Guo-dong Li,Ln-mei Chen∗,Xin-yu Wng,Ling-feng Wu,Xin-ming Jie,Jin-n Chen∗

a.School of Pharmacy,Guangdong Medical College,Zhanjiang 524023,China

b.The First Clinical Medical College,Guangdong Medical College,Zhanjiang 524023,China

c.Analysis Centre of Guangdong Medical College,Zhanjiang 524023,China

(Dated:Received on July 20,2013;Accepted on March 20,2014)

Electronic Structures,DNA-binding,SAR,and Spectral Properties of Ruthenium Methylimidazole Complexes[Ru(MeIm)4L]2+(L=iip,tip,2ntz)

Guo-dong Lia,Lan-mei Chena∗,Xin-yu Wangb,Ling-feng Wub,Xin-ming Jiec,Jin-can Chenc∗

a.School of Pharmacy,Guangdong Medical College,Zhanjiang 524023,China

b.The First Clinical Medical College,Guangdong Medical College,Zhanjiang 524023,China

c.Analysis Centre of Guangdong Medical College,Zhanjiang 524023,China

(Dated:Received on July 20,2013;Accepted on March 20,2014)

Theoretical studies on the electronic and geometric structures,the trend in DNA-binding affinities as well as the the structure-activity relationship(SAR)of a series of water-soluble Ru(II)methylimidazole complexes,i.e.[Ru(MeIm)4iip]2+(1)(MeIm=1-methylimidazole, iip=2-(1H-imidazo-4-group)-1H-imidazo[4,5-f][1,10]phenanthroline),[Ru(MeIm)4tip]2+(2) (tip=2-(thiophene-2-group)-1H-imidazo[4,5-f][1,10]phenanthroline),and[Ru(MeIm)42ntz]2+(3)(2ntz=2-(2-nitro-1,3-thiazole-5-group)-1H-imidazo[4,5-f][1,10]phenanthroline),were carried out using the density functional theory(DFT).The electronic structures of these Ru(II) complexes were analyzed on the basis of their geometric structures optimized in aqueous solution,and the trend in the DNA-binding constants(Kb)was reasonably explained.The results show that the replacement of imidazole ligand by thiophene ligand can ef f ectively improve the DNA-binding affinity of the complex.Meanwhile,it was found that introducing the stronger electronegative N atom and NO2group on terminal loop of intercalative ligand can obviously reduce the complex’s LUMO and HOMO-LUMO gap energies.Based on these f i ndings,the designed complex[Ru(MeIm)42ntz]2+(3)can be expected to have the greatest Kbvalue in complexes 1-3.In addition,the structure-activity relationships and antitumor mechanism were also carefully discussed,and the antimetastatic activity of the designed complex 3 was predicted.Finally,the electronic absorption spectra of this series of complexes in aqueous solution were calculated,simulated and assigned using DFT/TDDFT methods as well as conductor-like polarizable continuum model(CPCM),and were in good agreement with the experimental results.

Ruthenium methylimidazole complex,DNA-binding,Structure-activity relationships,Spectral property,DFT calculation

I.INTRODUCTION

It is well known that many anticancer agents,antiviral agents and antiseptic agents take action through binding to DNA[1-3].There are mainly three binding modes when a drug binds to DNA:the electrostatic binding,the groove binding,and the intercalation binding.Among them,the intercalation binding is the most important binding mode when the transition metal drugs,especially the antitumor ruthenium complexes interact with DNA.

Recently,more and more interests have been focused on the interaction and the binding mechanism between Ru(II)polypyridyl complexes and DNA [4-6],particularly on the well known[Ru(L1)2(L2)]2+(L1=phen or bpy;L2=polypyridyl)and their derivatives,which cannot only intercalate between the DNA base-pairs or form some outside binding,but alsocleavetheDNAdoublehelixef f ectively[2, 7-9].However,mostofthereportedRu(II) polypyridyl complexes are less soluble in water due to their big polycyclic heteroaromatic hydrophobic ligands.Recently,it has been reported the DNA-binding of a series of ruthenium methylimidazole complexes,such as[Ru(MeIm)4(L)]2+(L=phen,dpq,and dppz,phen=1,10-phenanthroline,dpq=pyrazino[2,3-f][1,10]phenanthroline,and dppz=dipyrido[3,2-a:20,30-c]phenazine)was with better aqueous solubility than thatofRu(II)polypyridylcomplexeswiththe general formula[Ru(L1)2(L2)]2+(L1=phen or bpy; L2=polypyridyl)[10-13].What is more important is that the Ru(II)-imidazole complexes have already been proven to possess antitumor activity and even are able to induce apoptosis in lung cancer A549 cells through intrinsic mitochondrial pathway[12,13].

