A Computational Way To Achieve More Effective Candidates for

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A Computational Way to Achieve More Effective Candidates for Photodynamic Therapy Xin Wang, Fu-Quan Bai, Ying-Tao Liu, Yu Wang, Hong-Xing Zhang, and Zhenyang Lin J. Chem. Inf. Model., Just Accepted Manuscript • Publication Date (Web): 06 Apr 2017 Downloaded from http://pubs.acs.org on April 6, 2017

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Journal of Chemical Information and Modeling

A Computational Way to Achieve More Effective Candidates for Photodynamic Therapy Xin Wang,†, § Fuquan Bai,*,†,‡ Yingtao Liu,§ Yu Wang,† Hongxing Zhang*,† and Zhenyang Lin*,‡ †

International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Institute

of Theoretical Chemistry, Jilin University, Changchun 130023, China. ‡

Department of Chemistry, The Hong Kong University of Science and Technology, Clear

Water Bay, Kowloon, Hong Kong SAR 999077, China §

School of Chemistry and Chemical Engineering, Ningxia University, Yinchuan 750021,

China.

ABSTRACT: The purpose of the work is to design high efficient photosensitizers (PS) for photodynamic therapy (PDT) in theory. A series of expanded Zn porphyrins have been studied as light activated PS. The main photophysical properties are systematically calculated by using density functional theory and its time-dependent extension. The mechanisms of PDT are discussed. All the considered candidates exhibit intense absorption in the therapeutic window (600-800 nm), efficient intersystem crossing and sufficient energy for singlet molecular oxygen production. Accordingly, the designed Zn pentaphyrins and sapphyrins would be proposed as potential PS for PDT. Moreover, the

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therapeutic effect of Zn pentaphyrins and sapphyrins are better than the referenced Zn iso-pentaphyrin. It is expected that the results could provide a new way to design and develop PS for PDT application.

1. INTRODUCTION

As an effective and minimally invasive medical treatment to destroy cancer cells without systemic toxicity, photodynamic therapy (PDT) has been received increased attentions.1-6 The working mechanism of PDT is starting with the activation of a nontoxic photosensitizer (PS) with visible light, then the activated photosensitizer transfers energy to ground state molecular oxygen to produce reactive-oxygen species (ROS), in particular, singlet oxygen, which can cause apoptosis in cancer cells.7, 8 The harmless visible light can be provided by a light source, so singlet oxygen 1O2 can be generated when photosensitizer is accumulated in diseased tissues in the presence of oxygen 3O2. The photochemical processes involved in PDT can be carried out by the following steps.9 Firstly, the photosensitizer is excited from the ground state (S0) the lower-energy excited states, usually the first singlet excited state (S1), by an absorption of light. If the absorption of the light induces the population of higher-energy excited states, the final population of S1 state could be achieved by a fast internal conversion process. Secondly, the S1 state of photosensitizer decays to triplet excited state (T1) through efficient intersystem crossing (ISC) transition, and the spin-orbit coupling (SOC) constants should be greater than 0.24 cm-1.10, 11 Thirdly, the energy of the T1 state is transferred to molecular oxygen (3O2), and then the reactive species 1O2 is formed. The main PDT photochemical reactions can generate ROS via either Type I mechanism or Type II mechanism. For Type I, the activated


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PS undergoes directly oxygen dependent reactions. The excited PS reacts with the substrate such as cell membrane to yield radical ions and free radicals accompanied by an electron transfer. These radicals are subsequently scavenged by molecular oxygen 3O2 to produce reactive intermediates (i.e., O2−, H2O2, and OH−), which are able to cause the diseased cells death. It is worth noting that the electron affinities of PS should be less than that of molecular oxygen for positive energy gain of the reactions. For Type II mechanism, the T1 excited PS transfers its energy to the ground state of molecular oxygen (3O2) to yield the cytotoxic excited singlet oxygen agent (1O2), and the energy of the T1 excited state should be higher than 0.98 eV.12-15 In recent years, many reports have demonstrated the potential use of PDT in clinical applications. Therefore, it is critical to developing new biomaterials for PDT. Actually, various PDT candidates featuring strong light absorbance, excellent photostability and high photochemical conversion efficiency have been produced. Examples of these candidates include organic compounds and their metal complexes.2,

13, 14, 16-18

These

compounds possess electronic absorption bands fall in the so-called therapeutic window (600.0-800.0 nm) where tissue penetration of light is at a maximum while still being energetic enough to produce singlet oxygen.19, 20 It is worth noting that the blue light and green light could also be used in PDT. However, the depth of the penetration doubles from the 4.0 mm observed between 500.0 and 600.0 nm to 8.0 mm at 800.0 nm, which defines the 600-800 nm range where light penetration is most effective.20 Meanwhile, the energy gaps between the singlet and triplet excited states of these compounds are great enough to generate 1O2, which are usually lying above 0.98 eV. In addition, effective ISC from the singlet to triplet excited state is a key parameter in the PDT working mechanisms.



