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Published in final edited form as: Inorg Chem. 2020 Jan 21;59(11):7380–7388. doi: 10.1021/acs.inorgchem.9b02775

Self-Assembly of Porphyrin-containing Metallacages and Cancer Photodynamic Therapy

Xin Jiang †,§, Zhixuan Zhou ‡,§, Huang Yang ╧, Chuan Shan #, Hao Yu †, Lukasz Wojtas #, Mingming Zhang ║, Zhengwei Mao ╧,*, Ming Wang †,*, Peter J Stang ‡,*
PMCID: PMC7821909  NIHMSID: NIHMS1660309  PMID: 31961145

Abstract

In this report, we describe the synthesis of two porphyrin-containing Pt (II) supramolecular cages via coordination-driven self-assembly. X-ray crystallographic analysis on one cage reveals that the metallacage formation imposes large interchromophore distances, leading to a higher 1O2 generation efficiency relative to the corresponding small molecular precursors. The metallacages were examined as photosensitizers for photodynamic therapy as the potential reduction of the unfavorable self-aggregation phenomenon. In vivo and in vitro investigations demonstrate that the metallacages exhibit enhanced anticancer activity with minimal dose requirement and side effects comparable to the small molecule precursors. Thus, our work demonstrates that self-assembly provides a promising methodology for enhancing the therapeutic effectiveness of anti-cancer agents.

Graphical Abstract

graphic file with name nihms-1660309-f0006.jpg

We designed and synthesized two metallacages via coordination-driven self-assembly between pyridyl-containing porphyrin motifs and a 120-degree di-Pt (II) motif. In vitro and in vivo experiments revealed that the metallacages efficiently inhibits the intramolecular and intermolecular stacking interactions of the porphyrin motifs and enhanced the effect of photodynamic therapy with a low dose and minimal side effects comparable to their small molecule precursors and cisplatin.

Introduction

Coordination-driven self-assembly is a powerful synthetic methodology for the preparation of discrete supramolecular coordination complexes (SCCs), including 2D metallacycles and 3D metallacages1. By the selection of electron-rich organic donors and electron-poor metal acceptors, SCCs with pre-designed, well-defined sizes and shapes can be obtained. As a result, the cavity size of the SCCs, as well as the distance and orientation of the functional groups incorporated within the SCCs, can be controlled, enabling precise functional modularity that lead to widespread applications in catalysis,2 separation3, and both light-emitting4 and polymeric materials5.

In the past few decades, photodynamic therapy (PDT) has been shown to be a promising clinical method for treating various types of cancer and infection6. PDT requires a combination of three elements: photosensitizer (PS), light, and molecular oxygen. Activation of PS by irradiation of a suitable wavelength of light leads to the formation of reactive oxygen species (ROS), which induce cell death7. Among the many PSs, porphyrin and its derivatives have attracted particular attention due to their favorable photophysical properties6b,8. However, porphyrin derivatives exhibit severe π-π stacking due to their large planar structures, which facilitate aggregation and thus reduce their ROS generation efficiency.6b,7b,9 This characteristic has restrained the potential clinical applications of porphyrin derivatives and many other PSs. Although a lot of novel carrier systems have been developed to increase the solubility of porphyrin based PSs, reduce aggregation10 and provide efficient transport direct to cancer cells,11 it is still challenging to achieve molecular level of separation of PSs in these systems because of their strong molecular interactions.

Here, in order to regulate the aggregation of porphyrin-based PSs for improving anti-cancer performance, we design and synthesize two [2+4] metallacages, 1 and 2, via the two-component coordination-driven self-assembly (Figure 1) between pyridyl-containing porphyrin motifs and a 120-degree di-Pt (II) motif. The two-component strategy provides structural simplicity and enhances stability compared to multi-component systems that explored previously,8h as shown by the NMR studies and electrospray ionization mass spectrometry (ESI-MS), which is favorable for studies in complicated biological systems. 3D coordination geometry of metallacage 1 was demonstrated by X-ray crystallographic analysis. The large, rigid structure of the metallacage has accurate component proportion and high structural stability. It can efficiently increase the distance of two porphyrin units and inhibits the aggregation caused by molecular interaction, contributing to obtain a higher ROS generation efficiency. In vitro and in vivo experiments were conducted to examine the anti-cancer activity of the metallacages, which revealed that both compounds exhibited potent anti-cancer activity with a low dose and minimal side effects. This work thus provides a promising methodology for efficient cancer treatment based on the design of supramolecular structures.