The distinctive antimetastatic activity and favorable DNA-binding abilities of water-soluble Ru(II)-imidazole complexes must be bound up with their characteristicsof electronic and geometric structures as well as the related properties.Therefore,clarif i cation of these correlations will be very helpful for comprehension of the action mechanisms of metal drugs,for regulation of interactions between the complexes and DNA,and further for the design of new clinic anticancer drugs and novel complexes with biochemical activities.

Recently,the Ru(II)polypyridyl complexes have also attracted many theoretical chemists,since the density functional theory(DFT)[14-16]can better consider electron correlation energies and obviously reduce the computational expenses,and the time-dependent DFT (TDDFT)methods[17,18]can suit the calculations of the spectral properties of such a kind of complex, more and more theoretical computations applying DFT and TDDFT methods on Ru(II)complexes have been reported[8-11,19-24].We have also reported some DFT/TDDFT results on the electronic structures and spectral properties of some Ru(II)complexes[10,11, 22-24].Such theoretical studies on the level of molecular electronic structures of the complexes are very significant in understanding the trend in DNA-binding and related properties of the complexes and thus guiding functional molecular design or molecular modif i cation. Moreover,the computed results of spectral properties are in good agreement with the experimental ones,and thus provide considerable explanations and predictions for the experimental f i ndings[10,11,22-24].

Inthiswork,thetheoreticalstudiesonthe water-soluble Ru(II)methylimidazole complexes,i.e. [Ru(MeIm)4iip]2+(1),[Ru(MeIm)4tip]2+(2),and [Ru(MeIm)42ntz]2+(3)by DFT method are carried out,the schematic structures of complexes 1-3 are shown in Fig.1.Complexes 1 and 2 have been synthesized and structurally characterized in our lab,while complex 3 is designed based on the theoretical f i ndings. The ef f ects of some substituents on the intercalative ligand on the geometric and electronic structures are investigated.We mainly focused on theoretically explaining the trend in DNA-binding affinities,and then inquirying of structure-activity relationships and antitumor mechanism of this series of complexes.In addition, the absorption spectra of these complexes in aqueous solution were also computed,simulated,and discussed by the TDDFT method.

II.COMPUTATIONAL DETAILS

From Fig.1,we can see that every title complexe forms from a Ru(II)ion,a main intercalative ligand (iip,tip or 2ntz),and four monodentate co-ligands (1-methylimidazole),and has no symmetry.In order to obtain a suitable calculation method,six dif f erent hybrid GGA exchange correlation functionals:B3LYP, BLYP,BP86,BPW91,TPSSh,and PBE1PBE with LanL2DZ,SDD and other dif f erent hybrid basis set were tested to f i nd a suitable functional for our investigated

FIG.1 Schematic structures of the ruthenium methylimidazole complexes[Ru(MeIm)4iip]2+(1),[Ru(MeIm)4tip]2+(2),and[Ru(MeIm)42ntz]2+(3).

systems.Since the crystal structures of the three title complexes have not been determined yet,the direct comparison between the computational results and the corresponding experimental data cannot be performed. So the analog[Ru(bpy)3]2+was used to test the calculation method.Comparing the calculated geometrical parameters of the[Ru(bpy)3]2+in vacuo and in aqueous solution with corresponding X-ray data[25]shown in Table I,we can clearly see that the error was the slightest when the complex was carried out using the density functional theory(DFT)at the level of PBE1PBE/SDD (D95V up to Ar and Stuttgart/Dresden ECPs on the remainder of the periodic table).Therefore,full geometry optimization of the three title complexes in ground state was carried out in aqueous solution using the DFT-PBE1PBE method and SDD basis set(SDD basis set for all the atoms).PBE1PBE is the exchangecorrelation functional of Perdew,Burke,and Ernzerhof(PBE)[26].The solvational calculations were carried out with a conductor polarizable continuum model (CPCM)[27,28]and employing a dielectric constant(εwater=78.39)for water.Moreover,in order to explore the solvent ef f ect on the geometrical structures and related properties,the calculations of these complexes in vacuo were also carried out by adopting the same method.