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According to El-Sayed’s rules,21 the SOC constant for the d electrons in heavy transition metal elements is significantly larger than that of other main group elements. The strong SOC effect of heavy metal atoms makes the transition metal complexes possess great advantages over organic compounds in ISC between the spin-forbidden states. In fact, some diamagnetic metals, such as Lu, Hg, Cd and Zn are known to enhance ISC and to elongate triplet lifetime of the photosensitizer.2, 22-24 Instead, the paramagnetic ones are found to deactivate the excited state, reduce the excited-state lifetime and prevent the occurrence of photochemical reactions.25 Among these diamagnetic metal complexes, the Zn-contained complexes remain widely used as PDT candidates due to their richly populated triplet excited states and efficient photodynamic production of singlet oxygen.2, 12, 26

The electron configurations of Zn ion are elucidated in detail to find the reason why Zn

complexes are so popularly applied in PDT. The closed-shells of ZnII are characteristic of diamagnetic, which is consistent with its electron configuration being 1s22s22p63s23p63d10. In such conditions, the d-d transition is forbidden due to the full filled with 3d electrons. In general, the SOC value is largest when the singlet (1dπ*) and the triplet (3d′π*) states are both strong with MLCT character and d ≠ d′. But the metal-centered (3MC) states which initiated from d-d transitions usually cause thermal quenching.27 This implies that the ISC rate for the organometallics systems may be sensibly enhanced if a change of orbital type involved in the radiationless transition. According to the electron configuration of ZnII, the charge transitions of the traditional ZnII complexes are always attributed to metal-ligand charge transfer (MLCT) transitions or ligand-ligand charge transfer (LLCT) transitions, instead of metal-metal charge transfer (MMCT) transitions. Hence, the strength of SOC in


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ZnII would be stronger than that of the other metal ions with empty d orbitals, and the ZnII complexes would be more efficient in PDT. In addition, the photophysical properties of such Zn porphyrins and phthalocyanines compounds can be appropriately tailored through structural modifications of the macrocycle. The expanded porphyrin macrocycles have attracted tremendous attention because of their potential applications as photosensitizers for photodynamic therapy.28-30 The lutetiumIII iso-pentaphyrin and zincII iso-pentaphyrin complexes have been studied as PS,2, 31 and they showed appropriate photophysical properties to be used in PDT. But lutetium is relatively expensive and rare compared to zinc. So the ZnII iso-pentaphyrin used as PS in PDT is more deserving of attention. However, the photodynamic effect of ZnII iso-pentaphyrin is not efficient as lutetiumIII iso-pentaphyrin, even though metallation strongly improves the photosensitizing property of the free metal iso-pentaphyrin derivative. Therefore, our current purpose is to design some efficient ZnII complexes for PDT candidates. Here, aromatic expanded pentaphyrin are considered to replace the nonaromatic iso-pentaphyrin. There are three types of expanded porphyrin systems containing five pyrrole rings, and they are pentaphyrin, sapphyrin, and smaragdyrin, respectively. These conjugated systems contain an additional pyrrole ring compared with porphyrin but differ from each other with the number of bridging methines or direct binding between connect two units of the five pyrrole rings. Pentaphyrin has five pyrrole units connected with each other through five methine bridges, and it has been reported that the pentaphyrin exist in different oxidation states: nonaromatic iso-pentaphyrin with 24 π-electrons and aromatic pentaphyrin with 22 π-electrons.32 Sapphyrin contains one direct bond and four bridging methines between the



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five pyrrole rings.28, 33-35 Smaragdyrin contains two direct bonds and three methine bridges connecting the five pyrrole rings.28 These expanded porphyrins are characterized absorption and emission in the NIR (near-infrared) region because of their extended π-conjugation pathways.34 We expect to obtain targeted photophysical properties by adjusting ligand and coordination mode of ZnII iso-pentaphyrin.

Scheme 1. Molecular structures of all complexes investigated in this work.

In this paper, [Znppy]+1, Znppy (ppy = pentaphyrin), [Znspy]+1, [Znspy]-1, and Znspy (spy = sapphyrin) are designed on the base of [Znisoppy]+1 (iso-ppy = iso-pentaphyrin),2 shown in Scheme 1. When pentaphyrin is coordinated to ZnII, it can lose one or two protons to yield [Znppy]+1 and Znppy, respectively. Sapphyrin has three protons, indicating that the coordination to ZnII can cause molecular sapphyrin to lose one, two or three protons which leading to cationic [Znspy]+1, neutral Znspy and anionic [Znspy]-1. In addition, the isomers Znspy (a) and Znspy (b) have been obtained in experiment.36 Based on Znspy (a) and Znspy (b), isomers [Znspy]+1 (a) and [Znspy]+1 (b) are designed. (see Figure 1). The structures and photophysical properties of these designed Zn pentaphyrins


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and sapphyrins are predicted by theoretical simulation. These expanded Zn porphyrin complexes are expected to be used as efficient PS for PDT.

Figure 1. Optimized geometry structure of complexes [Znisoppy]+1, [Znppy]+1, Znppy, [Znspy]+1, [Znspy]-1 and Znspy, top view (left) and side view (right).

2. THEORETICAL SIMULATION The quantum chemical study is more appropriate for PDT action mechanisms investigation and a powerful strategy to design new PDT candidates. The Density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations are carried out by using the Gaussian 09 program37 and the Amsterdam Density Functional (ADF) program,38,

39

respectively. Ground state molecular

optimizations and natural bond orbital (NBO) analysis are performed at the M06-2X40//6-31G(d)/lanl2dz level without symmetry restrictions, and the vibrational frequencies are calculated to confirm that all the optimized structures are actual minima on



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the whole potential energy surface. For electron affinity calculations, 6-311+G(d) are used on heteroatoms due to the s and p diffuse functions can better describe electron delocalization for negatively charged species.41 Then TD-M062X method is employed for frontier molecular orbitals properties and absorption spectra calculation. In addition, solvent effects are included by means of the polarizable continuum model (PCM)42, 43 in all the calculations. In this paper, dichloromethane and water are selected as solvent models. Different DFT and TD-DFT methods are employed for geometry optimization and absorption spectra calculation. Five different exchange-correlation functionals, namely, B3LYP,44 PBE0,45,

