbyUV−visspectrometryat298K.Thesamples(0.10 wereconductedusing2.0μMBSAinPBS.Quenchingoftheemission
mM)werepreparedinabuffersolution(25mMHEPESbuffer,pH= intensity of BSA tryptophan residues at 363 nm in the presence of
7.2)orPBS.Theworkingwavelengthofeachreactioncorresponded increasingconcentrationsofRhIIIcomplexes1a,1b,and1c(0−10.0
to that of a maximum change in absorption derived from the μM)wasmonitored.Fluorescencespectrawererecordedintherange
difference spectra. The absorbance at the selected wavelength was of 300−500 nm with excitation at 295 nm. Excitation and emission
recorded at 30 s intervals, and the absorption/time data for each bandwidths wereboth 10nm.
complex were fitted to the first-order rate equation, which gave the CellPreparationandCulturing.HCT-116cellswerepurchased
k value foreach aquation process. fromtheAmericanTissueCultureCollection.Cellsweremaintained
H2O
The kinetics of the substitution of coordinated chloride was in controlled physiological conditions and grown in DMEM
measured spectrophotometrically by following the change in supplemented with 10% fetal bovine serum, 100 IU/mL penicillin,
absorbance at suitable wavelengths as a function of time. Working and 100 μg/mL streptomycin in a humidified atmosphere with 5%
wavelengths were determined by recording spectra of the reaction CO at37°C.
2
mixturefrom220to450nm.Kineticmeasurementswereperformed Viability Effects. A standardized MTT colored reaction
under pseudo-first-order conditions, with nucleophile concentrations (Mosmann, 1983)38 was measured on an ELISA microplate reader
atleast10-foldinexcess.Reactionswereinitiatedbymixing0.50mL (Rayto-2100C) asdescribed inour previous work.39−41
of a nucleophile complex solution with 2.50 mL of thermally X-ray Diffraction Studies. X-ray diffraction data for
equilibratedcomplexsolutioninaUV−viscuvette,andreactionswere [RhIII(MeL*)Cl] (1b) were collected at room temperature on an
followed for at least eight half-lives. The observed pseudo-first-order Oxford D 2 iffractio 3 n Gemini S diffractometer. Graphite-monochro-
rate constant k represents an average value of three to four mated Mo Kα radiation (λ = 0.7107 Å) was used to measure
obs
independent kinetic runs for each experimental condition. Some diffraction from suitable single crystals of complex 1b. CrysAlisPro
reactionswerestudiedatthreetemperatures(288,298,and310K). and CrysAlisREDsoftwarepackages42 wereusedfordatacollection
Experimental data are summarized in the Supporting Information and data integration. Space group determinations were based on
(Tables S1−S9). Values for constants and other thermodynamic analysis of the Laue class and systematically absent reflections.
parameters were determined using Microsoft Excel 2007 and Collected data were corrected for absorption effects using the
OriginPro8. Multiscanmethod,applyinganempiricalabsorptioncorrectionusing
UV−Vis DNA Interactions. CT-DNA stock solutions were spherical harmonics as implemented in SCALE3 ABSPACK.42
prepared in PBS, resulting in a UV absorbance ratio A
260
/A
280
of Structuresolutionandrefinementwereperformedwiththeprograms
ca. 1.8−1.9, indicating negligible protein contamination. CT-DNA SHELXT and SHELXL-2014/6, respectively.43 MERCURY44 was
c c o m n − c 1 e .3 n 7 trations were determined using A 260 with ε = 6600 M−1 p em re p p l a o r y e ed m f a o te r r m ial ol f e o c r ul p a u r b g l r ic a a p t h io ic n s . ,a N n o d n W -hy in d G ro X g 4 e 5 n so at ft o w m a s re w w e a re su r s e e fi d ne t d o
Fluorescence spectra were recorded in the range of 550−750 nm anisotropically; C−H hydrogen atoms were included at calculated
withexcitationat527nm.Excitation andemissionbandwidthswere positionsridingontheirattachedatomswithfixeddistancesofCH=
both 10nm. 0.93Å andCH = 0.96Åwith U (H)= 1.2U (C)formethylene
UV−Vis Absorption Studies. To quantitatively compare the andmethynegro 2 ups,andCH =0. i 9 so 7ÅwithU ( e H q )=1.5U (C)for
3 iso eq
binding strength of the complexes, the intrinsic binding constant K b methyl groups. [RhIII(Me 2 L*)Cl 3 ] complex had contributions from
wasdeterminedbymonitoringchangesinabsorptionatthemetal-to- disordered solvent molecules that were removed by the SQUEEZE
ligandchargetransfer(MLCT)bandwithincreasingconcentrationof routineimplementedinPLATON,46andtheoutputfromSQUEEZE
CT-DNAusing thefollowing eq1. calculations is attached in the CIF file. Crystal data and refinement
parameters are summarizedinTable 1.