TABLE I Selected bond lengths,bond angles,and dihedral angles of complex[Ru(bpy)3]2+calculated by dif f erent methods.

For the obtained structures,the frequency calculations with the same method were also performed in order to verify the optimized structure to be an energy minimum.On the basis of the DFT optimized geometry,the electronic absorption spectra in aqueous solution were calculated with the TDDFT at the level of B3LYP/LanL2DZ(LanL2DZ basis set for all the atoms)[29,30].The CPCM model was applied to considering the solvent ef f ect in aqueous solution. Eighty singlet-excited-state energies of these complexes were calculated to reproduce electronic absorption spectra.All computations were performed with the Gaussian 09 quantum chemistry program package(revision B.01)[31].In addition,in order to clearly depict the detail of some frontier molecular orbitals of these complexes in ground state,their stereocontour graphs were drawn with the Molden v4.2 program[32]based on the DFT computational results.

III.RESULTS AND DISCUSSION

A.Computed geometrical structures characters of the Ru(II)methylimidazole complexes

Table II gives the computational selected geometric parameters of the ground-state complexes 1-3 in vacuo and in aqueous solution.From computational geometric parameters in aqueous solution in Table II,we can see the following:f i rst,the coordination bond length (0.2047-0.2049 nm)of the main ligand for every one of complexes 1-3 is slightly shorter than that(0.2093 nm) of the co-ligands.Secondly,the mean bond length of the skeleton of the main ligand(C-C(N)m)and that of the co-ligands(C-C(N)co)for complexes 1-3 are almost unchanged,and the former is only slightly longer than the latter for every one of complexes 1-3.Thirdly,although all related dihedral angles(listed in Table II)in the main-ligand of these complexes are close to 180◦, there is a detectable dif f erence among the dihedral angles(α)of complexes 1-3,which are 174.5◦,179.5◦, and 179.7◦,respectively.Such a fact shows that the planarity of the main-ligand of the complex 1 is worse than those of complexes 2 and 3,and thus the steric hindrance of its main-ligand intercalating between DNA-base-pairs must be bigger than those of later complexes (see Fig.2).In addition,α calculated for complex 1 in aqueous solution(174.5◦)is much larger than those in vacuo(155.5◦).Therefore,it is suggested that the solvent ef f ect plays a valuable role in modifying the geometrical structures characters of this kind of Ru(II) complex.

B.Theoretical explanation of DNA-binding behaviors

The intrinsic binding constants Kbof the complexes 1 and 2 to calf thymus(CT)DNA,which quantitatively express their DNA-binding affinities,have been experimentally measured.The results show that the trend in DNA-binding constants(Kb)of the two complexes isKb(1)(6.1×105L/mol)＜Kb(2)(7.2×105L/mol)[12]. Such a trend can be reasonably explained by the DFT computations and the frontier molecular orbital theory[33].At the same time,the DNA-binding constant Kb(3)of the complex 3 can be predicted by the calculated results.Some frontier molecular orbital(MO) energies are listed in Table III,while MO contour plots are shown in Fig.3.

TABLE II Calculated selected bond lengths,bond angles and dihedral angles of complexes 1-3.

TABLE III Energies(εi)and HOMO-LUMO gap of some frontier molecular orbitals of complexes 1-3 calculated in aqueous solution.

FIG.2 Optimized structures for complexes 1 and 2 in aqueous solution.

As well-known,there are π-π stacking interactions between the ruthenium complex and DNA-base-pairs while the complex binds to DNA in an intercalation(or part intercalation)mode[6,7].Moreover,many theoretical studies have shown that the factors a ff ecting DNA-binding affinity of these complexes are the planarity,the energy and population of the lowest unoccupied molecular orbital(LUMO,even,and LUMO+x) of the intercalated molecule[8,10,11,22-24].

FIG.3 The contour plots of some related frontier molecular orbitals of complex 1 in aqueous solution.Those of complexes 2 and 3 are given in Fig.S1 in supplementary material.

TABLE IV Cytotoxicities(IC50)of complexes 1,2,and cisplatin against selected human cancer and normal cell lines(HBE) [34].