46

M06-2X,40 BHandHLYP47 and M06-HF,48,

49

coupled with the

6-31G(d) basis set, have been used on [Znisoppy]+ in order to select the most rational one. Ground state molecular optimization and absorption spectra calculations of [Znisoppy]+ have been performed in dichloromethane solution by using the five different functionals. The absorption results of [Znisoppy]+ obtained from different functionals are collected in Table S1. The calculated results are compared with the experimental data,2 which shows that the M06-2X functional can better reproduce the absorption wavelength. So M06-2X functional is employed in this paper. The computation present above is carried out by using the Gaussian09 software.37 Then, the spin-orbit coupling matrix elements (SOCMEs) between singlet and triplet excited states, , is calculated by using the Amsterdam Density Functional (ADF) program based on the optimized structures at ground states.38,

39

The scalar

relativistic ZORA method is applied,50 and then a second-order perturbation method is performed on the relativistic scalar ZORA results.51 The SOCMEs are obtained by B3LYP functional with a Slater type TZP basis and a frozen core approximation.52 The SOC


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constant could be presented as the root of sum square of the SOC magnitude from three triplet sublevels. Tm,x, Tm,y and Tm,z are the three sublevels of one triplet excited state, Sn is singlet excited state.27 = ∑α=x,y,zRe2 +Im2 2 1

(1)

3. RESULTS 3.1. Molecular Structures for Candidates The optimized structures of the [Znisoppy]+, [Znppy]+, Znppy, [Znspy]+, [Znspy]-, and Znspy are shown in Figure 1, and the main geometrical parameters of these complexes are summarized in Table 1. Note that the experimental data of these complexes are still unavailable. As shown from the dihedral angle between adjacent pyrrole rings (labeled A, B, C, D and E in Figure 1), their optimized structures display distorted conformation in different degrees. The values of the relevant torsional angle are listed in Table 1. The torsional angles are large for [Znisoppy]+, [Znppy]+, Znppy, [Znspy]- and [Znspy]+. For example, the maximum torsional angles are 58.6°, 40.0°, 64.8°, 46.9°, 21.1° and 26.9° for [Znisoppy]+, [Znppy]+, Znppy, [Znspy]- [Znspy]+ (a) and [Znspy]+ (b), respectively. However, the maximum torsional angle of [Znspy]+ is smaller than those of [Znisoppy]+, [Znppy]+, Znppy and [Znspy]-. Hence, [Znspy]+ is found relatively flat compared with [Znisoppy]+, [Znppy]+ and Znppy. Moreover, Znspy (a) and Znspy (b) are almost planar due to the torsional angles are 0° for them. For [Znisoppy]+, [Znppy]+, [Znspy]+, and Znspy, the differences of bond angles between adjacent pyrrole rings (N1-Zn-N2, N2-Zn-N3, N3-Zn-N4, N4-Zn-N5 and N5-Zn-N1) are very large, ca. 45.0° between the minimum bond angle and maximum bond angle. However, these bond angles trend to be equal with each other in the case of Znppy and [Znspy]-1. This is because all the protons are



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Table 1. Main Bond Lengths (Å), Bond Angles (˚) and Dihedral Angles (˚) for the Studied Complexes in the Ground States, Calculated in Dichloromethane Solvent. [Znisoppy]+

[Znppy]+

Znppy

[Znspy]+ (a)

[Znspy]+ (b)

[Znspy]-

Znspy (a)

Znspy (b)

Bond Lengths Zn-N1

2.093

2.130

2.283

2.425

2.272

2.294

2.122

2.144

Zn-N2

3.450

2.043

2.296

2.014

1.982

2.294

3.694

3.731

Zn-N3

3.603

2.193

2.326

2.089

2.272

2.498

3.687

3.601

Zn-N4

2.352

3.784

2.340

3.592

3.506

2.259

2.170

2.169

Zn-N5

2.053

3.606

2.312

3.854

3.506

2.498

1.999

2.028

N1-Zn-N2

63.9

92.4

79.3

88.5

93.6

71.4

75.8

71.8

N2-Zn-N3

47.9

92. 7

76.1

96. 3

93.6

71.7

45.2

42.4

N3-Zn-N4

65.9

66.3

72.8

56.6

64.5

76.5

68.8

58.1

N4-Zn-N5

82.2

43.0

73.8

43.0

44.4

76.5

79.6

92.5

N5-Zn-N1

95.9

70.8

77.9

63.3

64.5

71.7

90.6

95.2

Bond Angles

Dihedral Angles Φ(A-B)

56.7

15.9

20.1

21.1

26.9

3.3

0.0

0.0

Φ(B-C)

38.2

21.4

46.6

7.5

26.9

35.4

0.0

0.0

Φ(C-D)

58.6

40.0

64.8

12.8

20.1

46.9

0.0

0.0

Φ(D-E)

32.7

33.6

59.5

16.3

26.7

46.9

0.0

0.0

Φ(E-A)

31.6

37.2

34.8

17.4

20.1

35.4

0.0

0.0

dissociated in the coordination for Znppy and [Znspy]-1, and the effect of steric hindrance arising from proton diminishes. The NH group in pyrrole ring also makes the Zn-N bond lengths longer than those bonds without NH proton in pyrrole ring, e.g. the Zn-N bond lengths are more equal in Znppy and [Znspy]-1 than in other complexes studied here. From


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the above discussions, we can see that the presence of methine bridged and NH group in the five pyrrole rings has a significant effect on the molecular structures of these Zn pentaphyrins, which could lead to interestingly photophysical properties for PDT. 3.2. Stabilization Energy E2 Analysis for Candidates In order to further confirm the good stability of these designed Zn pentaphyrins and sapphyrins, the NBO analysis is performed after the geometries optimization. Through analysis of the donor–acceptor interaction strength, the physical origin of intermolecular interactions of these Zn complexes can be understood. In NBO analysis, the stabilization energy E2 is associated with each donor NBO and acceptor NBO delocalization, and the ordering of the stabilization energies is consistent with the interaction between two bonds. According to NBO analysis, the stabilization energy E2 (kcal mol-1) for all the studied complexes are computed and presented in Figure 2. The explicit delocalization of each donor NBO and acceptor NBO are shown in Table S2. Meanwhile, the NBO overlaps of main donor–acceptor interactions for all the complexes are clearly illustrated in Figure 3.