Figure 1.

Figure 1.

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Self-assembly of supramolecular cages 1 and 2.

Results and discussion

Synthesis and Characterization of Metallo-Supramolecular Cages.

The metallacages were synthesized via the self-assembly of 5,10,15,20-tetra (3-pyridyl) porphine (3) or zinc 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine (4) with 120° diplatinium (II) motif (5) in a 1:2 stoichiometric ratio in DMSO at 80 °C for 12 h. The 1H NMR of 1 and 2 both showed six sets of aromatic protons from the porphyrin units and the phenyl groups, which are consistent with the expected structures. All the protons corresponding to the pyridyl groups (H1a to H1e) exhibited downfield shifts upon the formation of 1 due to the loss of electron density upon coordination with platinum metal centers, while the peak corresponding to the pyrrole H1f shifted upfield (Figure 2a–e). This phenomenon is also manifested in the 1H NMR spectra of 2 and its ligand 4. The 31P{1H} NMR spectra of 1 and 2 both display a singlet with concomitant 195Pt satellites (δ = 12.64 ppm for 1 and 12.73 ppm for 2, respectively) (Figure 2f–h), which was shifted upfield relative to the acceptor 5 (δ = 18.99 ppm), due to the electron back-donation from the platinum atoms. The signals in the 31P{1H} NMR, 1H NMR, and 2D COSY NMR (Figures S3–12) spectra illustrate the formation of discrete and highly symmetric metallacages.

Figure 2.

Figure 2.

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The structural characterization of metallacages. Partial 1H NMR (a–e) and 31P{1H} (f–h) spectra (500 MHz, DMSO-d6, 300 K) of 5 (a , g), 3 (b), 1 (c and f), 4 (d) and 2 (e, h). ESI-MS spectra of complexes 1 (i) and 2 (j). X-ray crystal structure of 1 (k).OTf anions and the ethyl groups on PEt3 are omitted for the sake of clarity.

Electrospray ionization mass spectrometry (ESI-MS) provides evidence for the formation of the metallacages. A series of peaks with different charge states from 3+ to 6+ were observed for both 1 and 2 due to the loss of the triflate (OTf−) counterions. The isotope patterns of these peaks are in good agreement with the theoretical simulations (Figures 2i, j and Figure S1–2). After deconvolution of m/z, the molecular weights for 1 and 2 were determined to be 6600 and 6732 Da, respectively, confirming that these complexes are composed of two 3 or 4 and four diplatinum (II) acceptors 5.

Single crystals of 1 were obtained by slow vapor diffusion of diethyl ether into a nitromethane solution of the cage (OTf− salt) over four weeks. In the solid state, 1•4OTf•solv crystallizes in monoclinic space group P2/c with a slight positional disorder, due to the flexible nature of the pyridyl groups in 3. The cage consists of two parallel porphyrins linked by four di-Pt (II) motifs. The di-Pt (II) motif adopts an angle of 125°, likely due to the slight twisting of the porphyrin group. The distance between the parallel Pt (II) building blocks is 23.4 Å, while the distance between the two porphyrin panels was found to be 18.3 Å (Figure 2k). The formations of ordered and complementary crystal arrangements are provided in Supporting Information (Figure S13 and Table S1). As such, the metallacage formation via coordination efficiently separates the porphyrin groups, prohibiting the tight packing that is undesirable for practical applications.

Photophysical Properties.

The UV-vis absorption spectra of 1 and 2 were recorded in DMSO (Figure 3a). Several absorption wavelengths were observed in Q band from 450 to 650 nm, which was attributed to the absorption transition between the ground state and the first excited singlet state (S0 - S1). A broad absorption band centered at 638 nm was observed in 1. The chelation of Zn ion in 2 led to hypsochromically-shifted Q-bands compared with 112. This indicates that 1 has more advantages over 2 in practical biological experiments owing to its stronger penetrating ability on account of the redder absorption wavelength.