[DNA]/(ε A −ε f )=[DNA]/(ε b −ε f )+1/[K b (ε b −ε f )] (1) Quantum Chemical Methods. To enable comparison with
earlier studies,47 we performed B3LYP/LANL2DZp hybrid DFT
K is given by the ratio of the slope to the y intercept in plots of
[D b NA]/(ε −ε)versus[DNA],where[DNA]istheconcentration calculations, with pseudopotentials on the heavy elements and the
of DNA i A n bas f e pairs, ε = A /[complex], ε is the extinction valence basis set augmented with polarization functions.48,49 During
coefficient for the unbou A nd c o o bs m d plex, and ε f is the extinction structure optimization, only symmetry constraints were applied. In
coefficient forthe complexinthe fully boundfo b rm. addition, resulting structures were characterized as minima, by
computation of vibrational frequencies. Relative energies were
EthidiumBromideDisplacementStudies.Therelativebinding
corrected for zero-point vibrational energies (ZPE). The influence
of complexes to CT-DNA was determined by calculating the
ofbulksolventwaterwasevaluatedviasingle-pointcalculationsusing
quenching constant (K ) from the slopes of straight lines obtained
fromthe Stern−Volmer sv equation(eq 2) CPCM formalism,50 that is, B3LYP(CPCM)/LANL2DZp//B3LYP/
LANL2DZp. The Gaussiansuite ofprograms was used.51
I /I=1+K [Q] (2) MolecularDockingSimulations.Structuralcoordinatesrepresent-
0 sv
ing a fragmentof (1) canonical B-DNA (PDB:1BNA) or (2)DNA
whereI andIareemissionintensitiesintheabsenceandpresenceof with an intercalation gap (PDB: 1Z3F) were obtained from the
0
quencher (complexes 1a, 1b, and 1c), respectively, [Q] is the total protein data bank (http://www.rcsb.org). Water molecules, ligands,
concentration of quencher, and K is the Stern−Volmer quenching and heteroatoms were removed if present. Hydrogen atoms and
sv
constant,whichwasobtainedfromtheslopeoftheplotofI/Iversus Gasteigerpartialchargeswereadded;nonpolarhydrogenatomswere
0
[Q]. merged in AutoDockTools52 (http://autodock.scripps.edu), and
Viscosity Measurements. Changes in DNA viscosity were coordinates were converted to PDBQT format. For ligands (1a, 1b,
measured in the presence of increasing amounts of complexes 1a, 1c, or [RhIII(HLtBu)Cl]), nonpolar hydrogen atoms were merged,
2 3
1b, and 1c. Flow time was measured with a digital stopwatch. Each andGasteigerpartialchargeswereaddedinAutoDockTools.52Natual
sample was measured in triplicate, and the average flow time was populationanalysis(NPA)partialchargesforRhandClatomswere
calculated. Data are presented as (η/η)1/3 against r, where η is the calculated in Gaussian16 with B3LYP/LANL2DZp and merged into
0
DNAviscosity in the presence of complex, and η is the viscosity of final ligand PDBQT files. Grid maps were calculated in AutoGrid4
0
DNA in buffer alone. Viscosity values were calculated from the usingcoordinatesfor1BNAor1Z3F.Gridmapswerecentered,anda
309 DOI:10.1021/acs.inorgchem.8b02390
Inorg.Chem.2019,58,307−319
Inorganic Chemistry Article
Table 1. Experimental Details: Crystalographic Data and mass spectrometry (MS). For the complex 1b single crystals
Refinement Parameters for [RhIII(Me L*)Cl ] Complex 1b suitable for the X-ray analysis were also obtained.
2 3
Elemental analyses on these complexes were in very good
crystaldata agreementwithacomplexcompositionof[RhIII(H L*)Cl ]or
2 3
chemicalformula C H ClNRh [RhIII(Me L*)Cl ]. The 1H NMR as well as the 13C NMR
29 37 3 5 2 3
M 664.89 spectra of the 1a and 1b complexes indicated that only this
r
crystalsystem,spacegroup orthorhombic,P222 distinctspeciesisformed.Theobtainedspectradisplayasetof
1 1 1
a,b,c(Å) 13.4941(3),19.4283(4), signals for the pyrazole moieties, pyridine moiety, and a
28.9799(13) camphor moiety, significantly shifted, compared to the free
V(Å3) 7597.6(4)
ligand. Further, the complexes are characterized by ESI-MS
Z 8 massspectrometry,inthem/zrangeof400−700thatincludes
radiationtype MoKα
main peaks at m/z = 599.18 (1+) and 628.14 (1+), which
No.ofreflectionsforcell 9233
representsfragmentsof the1aand1bcomplexes,whichcame
measurement
θrange(deg)forcellmeasurement 2.8−28.4 about by losing one chloride.
μ(mm−1) 0.68 Crystal Structure Discussion. A perspective view of the
molecular structure of 1b with adopted atom-numbering
crystalshape prism
crystalsize(mm) 0.51×0.42×0.14 scheme is shown in Figure 2. Selected metal−ligand bond
datacollection
diffractometer Xcalibur,Sapphire3,Gemini
absorptioncorrection multiscan
Tmin,Tmax 0.882,1.000
No.ofmeasured,independentandobserved 27626,13398,10655
[I>2σ(I)]reflections
R 0.052
int
θvalues(deg) θ =25.0,θ =2.5
max min
(sinθ/λ) (Å−1) 0.595
max
rangeofh,k,l h=−16→11,k=−23→15,
l=−34→29
refinement
R[F2>2σ(F2)],wR(F2),S 0.084,0.228,1.04 Figure 2. MERCURY44 drawing of the molecular structure of
complex1bwithlabelednon-Hatoms(onlymoleculeAisshownfor
No.ofreflections 13398
clarity).Displacementellipsoidsareshownat30%probability,andH
No.ofparameters 701
atoms aredrawn asspheres ofarbitrary radii.
No.ofrestraints 13
H-atomtreatment H-atomparametersconstrained
ρ ,ρ (eÅ−3) 0.96,−2.41 lengths, bond angles, and torsion angles are listed in Table 2.
max min
absolutestructureparameter 0.05(3) [RhIII(Me L*)Cl ] complex crystallizes in an orthorhombic
2 3
crystal system and P2 2 2 space group, where each
1 1 1
asymmetric unit consists of two 1b complex molecules
maximumgridboxsizewaschosentocovertheentireDNAmolecule.