Figure 2. Stabilization energy E2 (kcal mol-1) for these candidates.



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As clearly seen in Table S2, the stabilization energy energies E2 between pentaphyrins (sapphyrins) and zinc ions are mainly caused by the lone pair electrons of N in the pentaphyrin (sapphyrin) molecule and the virtual valence orbitals and Rydberg-type orbitals of the zinc ions. It is noteworthy that the total E2 value of Znspy is largest (ca. 260 kcal mol-1), and the E2 values of other designed [Znppy]+, Znppy, [Znspy]+ and [Znspy]are almost similar at ca. 220 kcal mol-1. Moreover, the total E2 values of all the designed [Znppy]+, Znppy, [Znspy]+, [Znspy]-, and Znspy are relatively larger than that of the referenced [Znisoppy]+ (about 200 kcal mol-1). The larger E2 values suggest that intermolecular interaction of the designed complexes is stronger than that of the experimentally synthesized one. Through the analysis of stabilization energy E2, it is concluded that all the calculated Zn complexes have a good stability. 3.3. Electron Affinity The vertical electron affinities (VEA) and adiabatic electron affinities (AEA) of molecular oxygen, [Znisoppy]+, [Znppy]+, Znppy, [Znspy]+, [Znspy]-, and Znspy are calculated. Here three functionals (B3LYP, M06, and M062X) are used to confirm the accuracy and reliability of the theoretical simulation, and the results are all presented in Table 2. The computed AEA of oxygen in vacuum is found to be 0.58 eV, 0.51 eV and 0.38 eV at the B3LYP, M06 and M062X levels, respectively, and the computed values compare well with the experimental gas-phase AEA of oxygen (0.45 eV).53 As we know, the inclusion of bulk solvation effects could give larger values for electron affinities due to more favourable electrostatic stabilization of anionic negative charge in polar solvent. Thus, the VEA and AEA are calculated in dichloromethane solution to be consistent with the conditions in experiment.2 But the dichloromethane solvent is hardly used in vivo inject.


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Hence, the water solvent is also included by means of PCM model.42, 43 As shown in Table 2, the AEA values of molecular oxygen range from 3.19 eV to 3.37 eV in dichloromethane solution,

Figure 3. NBO overlaps of donor–acceptor interactions in all the candidates.

whereas the AEA exhibits larger values and range from 3.50 eV to 3.68 eV in aqueous solution. For [Znisoppy]+, [Znppy]+, Znppy, [Znspy]+, [Znspy]-, and Znspy, different solvents also lead to different AEA values. For example, the AEA values cover the range of 1.61-5.22 eV in vacuo, 1.94-4.05 eV in dichloromethane solution, and 2.39-3.94 eV in aqueous solution, respectively. Meanwhile, the VEA values of all the studied complexes are also computed by the same level. The difference between VEA and AEA values is estimated to be about 0.10 eV In addition, the dipole moments are calculated for these Zn complexes to describe their solubility. The dipole moments of [Znisoppy]+, [Znppy]+, Znppy, [Znspy]+ (a), [Znspy]+ (b), [Znspy]-, Znspy (a) and Znspy (b) are found to be 3.88D, 1.98D, 0.49D,



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4.48D, 2.26D, 0.82D, 3.03D and 1.71D, respectively. In general, compounds with a large dipole moment tend to be soluble in polar solvent, while those with a near zero dipole moment tend to be insoluble. It appears that the solubility of [Znisoppy]+, [Znspy]+ (a) and Znspy (a) are relatively higher than others. In the following discussion, the type I photochemical reactions mechanism will be examined in detail. According to the type I reaction mechanism, the ROS can be generated by the following reactions. In the first step, the PS is excited from its ground state to the lowest excited triplet state (3PS1*): PS0 →

1

hv

PS*n →

1

PS*1

IC

ISC

1

3

PS*1

(2)

Secondly, the PS in its excited triplet state (3PS1*) reacts with an organic substrate S: 3

n-

3

n+

PS*1 +S → PS

PS*1 +S → PS

+S

(n+)

(3)

(n-)

(4)

+S

The third step is the reaction of the reduced PS(n-) species with molecular oxygen 3O2 to produce reactive intermediates (i.e., O2−, H2O2, and OH−), which are able to cause the diseased cells death. PS

n-

-

+ 3O2 → PS + O2

(5)

O2 + ↔ HOn2 n- HOn2 +O2 + → H2 O2 + O2 n- n

H2 O2 +O2 → OH+ +O2 n-

(6)

The most important thermodynamic factor determining the energetic processes is given by the electron affinities of the PS in its excited triplet states. The VEA and AEA values of PS in excited triplet states remain the same as those in ground states because the


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Table 2. Vertical Electron Affinities (VEA) and Adiabatic Electron Affinities (AEA) for Molecular Oxygen and all the Candidates in eV. VEA/eV ε=vacuo ε=CH2Cl2 ε=H2O Dioxygen