Figure 3.

Figure 3.

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Photophysical research and cartoon representation of PDT. (a) UV-Vis absorption spectra of 1 and 2 in DMSO (c= 1×10−5 M, 298K). (b) Schematic diagrams of the 1 NPs for cancer treatment. (c, d) Fluorescence intensity of the solution containing SOSG and different nanoparticles at 532 nm as a function of irradiation time (638 nm, 0.5 W/cm2).

Fabrication of Supramolecular Cage Loaded Nanoparticles.

Since 1 and 2 are hydrophobic and not well dispersed in the aqueous media, amphiphilic block polymer PEBP-b-PEG-cRGD (Figures 3b and Fig. S14) was used to encapsulate them into the core of hydrophilic nanoparticles (denoted as 1 NPs and 2 NPs, respectively) to enhance their colloidal stability and circulation time for further in vivo applications13. Furthermore, the accumulation of nanoparticles in tumors can be expected with the collective effects based on the enhanced permeability and retention (EPR) effect and active targeting ability of cRGD moieties14.

The morphologies and sizes of the nanoparticles were investigated by transmission electron microscopy (TEM) and dynamic laser scattering (DLS). Spherical 1 NPs with diameters ranging from 30 to 90 nm were observed in the TEM study (Figure S15A). A slightly larger hydrophilic diameter was recorded from DLS (Figure S15B) due to the hydration of the NPs. An enhancement in diameter from 35.7 to 61.8 nm was observed after loading 1 into the nanoparticles, indicating the successful encapsulation of the cages by the amphiphilic polymers. Furthermore, the zeta potential of the nanoparticles increased from −46.9 mV to −5.4 mV upon encapsulation of 1 (Figure S15C), suggesting that the electrostatic interaction is one of the major driving forces in the formation of self-assemblies, in addition to hydrophobic interaction. The 1 NPs are stable in phosphate-buffered saline (PBS) containing 10% fetal bovine serum at 37 °C over 48 h of incubation (Table S2), demonstrating promising colloidal stability of 1 NPs in biological milieus.

Singlet oxygen sensor green (SOSG) was used to quantify the reactive oxygen species (ROS) generation of the nanomaterials upon laser irradiation (638 nm, 0.5 W/cm2). We used the same molar concentration of porphyrin units (500 nM) to compare the ROS production ability between metallacage and porphyrin alone. As shown in Figure 3c, low fluorescence enhancement was observed from 3 and 3-cored nanoparticles (3 NPs) due to the poor ROS generation efficiency induced by strong π-π stacking interactions. In contrast, a 4-fold enhancement for the SOSG fluorescence is observed upon the introduction of cage structure (1 NPs), suggesting a high photosensitizing efficacy. The high yield of ROS generation from 1 NPs can be attributed to the supramolecular cage structure to efficiently prevent the aggregation of porphyrin units and the incorporation of platinum atoms in the cage. This is beneficial for the generation of reactive singlet oxygen species by promoting intersystem crossing15. Compared to 1 NPs, incorporation of Zn ions in 2 NPs leads to lower ROS generation efficiency under laser irradiation due to the hypsochromically-shifted Q-bands (Figure 3d).

In Vitro Cytotoxicity.

The presence of cRGD within 1 NPs should endow the nanoparticle with tumor targeting capability16. Receptor-mediated uptake of the 1 NPs in mouse triple-negative breast cancer cells (4T1) was quantitatively confirmed by flow cytometry and inductively coupled plasma mass spectrometry (ICP-MS) (Figure 4a and b). Faster and higher cellular internalization of 1 NPs is observed relative to the nanoparticles without cRGD modification.

Figure 4.

Figure 4.

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In vitro cell uptake and cytotoxicity of 1 NPs. (a) Mean fluorescent intensity (MFI) and intracellular platinum amount of 4T1 cells after treatment with the 1 NPs with or without cRGD targeting moiety for different incubation times (b). (c) Relative cell viability of 4T1 cells treated with different administrations.