(molecule A and molecule B). From a structural point of
For1BNAagridboxof54×56×106wascenteredatx,y,z=14.72,
20.99,8.82.For1ZF3agridboxof62×50×68wascenteredatx,y,z view,thecoordinationoftheRh1AandRh1Batomsinthe1b
complex is noteworthy. The rhodium centers in the
=2.27,15.76,37.63.Defaultgridspacingof0.375Åwasused.Maps
werecalculatedforallligandatomtypesalongwithelectrostaticand [RhIII(Me 2 L*)Cl 3 ] complex are coordinated in a slightly
desolvation maps using a dielectric value of −0.1465. Initial ligand distorted octahedral geometry.
position, orientation, and dihedral offset were set as random. The Because of the tridentate coordination of the N,N,N-donor,
numberoftorsionaldegreesoffreedomforeachligandwasfixedto0
the central nitrogen atom is pushed closer toward the
to ensure rigid docking. Docking simulations were conducted in rhodium(III) center, applying a trans influence on Cl2 that
AutoDock4 using the Larmarckian genetic algorithm and default explainstheslightlylargervalueoftheRh1Cl2bondlength,
parameters: the maximum number of energy evaluations was
whichisthesameinbothAandBmolecules(Table2).Bond
2500000, the genetic algorithm (GA) population size was 150, and anglesN3Rh1Cl1(inbothmoleculeAandB)areslightly
a total of 10 hybrid genetic algorithm with a local dearch (GA-LS)
largerthat90°,whileN3Rh1Cl3angles(inbothmolecule
runs were performed. Parameters for Rh atoms were added to
AutoDock as follows: R-eqm = 2.93 Å, weighted epsilon = 0.008, Aand B)are smaller than 90°, showing thestericinfluence of
At.frag.vol. = 12.000, At.solv.par. = −0.001, Hb R-eqm = 0.000, thebulkyMe L*chelatingligand.ThegroupRh1Cl2N2N3N4
2
weightedHbepsilon=0.000, Hbtype =0, bond index =1. Results is almost perfectly planar, since the largest displacement from
w■ereanalyzedinAutoDockTools (http://autodock.scripps.edu).52 the same weighted least-squares plane in both A and B
molecules is 0.111(9) Åforatom N3A.Comparing the angles
RESULTS AND DISCUSSION
between Rh1Cl2N2N3N4 plane and N1N2C3C2C1 and
Preparation and Structure of [RhIII(H L*)Cl ] (1a) and N4N5C11C10C9 planes in molecule A (21.0 (7)° and 10.7
2 3
[RhIII(Me L*)Cl ](1b).Complexes[RhIII(H L*)Cl ](1a)and (7)°,respectively)andthesameplanesinmoleculeB(5.2(7)°
2 3 2 3
[RhIII(Me L*)Cl ] (1b) (Figure 1) were synthesized by and17.4(7)°,respectively),onecanobservethatthemolecule
2 3
stirring equimolar amounts of RhCl ·xH O and H L* or A is more disordered from planarity. This leads to the
3 2 2
Me L* ligands in ethanol and by refluxing overnight. The conclusionthatmoleculesAandBof1bcomplexhaveslightly
2
synthesized RhIII complexes 1a and 1b were characterized by different conformations, which is confirmed by comparison of
1H and 13C NMR spectroscopy, elemental analysis, and ESI the values for torsion angles (Table 2). Visually, this result is
310 DOI:10.1021/acs.inorgchem.8b02390
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Table 2. Selected Geometric Parameters for solubilityinwater(TableS10).Thesolubilityofthecomplexes
[RhIII(Me L*)Cl ] Complex 1b is in line with oxaliplatin and a bit greater of cisplatin.
2 3
Kinetics of Aquation. The kinetics of aquation of
bondlength[deg]
complexes 1a, 1b, and 1c were quantitatively studied by
moleculeA moleculeB UV−vis spectroscopy of 0.1 mM solutions in HEPES buffer
Rh1−N3 2.027(9) 1.975(9) and PBS at 298 K. The UV−vis spectra of 1a and 1b
Rh1−N4 2.063(14) 2.051(14) complexes show no significant time-dependent changes in the
Rh1−N2 2.080(12) 2.051(12) region of 200−800 nm (Figure S2), which indicates that
Rh1−Cl1 2.332(4) 2.319(5) complexes 1a and 1b do not undergo hydrolysis in the
Rh1−Cl3 2.337(4) 2.341(4) observed time period in either 25 mM HEPES buffer or PBS.
Rh1−Cl2 2.351(3) 2.362(3) Complex 1c hydrolyzes with a constant k =3.5 × 10 −5 s −1
H2O
bondangles[deg] (t =330min)inPBSandk =1.1×10 −3s −1(t =9.68
1/2 H2O 1/2
N3−Rh1−N4 78.7(4) 78.4(5) min) in 25 mM HEPES buffer (Figures S3). The results
N3−Rh1−N2 80.4(4) 79.6(4) obtainedsuggestthatcomplex1cunderwentslowhydrolysisin
N4−Rh1−N2 158.3(4) 157.8(4) PBS and significantly hydrolyzed in HEPES buffer, but all
N3−Rh1−Cl1 91.8(3) 90.9(3) kineticmeasurementsforthisstudywereperformedinHEPES
N4−Rh1−Cl1 89.1(4) 85.4(4) buffer in the presence of 50 mM NaCl to prevent hydrolysis.