B3LYP M06 M062X

ε=vacuo 0.58 0.51 0.38

AEA/eV ε=CH2Cl2 3.37 3.31 3.19

ε=H2O 3.68 3.62 3.50

[Znisoppy]+ B3LYP 4.83 M06 4.87 M062X 4.76

3.49 3.53 3.43

3.29 3.32 3.25

4.93 4.98 4.89

3.76 3.64 3.58

3.41 3.43 3.38

[Znppy]+

B3LYP 4.99 M06 5.07 M062X 5.08

3.75 3.84 3.93

3.60 3.69 3.77

5.08 5.16 5.22

3.84 3.94 4.05

3.68 3.80 3.94

Znppy

B3LYP 1.61 M06 1.67 M062X 1.70

2.91 2.99 3.05

3.08 3.17 3.23

1.71 1.78 1.84

3.01 3.10 3.18

3.17 3.27 3.36

[Znspy]+ (a) B3LYP 4.65 M06 4.82 M062X 4.86

3.34 3.41 3.41

3.12 3.21 3.27

4.78 4.88 4.95

3.50 3.59 3.64

3.24 3.34 3.64

[Znspy]+ (b)

B3LYP 4.83 M06 4.93 M062X 5.05

3.50 3.60 3.73

3.33 3.43 3.55

4.93 5.04 5.19

3.60 3.71 3.88

3.42 3.53 3.69

[Znspy]-

B3LYP 1.87 M06 1.82 M062X 1.79

1.86 1.92 1.99

2.30 2.37 2.45

1.77 1.71 1.64

1.94 2.03 2.14

2.39 2.49 2.60

Znspy (a)

B3LYP 1.55 M06 1.64 M062X 1.70

2.72 2.82 2.89

2.84 2.94 3.02

1.64 1.73 1.84

2.80 2.91 3.03

2.94 3.04 3.16

Znspy (b)

B3LYP M06

1.44 1.52

2.64 2.74

2.78 2.89

1.53 1.61

2.73 2.84

2.87 2.98

M062X 1.58

2.82

2.97

1.72

2.96

3.11



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molecular structures are assumed to be unchanged in the instant electronic transition. These values of VEA and AEA represent a relative scale of the oxidation strength of the studied complexes against the target molecules (organic substrate S and molecular oxygen 3

O2). This reaction in equation (5) is possible only when the summation of the electron

affinity of 3O2 and VEA (PS) is positive: VEA (3O2) − VEA (PS) > 0

(7)

In order to verify whether the designed Zn complexes are able to used as PS in type I, the electron affinity of these candidates is compared with that of molecular oxygen 3O2. The comparison of the calculated electron affinities of all the investigated candidates with the corresponding values of oxygen in dichloromethane solution shows that the redox reactions in Znppy, [Znspy]-, Znspy (a) and Znspy (b) are energetically favorable. Hence, Znppy, [Znspy]-, Znspy (a) and Znspy (b) are able to pass one electron to 3O2 to form O2− in dichloromethane solution according to type I reactions. Then the electron affinities of all the Zn complexes in aqueous solution are compared. The results show that the summation of VEA (3O2) and VEA (PS) is positive for all the studied candidates except [Znppy]+. On the basis of the above analysis, we can conclude that the designed Znppy, [Znspy]-, Znspy (a) and Znspy (b) could be used as efficient PS in dichloromethane solution, and [Znisoppy]+, Znppy, [Znspy]+, [Znspy]- and Znspy could be used as efficient PS in water solution according to the type I PDT mechanism. 3.4. Absorption Spectra From the viewpoint of application, the absorption in the red region (600.0-800.0 nm) makes the PS suitable for photodynamic therapy which requires a deeper penetration into the diseased tissue. So the spectroscopic properties of Q-bands (occurs in 500.0-800.0 nm)


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of the PS could significantly affect the efficacy of PDT. Therefore, it is imperative to understand the characters of the lowest-lying singlet excited states (S1). The vertical excitation energies of the lowest singlet absorption in the Q-band region are collected in Table 3. The contours of the frontier orbitals of these complexes involved in absorption spectra are shown in Figure 4. The energies of the frontier molecular orbitals for these complexes are present in Figure 5 and Table S3. As we known, no dichloromethane can be used in vivo injection. Therefore, the nature of S1 states in water solution is also calculated at the same level, shown in Table S4. By comparing the calculated results getting in water solution with those in dichloromethane solution, we find that the difference between them is very small. However, in order to be consistent with the experimental case, we perform the current calculations in dichloromethane. Moreover, all the calculations are performed with the PCM model.42, 43 The longest absorption band of the Q-bands appears at ca. 812 nm for [Znisoppy]+1, which is in agreement with the experimental case of 817 nm,2 indicating the reliability of the method we used in this work. Table 3 shows that the Q-bands can be mainly assigned to HOMO→LUMO transition in nature (LUMO is the lowest unoccupied molecular orbital and HOMO is the highest occupied molecular orbital). It is widely accepted that the ligand usually has a dramatic effect on the absorption spectra and the corresponding electronic transition properties. For [Znppy]+1, Znppy, [Znspy]+1 (a), [Znspy]+1 (b), [Znspy]-1, Znspy (a) and Znspy (b), the lowest lying absorption is located at ca. 642.9 nm, 652.3 nm, 583.3 nm, 613.8 nm, 616.7 nm, 612.4 nm and 597.1 nm, respectively. From Table 3, it is noted that the Q-bands of [Znppy]+1 and Znppy are mainly due to HOMO→LUMO+1 and HOMO→LUMO transitions, and the Q-bands of Zn sapphyrins are mainly arising from



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Table 3. Lowest Vertical Singlet Excitation Energies (∆E), Oscillator Strengths (f), Main Transitions, and Molecular Orbital Contribution (%) for all the Studied Complexes, Calculated in Dichloromethane Solvent. (H=HOMO, L=LUMO) Excitation energy (eV)

Wavelength (nm)

f

Main configuration

[Znisoppy]+

1.5262

812.4

0.0836

H->L (96%)

[Znppy]+

1.9286

642.9

0.0011

H->L+1 (48%) H-1->L (45%)