The cytotoxicity of the compounds in the dark and subjected light irradiation (+Light) was quantified using 3-(4’,5’-dimethylthiazol-2’-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay (Figure 4c and Table S3). The Pt (II) acceptor displayed moderate cytotoxicity, with half-maximal inhibitory concentration in dark (IC50) values of 7.85 ± 0.8 μM and 8.15 ± 0.7 μM for 5 and 5 + Light, respectively. These values are higher than that of commercially available cisplatin (IC50 = 4.39 ± 0.7μM). This result also suggests that light irradiation on 5 cannot enhance its toxicity. In contrast, 3 NPs did not show obvious cytotoxicity without laser irradiation, while the half-maximal inhibitory concentration with light irradiation (LD50) of 3 NPs was determined to be 0.51 ± 0.12 μM upon light irradiation (638 nm for 2 min, 0.2 W/cm2). The most encouraging results were observed from the 1 NPs + Light group, showing an LD50 value of 0.087 ± 0.009 μM upon irradiation, which was much lower than those of the small molecular precursors. From our previous study, we found the SCCs can interact with DNA due to the binding effect between Pt and DNA bases.4h It is possible that the cages degrade in biological environment and release out Pt fragment and show anti-cancer actions. The phototoxicity index (PTI) which defines the ratio of the IC50 in the dark and LD50 under light irradiation was calculated to be 40.7. It is quite difficult to directly compare the PDT performance based on PTI because the lasers are different. At least the PTI of 1 NPs is comparable to aminolaevulinic acid (ALA), which is the porphyrin prodrug used in clinic.17 The results suggested the potential of the 1 NPs as an efficient PS for PDT treatment. Annexin V-FITC/PI assay (Figure S16) and fluorescence in diacetate/propidium iodide (FDA/PI) co-staining assay (Figure S17) also suggest that 1 NPs possesses potent PDT effect.

In Vivo Distribution.

In order to study their pharmacokinetics, the 1 NPs and free 5 were intravenously (i.v.) injected into the mice at a dose of 2 mg/kg platinum. Blood samples were collected at various time points after injection. By quantifying the blood platinum concentration using ICP-MS, the blood circulation half-life of the 1 NPs was calculated to be 2.39 ± 0.4 h, 4.5 times that of 5 (Figure 5a). Approximately 11.4% 1 NPs of the injected dose (ID) remained in the plasma at 24 h. While 5 was almost completely eliminated from the bloodstream 8 h post injection.

Figure 5.

Figure 5.

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In vivo distribution and anti-tumor effect on 4T1 orthotopic breast cancer-bearing mice. (a) In vivo blood elimination kinetics of 5 and the 1 NPs at a dose of 2 mg Pt/kg body weight (n = 4). (b) Tissue distributions of the platinum in the main organs after i.v. injection of the 1 NPs at a dose of 2 mg Pt/kg body weight (n = 4) for different times. (c) Tumor volume as a function of time after different treatments (n = 6). (d) Photos of 4T1 orthotopic tumors harvested from the mice receiving different treatments. (e) H&E and Ki67 analyses of tumor tissues after various treatments. Ki67-positive tumor cells were stained brown. Scale bar is 100 μm. (f) Kaplan-Meier plots and (g) body weights of the mice bearing 4T1 tumors after different treatments. The irradiation density was 0.5 W/cm2 at 638 nm for 6 min. Data are expressed as means ± s.e.m., **P<0.01.

The area under the curve (AUC) of the 1 NPs significantly increased to 149 μg mL−1 h, 18.9-fold higher than that of 5 (7.86 μg mL−1 h). These results suggest that 1 NPs possess a size favorable for long circulation and selective accumulation in the tumor site, which may lead to improved therapeutic efficacy and reduced side effects. Prolonged circulation of nanoparticles in the bloodstream is indispensable for successful targeted delivery and efficient treatment, which was achieved by surface-grafting of PEG shells, thereby preventing them from being cleared by the reticuloendothelial system (RES)18.