The above-mentioned trend in DNA-binding affinities,i.e.,Kb(1)＜Kb(2),can be explained as follows: fi rst,the energies of the LUMO+x(x=0-2)of these complexes are all negative and rather low(see Table III),and thus it suggests these complexes are very excellent electron acceptors in their DNA-binding.Secondly,the LUMO energies(εLUMO)follow the sequence of(1,-2.30 eV)≈(2,-2.33 eV)＞(3,-3.99 eV).Moreover,from Fig.3 and Fig.S1(see supplementary material),we can see that the components of the LUMO+x (x=0-2)come mainly from p orbitals of C and N atoms in intercalative ligands,they can be characterized by π-components.A lower LUMO energy of complex is advantageous on accepting the electrons from DNA base pairs in an intercalative mode,because electrons or“electron-cloud”can transfer from HOMO of DNA-base-pairs to LUMO of the complex via orbital interaction.So we can predict that the trend in DNA-binding constants(Kb)of these complexes is Kb(3)＞Kb(2)≈Kb(1)via the analysis in LUMO energies.Thirdly,from the geometric parameters of these complexes(see Table II and Fig.2),although the planarity and conjugated area of the main-ligand-skeletons of complexes 1-3 are not substantially dif f erent,the steric hindrance of the main ligand of complex 1 in the intercalative mode should be larger than those of complexes 2 and 3,because the important dihedral angle α (N1-C2-C3-N4)of main-ligand of complex 1 is obviously smaller than those of other two complexes in aqueous solution.So we can predict that the DNA-binding constant of complex 1 should be the smallest.In a word,considering both factors of LUMO energy and steric hindrance,the trend in DNA-binding affinities, i.e.,Kb(1)＜Kb(2),can be reasonably explained.Meanwhile,we can predict that the value of DNA-binding constant of designed complex 3 should be the largest in complexes 1-3,for its LUMO energy is the lowest and the planarity of its main ligand corresponds to that of complex 2 but the conjugated area of its main ligand is larger.

C.The inquiry of structure-activity relationships and antitumor mechanism

The IC50values of complexes 1 and 2 determined in a series of human tumor cell lines by our group are given in Table IV[34].From Table IV,we can see clearly that the trend in the antitumor activities(expressed by A,the lower the IC50value,the higher the A is)of the two ruthenium methylimidazole complexes is A(1)＜A(2).Moreover,complex 2 exhibited lower cytotoxicity towards normal cells compared with cisplatin and characterized the biological activities of a new class drugs.

It is commonly believed that DNA is the main target of many antitumor ruthenium agents[35].Ruthenium complexes can be designed to target particular sequences or structural features of the DNA double helix,and it has been found that the structure of DNA can also be greatly inf l uenced upon the binding of these complexes[36].Many anticancer agents,antiviral agents,and antiseptic agents take action through binding to DNA.The DNA-binding of drugs can be attributed to the hydrophobic interaction,electrostatic forces,hydrogen bond,and so on.In our experiments,it has been found that these Ru(II)methylimidazole complexes possess some common characteristics,e.g.,such complexes can bind to DNA in an intercalation mode,and their Kbare rather high (6.1×105-7.2×105L/mol).Therefore,the interaction between the complexes and DNA in an intercalative mode may be the most important cause which endows the complexes with an excellent antitumor activity.

For cisplatin,the aquation process is believed to be the key activation step before the drug reaches its intracellular target[37],since the aqua complexes are generally much more reactive towards DNA bases than the parental chloro complex[38].Dif f erent from cisplatin, the studied ruthenium methylimidazole complexes are coordination-saturated,and they have no leaving group, while the most important structural feature of them is that they contain planar aromatic moieties(intercalative ligand)and can bind to DNA in an intercalation binding mode.Therefore,their strong DNA-binding affinities may account for the excellent antitumor activities of these complexes.Because of the strong DNA-binding affinities,they can easily interact with the DNA of tumor cells,even make them be cleaved or unbinded, and thus reduce the proteolytic activities of tumors and arrest the cell cycles.Such a mechanism is the same as that proposed for acridine,bleomycin,and daunorubicin[39,40].

From the above ideas,we can discuss the inquiry of structure-activity relationships from DNA-binding affinities,the HOMO-LUMO gap as well as the hydrophobic parameter.

Firstly,thetrendinDNA-bindingaffinitiesof twotitleRu(II)methylimidazolecomplexes,i.e., Kb(1)＜Kb(2),is in agreement with that of A,i.e., A(1)＜A(2).