Znppy

1.9008

652.3

0.0082

H->L+1 (40%) H-1->L (33%) H->L (15%) H-1->L+1 (12%)

[Znspy]+ (a)

2.1255

583.3

0.0233

H->L (60%) H-1->L+1 (36%)

[Znspy]+ (b)

2.0200

613.8

0.1295

H->L (77%) H-1->L+1 (22%)

[Znspy]-

2.0103

616.7

0.0543

H->L (70%) H-1->L+1 (29%)

Znspy (a)

2.0246

612.4

0.0669

H->L (68%)


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H-1->L+1 (31%)

Znspy (b)

2.0766

597.1

0.0196

H->L (37%) H-1->L+1 (22%) H-1->L (21%) H->L+1 (20%)

HOMO→LUMO and HOMO-1→LUMO+1 transitions. Changing the ligand from nonaromatic iso-pentaphyrin to aromatic pentaphyrin and sapphyrin, the lowest lying absorption of the [Znppy]+1, Znppy, [Znspy]+, [Znspy]- and Znspy all shift to blue. Additionally, no significant changes are observed in the wavelength of the Q-bands when going from cation to anion for Zn pentaphyrins ([Znppy]+1 and Znppy) and Zn sapphyrins

Figure 4. Electronic density contours for the frontier molecular orbitals of these complexes in absorption spectra. (H=HOMO, L=LUMO)



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([Znspy]+, Znspy and [Znspy]-), just with a difference of a few nanometers. The number and position of the dissociated protons in these complexes also do not affect the Q-bands significantly. Nevertheless, all the Zn complexes investigated in this work have absorption bands falling in the PDT therapeutic window (ca. 600-800 nm), which enables them to be used as PS in PDT. For all the complexes, the four frontier molecular orbitals (HOMO-1, HOMO, LUMO and LUMO+1) are mainly composed by the conjugated penta cyclic ligand (see Figure 4), so the Q-bands are all typical π→π* in character. In the case of [Znisoppy]+1, the transition of Q-bands only involves two orbitals (HOMO and LUMO) due to the larger energy gaps between HOMO and HOMO-1, LUMO and LUMO+1, see Figure 5. However, the

Figure 5. Energy diagrams of the frontier molecular orbitals for these complexes. The highest occupied molecular orbitals (HOMO) are highlighted in blue, the lowest unoccupied molecular orbitals (LUMO) are magenta, and the other orbitals (LUMO+1, LUMO+2, HOMO-1, and HOMO-2) are black. Energy gaps between HOMO and LUMO are reported in eV.


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presence of aromatic penta cyclic ligands in [Znppy]+, Znppy, [Znspy]+, [Znspy]- and Znspy makes the transitions of the Q-bands involve four frontier molecular orbitals (HOMO-1, HOMO, LUMO and LUMO+1). As can be deduced from Table S3 and Figure 5, the HOMO-1, HOMO, LUMO and LUMO+1 of [Znisoppy]+1 are well separated in energy. But for [Znppy]+, Znppy, [Znspy]+, [Znspy]- and Znspy, the energy gap between HOMO and HOMO-1 is less than 0.4 eV, and the HOMO and HOMO-1 are nearly degenerate. The LUMO and LUMO+1 of Zn pentaphyrins and sapphyrins are also close in energy, and the energy gap between LUMO and LUMO+1 is less than 0.6 eV. However, these orbitals (HOMO-1, HOMO, LUMO and LUMO+1) in [Znppy]+, Znppy, [Znspy]+, [Znspy]- and Znspy are well separated from the other molecular orbitals (LUMO+2 and HOMO-2) in energy, and the energy gaps are greater than 1.5 eV (see Figure 5). For these Zn complexes with aromatic pentaphyrin and sapphyrin ligands, the characteristics of the frontier molecular orbitals are analogous to the four orbital model of Gouterman.54-56 Therefore, the transition of Q-bands is directly related to the four frontier molecular orbitals calculated for [Znppy]+, Znppy, [Znspy]+, [Znspy]- and Znspy. On the contrary, in the case of the [Znisoppy]+1, the transition of Q-bands is only related to the two frontier molecular orbitals (HOMO and LUMO). The excitation energy of Zn iso-pentaphyrin, Zn pentaphyrins and Zn sapphyrins is at about 1.5 eV, 1.9 eV and 2.0 eV, respectively. The trend of the relative positions of Q-bands obtained for these studied complexes is thus reasonable when considering the four frontier molecular orbitals energies.



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Figure 6. Vertical lowest singlet and triplet excitation energies (eV) for all the studied complexes in CH2Cl2, the energy line of 0.98 eV are highlighted in the green dash.

To apply the photodynamic processes to PDT, it is crucial to test the energy of first triplet excited states (T1) for PS. For Type II PDT photosensitizers, energy transfers from T1 to the ground states molecular oxygen (3O2), generating singlet oxygen species (1O2): 3

1

PS*1 + 3O2 → PS0 + 1O2

(8)

In order to efficiently yield singlet oxygen, the T1 energy of PS is required to lie above 0.98 eV.12-14 The singlet-triplet energy gaps (∆ES-T) of all the studied complexes are computed to verify if the Zn pentaphyrin and sapphyrin series can be used as photosensitizers. The energy positions of low-lying singlet and triplet excited states energy are clearly shown in Figure 6. Meanwhile, the nature of the low-lying triplet excited states is listed in the Table S5. There is only one excited triplet state lying below the first excited singlet states (S1) in [Znisoppy]+1, and the T1 energy is ca. 0.91 eV, which is less than 0.98 eV. Therefore, the Zn iso-pentaphyrin is not a good candidate for application in PDT based on the theoretical computation results. In fact, the capacity of ZnII iso-pentaphyrin to generate ROS species is lower compared to LuIII iso-pentaphyrin when they are all tested in the