N2−Rh1−Cl1 86.0(3) 92.1(4) Kinetic Studies. To measure the reactivity of the RhIII
N3−Rh1−Cl3 87.0(3) 86.7(3) complex under physiological conditions, substitution reactions
N4−Rh1−Cl3 91.2(4) 93.1(4) of RhIII complex (1a, 1b, and 1c) (Figure 1) with selected
N2−Rh1−Cl3 93.2(3) 88.5(4)
nucleophilesL-Met,GSH,and5′-GMPwereinvestigated.The
Cl1−Rh1−Cl3 178.73(15) 177.38(17) kinetics of the substitution of coordinated chloride were
N3−Rh1−Cl2 176.3(3) 176.5(3) investigated byUV−visspectroscopy,byfollowing thechange
N4−Rh1−Cl2 100.9(3) 101.1(4) inabsorbanceasafunctionoftime.NucleophilesL-Met,GSH,
N2−Rh1−Cl2 100.3(3) 101.1(3) and 5′-GMP were chosen because of their different
Cl1−Rh1−Cl2 91.82(17) 92.51(19) nucleophilicity, steric hindrance, binding properties, and
Cl3−Rh1−Cl2 89.33(16) 89.87(17) biological relevance. Since our overal goal is to investigate
torsionangles[deg]
theanticancerpotentialofRhIIIcomplexes,kineticexperiments
Rh1−N2−N1−C1 154.1(11) −178.1(12) weredesignedtomimicphysiologicalconditions:measurments
Rh1−N2−N1−C12 −19(2) 6(2) were conducted at pH 7.2 (maintained with 25 mM HEPES
Rh1−N2−C3−C4 7.3(15) −3.8(15)
buffer)in50mMNaCl(tosuppressthesolvolyticpathway)at
Rh1−N3−C4−C5 −175.6(10) −175.0(10) 310 K. Kinetic experiments were performed under pseudo-
Rh1−N3−C8−C7 173.5(10) 172.1(11) first-order conditions, with nucleophile concentrations at least
Rh1−N3−C8−C9 −1.7(16) −6.1(16) 10-fold in excess. Proposed reaction pathways for all observed
Rh1−N4−C9−C10 179.5(10) 166.9(11) substitution processes are shown in Scheme 1.
Rh1−N4−C9−C8 11.6(17) −5.5(16)
Scheme 1. Schematic Representation of Substitution
depicted in Figure 3, which displays an overlay of A and B
ReactionsofComplexes1a,1b,and1cwithNucleophiles:L-
Met, GSH, and 5′-GMP
molecules of 1b complex.
Directnucleophilicattackproceedsinareversiblemanneras
in Scheme 1. Substitution rate constants were determined
under pseudo-first-order conditions by plotting the linear
dependenceofk versustotalnucleophileconcentration(see
obs
eq 3). All kinetic data are summarized in Tables S1−S9 (see
Supporting Information).
Figure 3. MERCURY44 drawing showing an overlay of two
independentmoleculesin[RhIII(Me 2 L*)Cl 3 ]1bcomplex:A(yellow) k obs = k 2 [nucleophile] + k 1 [Cl−] (3)
andB (red). Hydrogenatoms wereomittedforclarity.
Direct nucleophilic attack is characterized by rate constant
k , and the reverse reactions are represented by rate constant
2
k . The second-order rate constant k characterizes product
1 2
The crystal packing of [RhIII(Me L*)Cl ] complex is formation and was evaluated from the slope of a plot k
2 3 obs
dominantly arranged by van der Waals forces, since classic versus nucleophile concentration. Experimental results for the
hydrogen bonds were not found in intra- or intermolecular displacement of a chloride ion from 1a, 1b, and 1c are shown
space. in Table 3. Representative plots are shown in Figure 4.
Solubility of the Studied RhIII Complexes. The Ascanbeseen,1a,1b,and1carereactivetowardallofthe
prepared RhIII complexes are neutral; UV−vis spectrophoto- testednucleophiles,withorderofreactivity5′-GMP>GSH>
metric measurements showed that they have moderate L-Met.RhIIIcomplexesareexpectedtohavethehighestaffinity
311 DOI:10.1021/acs.inorgchem.8b02390
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Table 3. Rate Constants for the Substitution Reactions of the RhIII Complex with L-Met, 5′-GMP, and GSH at pH = 7.2 (25
mM HEPES Buffer) in the Presence of 50 mM NaCl
[RhIII(HL*)Cl](1a)
2 3
T(K) 1×101k,M−1s−1 1×104k[Cl−],M−1s−1 ΔH⧧,kJmol−1 ΔS⧧,JK−1mol−1
2 1 2 2
L-Met 310 2.4±0.1 0.20±0.01
5′-GMP 288 7.6±0.1 0.27±0.01 40±2 −120±8
298 13±0.1 0.35±0.01
310 27±0.1 0.80±0.02
GSH 288 1.7±0.1 26±1 −183±2
298 2.5±0.1
310 4.0±0.1
[RhIII(MeL*)Cl](1b)
2 3
T,K 1×101k,M−1s−1 1×104k[Cl−],M−1s−1 ΔH⧧,kJmol−1 ΔS⧧,JK−1mol−1
2 1 2 2
L-Met 288 2.1±0.1 0.10±0.01 17±6 −212±22
298 3.3±0.1 0.15±0.01
310 3.8±0.2 0.20±0.01
5′-GMP 288 38±0.1 0.50±0.01 10±2 −212±8
298 43±0.1 2.0±0.1
310 56±0.1 7.8±0.2
GSH 310 19±0.1 0.16±0.01
[RhIII(terpy)Cl](1c)
3
T,K 1×101k,M−1s−1 1×105k[Cl−],M−1s−1 ΔH⧧,kJmol−1 ΔS⧧,JK−1mol−1
2 1 2 2
L-Met 310 0.34±0.01 0.01±0.01
5′-GMP 288 1.3±0.1 35±5 −154±16
298 2.5±0.1
310 4.0±0.1
GSH 310 0.72±0.01
Figure4.Pseudo-first-orderrateconstantsasafunctionofnucleophileconcentration.(right)k vsnucleophileconcentationforreactionof1a,
obs
1b,and1ccomplexesand5′-GMP.(left)k
obs
vsnucleophileconcentationforreactionof1bcomplexand5′-GMP,L-Met,andGSH;pH=7.2and
310K in25mM HEPESand 50mM NaCl.