Secondly,∆εL-Hof a compound molecule is generally an important factor characterizing the reactivity of the molecule on the kinetics[41],i.e.,the smaller∆εL-H,the greater the reactivity of the molecule is. The trend in∆εL-Hbeing∆εL-H(2)＜∆εL-H(1)is also in agreement with that in the anticancer-activity(A). Therefore,it clearly shows that the energies of∆εL-Hfor the title complexes are important factors af f ecting their anticancer-activities.The lower energy of LUMO and smaller HOMO-LUMO gap of the complexes must be advantageous on improving their anticancer-activities.

Thirdly,the hydrophobic parameter(usually expressed as lgP)has been investigated as a factor relevant to anticancer activity of metal-based drugs for many years,because lgP af f ects the absorption of pharmaceutical molecules.In general,the absorbed velocity of the drugs exhibits a linear relationship within a certain varied extent of the lgP.A correlation between increased hydrophobicity and increased cytotoxic activity has been reported for several classes of organic and metal-base drugs[42-46].

For our system,although the lgP data of the Ru(II) methylimidazole complexes are not experimentally measured,the lgP and ClgP data of the main ligand can be obtained from chemoffice software.Since the ancillary ligands of the studied complexes 1-3 are the same,the lgP(or ClgP)data of the main ligand can be used to qualitatively analyze the trend in the hydrophobic values of the whole complexes.The lgP(and ClgP)of the main ligand are listed in Table V.From Table V,we can see that the order of the lgP(and ClgP)of the mainligand is lgP(2)＞lgP(3)＞lgP(1).It means that complex 2 has a rather excellent fat-solubility than that of complex 1.Since many antimetastatic agents usually perform their activity in some organic solvents[47,48], the higher lgP(and ClgP)of 2 should be a considerable factor for its higher cytotoxicity.

TABLE V The lgP and ClgP data of the intercalative ligand of complexes 1-3.

D.Prediction for activity of designed complex 3

The designed complex 3 is calculated using the same method and basis set(PBE1PBE/SDD),the geometric and electronic structures parameters as well as the hydrophobic parameter are listed in Tables II,III,and V respectively.It can be observed that:(i)the geometric structure of complex 3 is similar to that of complex 2.Moreover,the plane area of the intercalative ligand of complex 3 is larger than that of complex 2.(ii)The energies(εL)of the LUMO are in sequence of εL(3)＜εL(2)＜εL(1),and the trend in∆εL-His∆εL-H(3)＜∆εL-H(2)＜∆εL-H(1).(iii)The hydrophobic parameter(lgP and ClgP)of the main ligand are in sequence of lgP(2)＞lgP(3)＞lgP(1).Based on the above discussion on the DNA-binding behaviors and structure-activity relationship of the title complexes 1, 2 as well as the structural character of complex 3,we can predict that complex 3 has high anticancer activity which is even higher than that of complex 2.

In general,factors af f ecting the antimetastatic activity are very complicated.Many factors might af f ect the biological activity,e.g.,the coordination to possible biological target(DNA,etc.)[13,49],dif f erences of uptake and transport into cells among the metal-base drugs molecules[33,49-51],and other physicochemical properties,etc.Here,we have only made a prediction theoretically for the designed complex 3,and these results are awaiting experimental verif i cation.

E.Theoretical explanation of electronic absorptionspectral properties

Since the electronic absorption spectra play a very important role in the study of interaction between the complex and DNA,especially a singlet metal-to-ligand charge transfer(1MLCT)which is very widely applied in bioinorganic chemistry,it is necessary and signif i cant to clarify the detail of these spectral properties theoretically.The TDDFT approach is a very good tool forcomputing the wavelengths and revealing the spectral properties of the complexes.Based on the experimental work,the complete electronic absorption spectra of the title complexes in aqueous solution were minutely studied,simulated and discussed with the TDDFT at the level of B3LYP/LanL2DZ combined with CPCM model.The calculated wavelengths in the range of 250-600 nm,oscillator strengths(f≥0.07),main orbital transition contributions(≥25%)and related orbital characters(see Fig.3 and Fig.S1)of the complexes 1-3,as well as the experimental values are given in Table VI and Table S1 in supplementary material.In addition,the simulated absorption spectra in aqueous solution are given in Fig.4.

TABLE VICalculated wave lengths(λmax),oscillator strengths(f≥0.07),and main orbital transition contributions(≥25%)of complex 1 in aqueous solution as well as the experimental values.