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cancer cell lines.2 Moreover, the cytotoxicity of aromatic pentaphyrin analogues could be comparable to LuIII iso-pentaphyrin in the experiment.32 Therefore, the aromatic pentaphyrin analogues are considered to replace the nonaromatic iso-pentaphyrin in this work. For Zn pentaphyrins, four triplet excited states are found to lie below the S1 state. The energy ranges from 1.1 to 1.8 eV in [Znppy]+, from 1.2 to 1.8 eV in Znppy. For Zn sapphyrins, there are also at least three states to be considered for the intersystem crossing reaction mechanism. All the first excited triplet states energies of [Znspy]+, [Znspy]- and Znspy lie above 0.98 eV, which are greater than energetic limit required for 1

O2 yielding. Moreover, the singlet-triplet energy gaps of [Znppy]+, Znppy, [Znspy]+,

[Znspy]- and Znspy are all higher than that of [Znisoppy]+1. The results show that replacing the nonaromatic ligand with the aromatic group in the penta pyrrole chelated ligand could sensibly increase the energy gap between the lowest lying excited triplet state and ground state, which can efficiently tune the ability to generate ROS in PDT. After checking the energy of T1 states, we can conclude that all the complexes we designed here could be proposed as efficient PS in PDT according to the type II PDT mechanism. 3.5. Relative Magnitude of SOC between Singlet and Triplet Excited States The singlet oxygen production will depend also on the efficiency of the intersystem crossing that in turn depends on the amplitude of the spin−orbit coupling. In quantum physics, the spin-orbit coupling is an interaction of a particle's spin with its motion, and the strength of SOC has a remarkable effect on the ISC efficiency, that is, the stronger SOC causes the faster ISC process. Hence, the spin-orbit coupling matrix elements (SOCMEs), ĤSO between the initial Ψ (S1) and final Ψ (Tn, n=1, 2, 3 and 4) wave functions have been



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computed for these complexes by using ADF program,38, 39 presented in Figure 7 and Table S6. According to the El-Sayed rules, the SOC integral is essentially related to the detailed orbital transitions involved in the singlet and triplet excited states.27,57 In the case of [Znisoppy]+1, there is only one excited states (T1) lying below S1. As shown in Table 3 and Table S5, the S1 is similar to T1 in nature for [Znisoppy]+1, involving nearly identical orbital transition contributions from HOMO to LUMO. As demonstrated by the El-Sayed’s rules, the SOC integral would be almost zero when the singlet and the triplet excited states originate through the same orbital excitation. The obtained value of is actually quite small (ca. 0.20 cm-1) in [Znisoppy]+1, and it is smaller than the referenced ĤSO value (0.24 cm-1).10,

11

Therefore, the features of complex Zn

ios-pentaphyrin have been found may not to be perfect for PDT in experiment.2

Figure 7. Spin-orbit coupling matrix elements (ĤSO, cm-1) between low-lying singlet and triplet excited states for all the studied complexes.

Here, the SOCMEs of the radiationless S1/T1, S1/T2, S1/T3 and S1/T4 couplings are computed for Zn pentaphyrins and sapphyrins, because there are four or three triplet excited states lying below the first singlet excited states in energy. As accounted by the El-Sayed's rule, a larger SOC


Page 25 of 45

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integral occurs between states with different orbital excitations, e.g. the S1 and T2 in Znsap (a) (5.56 cm-1). On the other hand, a singlet and a triplet excited states may be weakly coupled if they involve the same major orbital excitation but different excitation energies, e.g. the major excitation are HOMO to LUMO and HOMO-1 to LUMO+1 for both S1 and T2 in [Znsap]+ (a), but the minor composition in T2, from HOMO-1 to LUMO, is able to couple with T1 to contribute a small SOC integral (4.92 cm-1). Likewise, the S1 and T1 in Znsap (b), and the S1 and T1 in [Znsap]+ (b) possess also a small SOC integral, respectively, as shown in Table S6. Similarly, if the singlet and triplet excited states involve some extent of charge transfer mixing apart from the same major excitation, there would also be a finite small SOC integral, e.g. between S1 and T1 in [Znppy]+. For [Znppy]+, [Znspy]+1 (a), [Znspy]+1 (b), Znspy (a) and Znspy (b), the values are all larger than 0.24 cm-1. For Znppy and [Znspy]-1, the SOC values associated with the S1/T1 transition are very small, but increase for S1/T2 one. It could be hypothesized that the energy transfers from S1 to T2 through ISC due to the T2 also lying below S1, and then T2 relaxes to T1 by internal conversion process before relaxation to S0. In this case, the transition between S1 and T2 states also contribute to the inducement of the 3O2→1O2 transformation. Therefore, the designed Zn pentaphyrins and sapphyrins all satisfy the criteria for PDT utilization in principle. Comparing the ĤSO values for all the complexes, we note that the aromaticity of the ligand influences the SOCMEs significantly. Moreover, the number and position of the dissociated protons in the penta pyrrole macrocyclic ligand also contribute to the change of SOCMEs. For example, the presence of the aromatic penta pyrrole chelated ligand in the designed Znppy, [Znppy]+, [Znspy]+1, [Znspy]-1 and Znspy leads to the larger SOCMEs than the referenced [Znisoppy]+1 with nonaromatic iso-pentaphyrin, and the presence of protons in the Zn sapphyrins