for N-bonding nucleophiles, because in addition to the [RhIII(Me L*)Cl] (1b) > [RhIII(H L*)Cl] (1a)
presence of the nitrogen donor atom RhIII ions are borderline 2 3 2 3
hard−softacids.ThelowerreactivityofL-MetoverGSHcould > [RhIII(terpy)Cl
3
] (1c)
be due to the bulky methyl group in L-Met, making access to
the RhIII complexes difficult. Furthermore, the N-donor The camphor-derived bis(pyrazolylpyridine) RhIII com-
nucleophile 5′-GMP is able to compete with S-donor plexes react ∼10 times faster than [RhIII(terpy)Cl 3 ]. Although
nucleophiles L-Met and GSH, and display greater affinity complexes 1a and 1b have similar structure, 1b is more
toward the RhIII complexes. These observations are of special reactive. Considering steric effects, 1b is the most bulky RhIII
interest,sinceunderbiologicalconditionswithinthecell,these complex, suggesting that electronic effects have a greater
S-donor biomolecules are present in relatively high concen- impact on reactivity than steric effects. The obtained rate
trations and therefore compete with the DNA; suggesting the constants are in agreement with an earlier studied complex
possibility that the investigated complexes could be bound to [RhIII(H LtBu)Cl ].20
2 3
DNA and that DNA could be considered a potential target. The thermodynamic properties and relative stability of the
The order of reactivity of the investigated RhIII complexes is RhIII complexes were examined comparing 2,6-di(1H-pyrazol-
(Table 3): 3-yl)pyridine (H LH) (representing the smallest possible
2
312 DOI:10.1021/acs.inorgchem.8b02390
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Scheme 2. Model Equation to Evaluate (B3LYP/LANL2DZp) the Relative Stability of [Rh(H LH)(Cl) L]+ Versus
[Rh(terpy)(Cl)
L]+a 2 2
2
aL: Gua, S(CH),HSCH.
3 2 3
ligand without hampering substituents) and terpy. Therefore, complex. In the case of trans-coordinated Gua a hydrogen
the following model was calculated as presented in Scheme 2. bond of 1.7 Å between the CO group in Gua and the NH
As can be seen in Table 4, in gas phase, regardless of group in H LH is formed (see Figure 5). This moderate
2
whetherthetransorciscomplexesareinvestigated,thegeneral preference for the terpy complexes likely originates from the
slightly smaller size of H LH versus terpy, leading to weaker
2
Table 4. Calculated Relative Stabilities for the Model charge stabilization. Incorporating solvent effects in our
Equation from Figure 5 a calculations supports this, resulting in all RhIII−H LH
2
complexes being favored: the cis-[Rh(H LH)(Cl) Gua]+ by
[kcalmol−1] cis trans 2 2
more than 5 kcal/mol. Generally, the complexes are best
ligand(L) B3LYP B3LYP(CPCM) B3LYP B3LYP(CPCM) addressed as equally stable.
HS−CH 3 1.51 −0.72 2.78 −1.40 Inallinvestigatedterpycomplexes,thedistancebetweenthe
CH 3 −S−CH 3 −0.98 −0.98 2.40 −2.11 central pyridine moiety nitrogen atom and the RhIII center is
TU 1.37 −0.41 1.88 −0.95 ∼1.5%smallerthaninH LHsystems.TheN−Rhbondsinthe
2
Gua 1.23 −2.40 −3.94 −5.53 equatorialplanecistothecentralpyridineringisinthecaseof
Imi 0.96 −0.09 3.70 −0.13 theterpy-ligand∼2%longer,whereastheRh−Ldistancedoes
aB3LYP: RB3LYP/LANL2DZp + ZPE(B3LYP/LANL2DZp) not seem affected by the type of tridentate ligand (see Tables
B3LYP(CPCM): RB3LYP(CPCM)/LANL2DZp // RB3LYP/ S11 and S12). Rh−L coordination is much more affected by
LANL2DZp+ ZPE(B3LYP/LANL2DZp). the trans influence of pyridine or Cl − depending on the
investigated isomer, indicating that average Rh−N coordina-
trend favors the terpy complexes, with two exceptions, L: tion in all test complexes is similar and the H LH ligand is a
2
dimethyl sulfide in the cis complex and Gua in the trans good alternative to terpy (see Figure S1).
Figure 5.Calculated (B3LYP/LANL2DZp)structureof cis-and trans-[Rh(terpy)(Cl)Gua]+andof cis-and trans-[Rh(HLH)(Cl)Gua]+.
3 2 2
313 DOI:10.1021/acs.inorgchem.8b02390
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Inorganic Chemistry Article
Figure6.UV−Vistitrationspectraof1a,1b,and1ccomplexes(8μM)inPBSpH7.4withincreasingconcentrationofCT-DNA(0−40μM).The
arrowshows hyperchromism inthe spectralband. (inset) Plots of[DNA]/(ε − ε)] vs[DNA].
a f
Table 5. Interaction Constants for RhIII Complexes with CT-DNA and BSA
CT-DNA BSA
K,M−1 K ,M−1 K ,M−1
b sv sv
[RhIII(HL*)Cl](1a) (5.0±0.1)×104 (5.0±0.1)×104 (3.5±0.1)×104
2 3
[RhIII(Me2L*)Cl3](1b) (8.3±0.1)×104 (5.5±0.1)×104 (3.9±0.1)×104
[RhIII(terpy)Cl](1c) (7.0±0.1)×104 (3.8±0.1)×104 (3.4±0.1)×103
3
[RhIII(HLtBu)Cl]20 (9.7±0.1)×104 (1.9±0.1)×104 (3.0±0.1)×104
2 3
While tridentate complexes allow only one ligand to be Absorptionspectraof1a,1b,and1ccomplexesintheabsence
substituted due to the chelate effects in square-planar and presence of CT-DNA at varying concentrations are given
complexes, octahedral complexes offer three possibilities: in in Figure 6.