As shown in Table VI,for complex 1,in the range of 250-550 nm,there a strong transition at 521.5 nm (f=0.070)with1MLCT(metal-to-ligand)character comes mainly fromtransition,such a band can be mainly responsible to the experimental one at 523 nm.The experimental band at 456 nm can be assigned to a band at 440.8 nm(f=0.106)also with a metal-to-ligand transition(feature. Besides these two1MLCT transitions,there also a strong band at 347.6 nm(f=0.135)with1LL(ligandto-ligand)character comes mainly from intraligand iip π→π∗transition.The experimental broad band at 276 nm can be assigned to a superposition of these f i ve bands at 295.8 nm(f=0.480),287.6 nm (f=0.116),277.6 nm(f=0.152),276.2 nm(f=0.265), and 261.8 nm(f=0.318).These bands mainly involve the orbital transitions of HOMO-3→LUMO+2, HOMO-8→LUMO,HOMO-6→LUMO+1,and HOMO-9→LUMO,and they can be respectively characterized byand

FIG.4 Simulated electronic absorption spectra(dash line) with TDDFT method considering solvent ef f ect with CPCM method at the level of B3LYP/LANL2DZ for(a)complex 1,(b)complex 2,and(c)complex 3 in aqueous solution as well as the experimental spectra(solid line).

Similar analysis can be applied to complex 2(see Table S1).First,the experimental band at 523 nm which can be assigned to a band at 525.2 nm(f=0.078) comes mainly fromtransition.The experimental band at 456 nm can be also assigned to a band at 447.3 nm(f=0.101)with a metal-to-ligand transition(dRu→feature.Secondly,besides these two1MLCT transitions,there are also three strong transitions at 385.5 nm(f=0.091),354.0 nm(f=0.304), and 326.8 nm(f=0.746)with1LL(ligand-to-ligand) character coming mainly from intraligand tiptransition.Thirdly,the experimental band o at 287 nm can also be assigned to a superposition of these two bands at 285.4 nm(f=0.151)and 282.2 nm (f=0.167),and both of them can be characterized by

From the simulated spectrum of complex 3 in aqueous solution(see Table S1 and Fig.4(c)),we can see that there are main two strong absorption bands observedat 530.0 and 274 nm.The broad band at 530.0 nm can be mainly attributed to a superposition of two bands (536.1 and 520.5 nm)with a metal-to-ligandtransition feature.The other sharp band at 274.0 nm can be assigned to a superposition of three bands(270.6, 270.2,and 274.3 nm)with a ligand-to-ligand transitionfeature.

In summary,the calculated results show that the TDDFT method combined with the CPCM model at B3LYP/LanL2DZ level can reliably reproduce the electronic absorption spectra of such a kind of complex,and the largest absolute error is～16 nm(see Table VI and Table S1).Moreover,comparing the spectra of complexes 1 and 2 with that of designed complex 3,it is interesting to f i nd that the1MLCT band of complex 3 obviously red shifts relative to the those of complexes 1 and 2,and it is in agreement with the fact that∆εL-Hof complex 3 is obviously smaller than those of complexes 1 and 2(see Table III).

IV.CONCLUSION

TheDFTstudiesofaseriesofcomplexes [Ru(MeIm)4(L)]2+(L=iip,tip,2ntz)1-3 show that the substituents on the intercalative ligands have important ef f ects on the electronic structures,trend in the DNA-binding affinities,antimetastatic activity and spectral properties of these complexes.Based on the discussion on the DNA-binding behaviors and structure-activity relationship of the title complexes 1,2 as well as the structural character of complex 3,the antimetastatic activity of the designed complex 3 has been predicted with high anticancer activity which is even better than that of complex 2.In particular,it is interesting to f i nd that∆εL-Hof complex 3 decreases more than those of complexes 1 and 2,and thus its observable red shift in corresponding1MLCT band can be reasonable explained.

Supplementary material:Calculated wavelengths (λmax),oscillator strengths(f≥0.07),and main orbital transition contributions(≥25%)of absorption spectra of complexes 2 and 3 in aqueous solution(Table S1), and the contour plots of some related frontier molecular orbitals of complexes 2 and 3 in aqueous solution (Fig.S1).

V.ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China(No.20903027),the Natural Science Foundation of Guangdong Province of China(No.9452402301001941),the Medical Scientif i c Research Foundation of Guangdong Province of China (No.B2013297),and the University Student in Guangdong Province Innovation and Entrepreneurship Training Program(No.1057112019 and No.1057112013).

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∗Authors to whom correspondence should be addressed.E-mail：jincanchen@126.com,lanmeichen@126.com