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leads to an increase of the spin-orbit coupling between S1 and T1 states. Based on the relative magnitude of SOC between the low-lying singlet and triplet exited states, we can conclude that the designed [Znppy]+, Znppy, [Znspy]+1, [Znspy]-1 and Znspy could be used as PDT agent, and the efficiency of them may be higher than that of [Znisoppy]+1 which has been tested in previous experiments. 4. CONCLUSIONS DFT and TD-DFT methods have been employed to calculate the geometrical structures, electron affinity, absorption spectra properties, singlet-triplet energy gaps, and spin-orbit coupling matrix elements for a series of Zn iso-pentaphyrin, Zn pentaphyrins and Zn sapphyrins. Our work verifies that these Zn complexes are efficient PS in PDT application in theory. Both type I and type II PDT mechanisms have been discussed. According to the calculated results, the following conclusions can be drawn: 1. The electron affinity of the studied candidates is compared with that of molecular oxygen 3O2. The designed Znppy, [Znspy]-, Znspy (a) and Znspy (b) are active as PS in dichloromethane solution, and [Znisoppy]+, Znppy, [Znspy]+, [Znspy]- and Znspy are active in water solution according to the type I PDT mechanism. 2. The longest absorption wavelength of [Znisoppy]+1, Zn pentaphyrin and Zn sapphyrin series are all in the range of the therapeutic window. Moreover, the singlet-triplet energy gaps of the Zn pentaphyrins and sapphyrins are all larger than 0.98 eV, indicating that they can generate singlet oxygen for PDT via type II mechanism. 3. The SOCMEs are computed for the S1→Tn. Changing the aromaticity and the number of the dissociated protons of the penta cyclic ligand have significantly influenced onto the SOCMEs. In addition, the relevant ĤSO values of [Znppy]+, Znppy, [Znspy]+1, [Znspy]-1 and Znspy are


Page 27 of 45

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all larger than referenced 0.24 cm-1. Therefore, all the designed Zn complexes can be applied in PDT in the view of the SOC values. In conclusion, the designed Zn pentaphyrins and sapphyrins could meet the criteria for PDT, and such complexes have a dual type I/type II photoactivity. Moreover, the therapeutic effect of Zn pentaphyrins and sapphyrins are better than the Zn iso-pentaphyrin complex by substituting the nonaromatic ligand. In present work, only two typical pentaphyrin and sapphyrin are tested, other aromatic rings, such as smaragdyrin and isosmaragdyrin are also worthy to be studied. We hope the current work could pave the way for the design of more effective and economical PS for PDT application in future.

■ ASSOCIATED CONTENT Supporting Information Supporting Information Available: Comparison of different functionals with experimental results; NBO analysis of donor–acceptor orbitals interaction; the energy levels of frontier molecular orbitals in ground states; nature of the lowest singlet excited states in water solvent; nature of the low-lying triplet excited states in dichloromethane solvent; detailed spin-orbit coupling matrix elements. This material is available free of charge via the Internet at http://pubs.acs.org. ■ AUTHOR INFORMATION Corresponding Author *E-mail addresses: [email protected] (F.-Q. Bai), [email protected] (H.-X. Zhang) and [email protected] (Z. Lin) ORCID ID



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Fuquan Bai: 0000-0001-9398-1407 Hongxing Zhang: 0000-0001-5334-733X Zhenyang Lin: 0000-0003-4104-8767 Notes The authors declare no competing financial interest. ■ ACKNOWLEDGMENTS This work was supported by the State Key Development Program for Basic Research of China (Grant No.2013CB834801), the National Natural Science Foundation of China (Grant No. 21364009, 21573088 and 21173096) and Young Scholar Training Program of Jilin University. ■ REFERENCES 1.

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for Table of Contents use only

SYNOPSIS: These designed photosensitizers of [Znppy]+, Znppy, [Znspy]+, [Znspy]- and Znspy are more effective than the referenced [Znisoppy]+1 in photodynamic therapy according to the absorption spectra, singlet-triplet energy gaps and spin-orbit coupling matrix elements.


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These designed photosensitizers of [Znppy]+, Znppy, [Znspy]+, [Znspy]- and Znspy are more effective than the referenced [Znisoppy]+1 in photodynamic therapy according to the absorption spectra, singlet-triplet energy gaps and spin-orbit coupling matrix elements. 34x23mm (600 x 600 DPI)

ACS Paragon Plus Environment


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Scheme 1. Molecular structures of all complexes investigated in this work. 57x39mm (600 x 600 DPI)


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Figure 1. Optimized geometry structure of complexes [Znisoppy]+1, [Znppy]+1, Znppy, [Znspy]+1, [Znspy]-1 and Znspy, top view (left) and side view (right). 85x87mm (300 x 300 DPI)



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Figure 2. Stabilization energy E2 (kcal mol-1) for these candidates. 54x35mm (600 x 600 DPI)


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Figure 3. NBO overlaps of donor–acceptor interactions in all the candidates. 83x76mm (300 x 300 DPI)



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Figure 4. Electronic density contours for the frontier molecular orbitals of these complexes in absorption spectra. (H=HOMO, L=LUMO) 177x80mm (300 x 300 DPI)


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Figure 5.Energy diagrams of the frontier molecular orbitals for these complexes. The highest occupied molecular orbitals (H) are highlighted in blue, the lowest unoccupied molecular orbitals (L) are magenta, and the other orbitals (L+1, L+2, H-1, and H-2) are black. Energy gaps between H and L are reported in eV. 59x42mm (600 x 600 DPI)



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Figure 6. Vertical lowest singlet and triplet excitation energies (eV) for all the studied complexes in CH2Cl2, the energy line of 0.98 eV are highlighted in the green dash. 43x10mm (600 x 600 DPI)


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Figure 7. Spin-orbit coupling matrix elements (ĤSO, cm-1) between low-lying singlet and triplet excited states for all the studied complexes. 45x24mm (300 x 300 DPI)


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