ourcase,twoequivalentcistothecentralpyridinemoietyand Results show that the RhIII complexes have a strong
onetrans.Toexaminetheoverallthermodynamicequilibrium, absorption at ca. 258 nm. The absorption spectra of all three
wecomparedthestabilityofcisandtransisomersofcalculated complexes showed hyperchromism and red shift, ∼2 or 3 nm,
model complexes [Rh(H LH)(Cl) L]n+ and [Rh(terpy)- at the maximum peak with increasing CT-DNA concen-
2 2
(Cl) L]n+, where in all cases the cis isomer was considered trations. This observed hyperchromism and shift at the
2
to be the 0 value (Table S13). maximum peak could indicate an intercalative binding mode,
As shown in Figure 5, application of the CPCM solvent possibly involving stacking interactions between the planar
modelreducesthecalculatedenergygapequalizingthecisand aromatic chromophore of the complex and nucleotide base
trans isomer. However, the overall trend in the gas phase and pairs in CT-DNA.54 However, the exact mode of binding
especially after application of a solvent model favors the trans cannot be proposed based on UV−vis spectroscopic
isomers. This is likely because, as shown in Figure 5, L has
methods.55−57
Intrinsic equilibrium binding constants (K b )
more free space in front of the chelating ligand trans to the of the RhIIIcomplexes withCT-DNA were evaluated usingeq
central pyridine ring compared to the cis position, where L is 1. The intrinsic binding constant K b (Table 5) obtained for
above or below the chelating ring. these complexes with CT-DNA follows the order: 1b > 1c >
■
1a, with 1b displaying the strongest interaction with DNA.
However, both camphor-based ligand and terpiridine ligand
DNA BINDING STUDIES
complexes have nearly the same binding affinity; the intrinsic
Electronic Absorption Method. Electronic absorption binding constants, K , do not differ considerably among the
b
spectrometry was used to investigate the interactions of metal studied complexes. Kinetic data show that 5′-GMP reacts
ion complexes and CT-DNA molecules. In the present study, much more slowly with the RhIII terpy complex than with the
metal complex absorption titration studies were conducted at camphor-based RhIII complexes. Considering that DNA is a
room temperature using fixed concentration of complexes (8 relatively “crowded” molecule, it is possible that steric effects
μM) in PBS and varying amounts of CT-DNA (0−40 μM).53 play a significant role in binding RhIII complexes, and steric
314 DOI:10.1021/acs.inorgchem.8b02390
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Inorganic Chemistry Article
effectsarethusmorepronouncedinthecaseofcamphor-based inlengtheningandstiffeningoftheDNAdoublehelix,leading
RhIII complexes. to increased DNA viscosity.59,60
Fluorescence Spectroscopic Methods. Fluorescence Addition of increasing amounts (up to r = 1.0) of RhIII
spectroscopic studies were used to confirm DNA interactions complexes to a CT-DNA solution (0.01 mM) resulted in an
withrhodiumcomplexes.BecauseourRhIIIcomplexesinteract increase in the relative viscosity of CT-DNA (Figure S6),
with DNA by UV−vis, competitive binding experiments were which was most pronounced upon addition of 1b, in
also conducted by adding ethidium bromide (EB)as a known accordance with UV−vis and fluorescence measurements. In
DNA intercalator. While EB itself fluorescences weakly,54 in thecaseofclassicintercalation,DNAbasepairsmustseparate
the presence of CT-DNA, EB intercalates its planar to host the bound compound, resulting in increased DNA
phenanthridinium ring between adjacent base pairs of the viscosityasafunctionofinteractionstrength.Thus,ourresults
DNAdoublehelix,resultinginstrongfluorescenceemissionat are in agreement with an increase in overall DNA length,
∼600nm.58Additionofcomplexes1a,1b,and1ctoEB-DNA possiblycausedbycompoundintercalationbetweenDNAbase
resulted in fluorescence quenching due to displacement of EB pairs via aromatic chromophores such as pyridine or pyrazole
from the DNA. Quenching parameters for RhIII complexes l■igands in the complexes.
were calculated using the Stern−Volmer equation (eq 2). EB
PROTEIN BINDING STUDIES
displacement studies were performed by changing the
concentrationofmetalcomplexesandmonitoringtheemission Fluorescence Spectroscopy of BSA. Metal ion com-
intensityoftheEB-DNAcomplex.53Increasingconcentrations plexes with antitumor activity often interact with specific
of complexes 1a, 1b, and 1c (0−10 μM) resulted in a proteins, both as part of their mechanism of action as well as
significant decrease in fluorescence intensity with a noticeable transport and metabolism. In the present study we examined
redshift(Figure7;seealsoSupportingInformationFiguresS4 the affinity of 1a, 1b, and 1c for BSA, using tryptophan
and S5). fluorescence quenching experiments. Fluorescence spectrosco-
py can monitor changes in protein structure, dynamics, and
folding.61−63ThechangeinBSAfluorescenceuponadditionof
increasing concentrations of 1a, 1b, and 1c (0−30 μM) over
the range of 300−500 nm (λ , = 295 nm) is presented in
ex
Figures S7−S9, Suporting Information. As shown, a decrease
influorescenceintensityat363nmwasobserved.Fluorescence
quenching data were analyzed using the Stern−Volmer
equation(eq2),andaquenchingconstant(K )wascalculated
sv
from I /Iversus[Q], FiguresS7−S9, SupportingInformation.
0
On the basis of these results, 1a and 1b have reasonable
affinity for BSA, while 1c displayed slightly lower affinity
(Table 5). Quenching constants (K ) for camphor-derived
sv
RhIII complex interactions with CT-DNA and BSA are
approximately the same (Table 5 and Figure 8), although
Figure 7. Fluorescence titration spectra of EB-DNA and of EB (10
μM)boundtoDNA(10μM)inthepresenceofvaryingamountsof
complexes 1a. [Arrow shows changes in fluorescence intensity upon
increasing concentration of 1a (0−10 μM)]. (inset) Stern−Volmer
plots forEB-DNAfluorescencetitration with 1a.
These results suggest that EB is released from the EB-DNA
complex due to displacement by the RhIII complexes,
indicating that complexes 1a, 1b, and 1c have moderate
DNA intercalative ability, with 1b somewhat stronger than 1a
and 1c.
As seen in Table 5, the studied RhIII complexes interact
moderately with CT-DNA. UV−Vis and fluorescence spectro-
scopic studies both show that the 1b complex interacts more
Figure8.ObtainedK valuesforcomplexes1a,1b,and1cwithBSA
strongly than 1a or 1c. A previously studied complex, sv
or CT-DNA.
[RhIII(H LtBu)Cl ], was shown to have very similar affinity
2 3
toward CT-DNA as the 1a, 1b, and 1c complexes.20 All three
complexes show somewhat higher affinity for CT-DNA than somewhat higher for 1b, whereas the terpiridine−RhIII
BSA, in agreement with obtained result from kinetic studies, complex1cappearstointeractstrongerwithCT-DNA.Values
where all complexes reacted faster with 5′-GMP than with for these constants for 1a, 1b, and 1c are in agreement with
sulfur-donor molecules. those obtained for a previously investigated complex
Viscosity. Viscosity measurements were conducted to [RhIII(H LtBu)Cl ], Table 5.
2 3
further confirm interactions between 1a, 1b, and 1c with UV−VisSpectroscopyofBSA.UVspectroscopywasused
CT-DNA. In classical intercalation, complex formation results to investigate the mode of binding between RhIII complexes
315 DOI:10.1021/acs.inorgchem.8b02390
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Inorganic Chemistry Article
Figure9.(left)Dose−responsecurvesfortheeffectof1bonHCT-116cellgrowthafter24and72hofexposure.Theantiproliferativeeffectwas
measured by MTT assay. All values are mean ± standard error, n = 3, *P < 0.05 as compared with controls. (right) IC values for studied
50
complexes1a,1b,and 1cafter incubation withHCT-116cancer celllinesfor24and 72h.
and BSA, which can be considered to be either dynamic
quenching or static quenching. In dynamic quenching, upon
addition of a quencher, only the excited-state fluorescence
molecule is affected, resulting in no change in the UV
absorptionspectraforBSA,whereasinstaticquenching,anew
compound is formed between BSA and the quencher,
considerably affecting the UV−vis spectra. UV spectra for
BSAwererecordedfollowingadditionofequalconcentrations
of 1a, 1b, or 1c. Figure S10 shows a peak at ∼280 nm due to
aromatic residues (Trp, Tyr, and Phe).64 As shown, the
absorption spectra of a mixture of BSA + RhIII complexes
descreasesinintesity,indicatingthat themicroenvironmentof
these aromatic side chains is changed, possibly due to
interaction with one of the RhIII complexes and consistent
with a static quenching mechanism for 1a, 1b, and 1c.
CellViability.Transition-metalcompoundshavebeenused
toinhibitcancerproliferation,65andwehavepreviouslyshown
that RhIII complexes display cytotoxicity against HCT-116
cells.40 Thus, in the present study we investigated the
Figure 10. Molecular docking suggests that compounds 1b, 1c, and
antiproliferative potential of 1a, 1b, and 1c as well as [RhIII(HLtBu)Cl]havepotentialforDNAintercalation,whileallof
2 3
corresponding ligands on human colorectal cancer HCT-116 the tested compounds have affinity for the minor groove of DNA.
cells using an MTT assay. Compound 1b showed the most Minorgroove bindingby 1ato B-DNA isshown(upperleft).
significant effects with an IC of 80.01 and 7.26 μM after 24 ■
50
and72htreatment,respectively;seeFigure9,FigureS11,and
CONCLUSIONS
Table S14.
This antiproliferative effect by 1b was concentration- and We used a camphor-derived bis(pyrazolylpyridine), tridentate
nitrogen-donor chelate system for the synthesis of two new
time-dependent. In contrast, 1a and 1c were not cytotoxic
RhIII complexes. The crystal structure of 1b complex was
against HCT-116 cells under our laboratory conditions.
determined. Kinetic experiments were performed with small
Molecular Docking. Molecular docking simulations were
biomolecules (L-methionine, L-histidine, and glutathione)
used to test if DNA intercalation or minor groove binding is under pseudo-first-order conditions as a function of complex
possible between the studied compounds and DNA. Using concentration and temperature by UV−vis spectroscopy.
Autodock4, ligands (1a, 1b, 1c, or [RhIII(H L tBu)Cl ]) were These results show that the synthesized complexes have
2 3
docked into DNA fragments representing either (1) canonical affinityforthestudiedligands,withorderofreactivity5′-GMP
B-DNA (PDB 1BNA) or (2) DNA with an intercalation gap > GSH > L-Met. The interaction between the synthesized
(PDB1Z3F).1BNAisthecrystalstructureofasyntheticDNA complexes and CT-DNA and BSA were also examined by
dodecamer,while1Z3Fisthecrystalstructureofa6bpDNA absorption (UV−vis) and emission spectral studies (EB
displacement studies). Overall, results show that our RhIII
fragment in complex with an intercalating anticancer drug,
complexes have good affinity to interact with CT-DNA and
ellipticine. All test compounds were predicted to interact with
BSA, with somewhat higher affinity toward CT-DNA, with 1b
the minor groove of the B-DNA fragment, with estimated
having the highest affinity toward CT-DNA and BSA. A RhIII
affinities in the micromolar range. In addition 1b, 1c, and
complex with terpiridine ligand, 1c, was also synthesized, and
[RhIII(H L tBu)Cl ] showed similar potential for DNA
2 3 the same type of interactions were examined. In all studied
intercalation in the gap created by ellipticine, with estimated interactions the RhIII−terpy complex reacted slower than the
binding affinities also in the micromolar range (Figure 10). camphor-derived bis(pyrazolylpyridine) complexes, indicating
These results are in agreement with our experimental UV−vis that introduction of a camphor-derived spectator ligand can
and fluorescence studies and further support the anticancer improvethereactivityofrhodium(III)complexesoveruseofa
potential of these RhIII complexes. terpy spectator ligand. In vitro viability effects against human
316 DOI:10.1021/acs.inorgchem.8b02390
Inorg.Chem.2019,58,307−319
Inorganic Chemistry Article
epithelial colorectal carcinoma HCT-116 show that 1b has Serendipity and Rational Design. Angew. Chem. 2008, 120, 8924−
significant cytotoxic activity, while 1a and 1c showed no 8956; Angew. Chem.,Int. Ed. 2008,47,8794−8824.
cytotoxic effects. Molecular docking suggests that all test (2) Beller, M.; Bolm, C. Transition Metals for Organic Synthesis:
compounds have affinity for the minor groove of DNA, while BuildingBlocksandFineChemicals;Wiley-VCH:Weinheim,Germany,
2004.
■1b and 1c have potential for DNA intercalation.
(3) Alessio, E. Bioinorganic Medicinal Chemistry; Wiley-VCH:
Weinheim, Germany, 2011.
ASSOCIATED CONTENT
(4)Kastl,A.;Wilbuer,A.;Merkel,A.L.;Feng,L.;Meggers,E.;etal.
*
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ACS Publications website at DOI: 10.1021/acs.inorg- 2012,48, 1863−1865.
chem.8b02390. (5) Peña, B.; David, A.; Pavani, C.; Baptista, M. S.; Pellois, J.-P.;
Turro, C.; Dunbar, K. R. Cytotoxicity Studies of Cyclometallated
Illustrated superposition of calculated structures, UV−
Ruthenium(II)Compounds:NewApplicationsforRutheniumDyes.
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CCDC 1847938 contains the supplementary crystallographic Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells.
data for this paper. These data can be obtained free of charge Biochemistry 2011, 50,10919−10928.
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing (9) Harris, A. L.; Yang, X.; Hegmans, A.; Povirk, L.; Ryan, J. J.;
Kelland, L.; Farrell, N. P. Synthesis, Characterization, and
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
Cytotoxicity of a Novel Highly Charged Trinuclear Platinum
bridge Crystallographic Data Centre, 12 Union Road,
Compound. Enhancement of Cellular Uptake with Charge. Inorg.
■Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
relaxation agents for NMR imaging: theory and design. Chem. Rev.
Corresponding Author 1987,87, 901−927.
*Phone: +381(0)34336223. Fax: +381(0)34335040. E-mail: (11) Della Rocca, J.; Liu, D.; Lin, W. Nanoscale Metal−Organic
jrosic@kg.ac.rs. Frameworks for Biomedical Imaging and Drug Delivery. Acc. Chem.
Res. 2011, 44,957−968.
ORCID
́ (12) Anderson, C. J.; Welch, M. J. Radiometal-Labeled Agents
Milan M. Milutinovic: 0000-0003-4838-3998 (Non-Technetium) for Diagnostic Imaging. Chem. Rev. 1999, 99,
Andreas Scheurer: 0000-0002-2858-9406 2219−2234.
Jovana Bogojeski: 0000-0002-3433-7774 (13)Domaille,D.W.;Que,E.L.;Chang,C.J.Syntheticfluorescent
sensorsforstudyingthecellbiologyofmetals.Nat.Chem.Biol.2008,
Author Contributions
4,168−175.
The manuscript was written with contributions from all (14)Minus,M.B.;Kang,M.K.;Knudsen,S.E.;Liu,W.;Krüger,M.
authors.
J.; Smith, M. L.; Redell, M. S.; Ball, Z. T. Assessing the intracellular
Notes fate of rhodium(II) complexes. Chem. Commun. 2016, 52, 11685−
T■he authors declare no competing financial interest. 11688.
(15) Sliwinska, U.; Pruchnik, F. P.; Pelinska, I.; Ułaszewski, S.;
ACKNOWLEDGMENTS Wilczok, A.; Zajdel, A. Synthesis, structure and antitumor activity of
Theauthorsgratefullyacknowledgefinancialsupportfromthe [
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(16) Cwikowska, M.; Pruchnik, F. P.; Starosta, R.; Chojnacki, H.;
ment Serbia, Project Nos. 172011, 172057, and III41010. We Wilczok, A.; Ułaszewski, S. Dinuclear Rh(II) complexes with one
alsothankProf.T.ClarkforhostingthisworkattheComputer polypyridylligand,structure,propertiesandantitumoractivity.Inorg.
Chemistry Center and the Regionales Rechenzentrum Chim. Acta2010,363,2401−2408.
■Erlangen for a generous allotment of computer time. (17)Frade,R.F.M.;Candeias,N.R.;Duarte,C.M.M.;Andre,V.;
Duarte, M. T.; Gois, P. M. P.; Afonso, C. A. M. New dirhodium
DEDICATION complex with activity towards colorectal cancer. Bioorg. Med. Chem.
Lett. 2010, 20,3413−3415.
This article is dedicated to the memory of Professor Dr.
Z ̌ ivadin D. Bugarc ̌ ic ́ (1954−2017), a great mentor and (18)Morrison,D.E.;Aitken,J.B.;deJonge,M.D.;Issa,F.;Harris,
H.H.;Rendina,L.M.SynthesisandBiologicalEvaluationofaClass
■excellent chemist.
ofMitochondrially-TargetedGadolinium(III)Agents.Chem. -Eur. J.
2014,20, 16602−16612.
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319 DOI:10.1021/acs.inorgchem.8b02390
Inorg.Chem.2019,58,307−319