To acquire a quantitative assessment of the bio-distribution profile of the 1 NPs, the platinum contents of different organs were analyzed by ICP-MS (Figure 5b). Bio-distribution evaluations indicated that the 1 NPs effectively accumulated in the tumor, approaching 2.24 ± 0.31 μg/g tissue 24 h post administration, which was significantly higher than that of 5 (0.39 ± 0.05 μg/g tissue, Figure S18). A high concentration of 1 NPs can be observed in the liver, which was attributed to the RES capture and subsequent excretion. Precursor 5 showed a significantly different distribution in major organs compared to that of 1 NPs, mainly located at the kidney. These findings suggest that 1 NPs were more widely available for tumor uptake than small molecular drugs, while also reducing the adverse effects towards normal tissues.

In Vivo PDT.

In vivo antitumor efficacy of the 1 NPs was evaluated on the highly aggressive 4T1 orthotopic breast cancer-bearing mice. 4T1 orthotopic tumor-bearing mice with tumor volume around 130 mm3 were randomly divided into six groups, and administered with physiological saline, cisplatin, 5, 3 NPs + Light, 1 NPs, and 1 NPs + Light, respectively. A laser with low power density (0.5 W/cm2) and optimized irradiation time (6 min) was chosen for PDT at 24 h post i.v. injection. No noticeable skin burning was observed by application of the laser alone. The tumors of the mice administered with saline grew rapidly (Figure 5c), exhibiting a 13.0-fold increase of tumor volumes after 21 days as compared with their original volume. The growth of tumors was slightly reduced by cisplatin, 5 or 1 NPs. Although the tumor size was notably reduced by the PDT in the first 6 days for the group subjected to 3 NPs + Light, a rapid recovery of tumor growth was evident afterwards, likely due to the relatively low ROS generation of 3 NPs that was unable to clear all cancer cells distal from the primary tumor. 1 NPs + Light displayed the highest anti-tumor efficacy among these groups and almost completely eradicated tumors without recurrence (5 out of 6 mice) in the experimental period. The tumors were excised after 21 days post-treatment, and the weights of the tumors were assessed (Figures 5d and S19). The tumor growth inhibition ratio of the groups treated with 1 NPs upon light irradiation was 98.4%, while those for 1 NPs, 5, 3 NPs + Light, and cisplatin was 51.5%, 37.3%, 60.5%, and 31.2%, respectively. These results demonstrated the anti-tumor efficacy of 1 by laser-irradiation-activated PDT to ablate the tumor without recurrence after a single treatment.

Immunohistochemical analyses were supportive of the results concerning tumor inhibition discussed above (Figure 5e). Hematoxylin and eosin (H&E) stain revealed that tumors in the control groups showed varying levels of recession compared with the saline-treated group. For the mice treated with 1 NPs + Light, no tumor cells were observed, suggesting successful destruction of the tumor. Ki67-positive immunohistochemical staining further revealed the lowest proliferation (brown spots) in the tumor area from the photo-chemotherapy group (1 NPs+ Light).

The systemic toxicity of the nanomedicine was evaluated using body weight loss and survival rate as indications. For 5 and cisplatin administrations, the body weight of mice decreased within the first week due to their systematic toxicity and related side effects (Figure 5g). Histological analyses provided insight into the systemic toxicity caused by 5 or cisplatin. Some pulmonary and hepatic damage was observed from the mice in 5 in cisplatin groups (Figures S20–21). In contrast, no apparent changes in body weight and histological examination were observed from the mice receiving other treatments (Figures S22–24), implying that 1 NPs + Light has minimal systemic toxicity to mice after a single injection. The median survival rates for the mice treated with saline, 1 NPs, 5, 3 NPs + Light, and cisplatin were calculated to be 36, 49, 42, 54, and 42 d, respectively; whereas PDT using 1 NPs + Light greatly prolonged mice survival over 75 days with a single death (Figure 5f). These results demonstrated PDT using 1 NPs + Light effectively prolonged mice lifespans without obvious side effects. A positive therapeutic effect was also observed on the cisplatin-resistant tumor model in vitro and in vivo (Figures S25–26).

The lung tissues were collected and investigated after the mice were sacrificed (Figure S27A) to study the anti-metastatic effect of 1 NPs. The average metastatic tumor nodules per lung were counted to be 5.67, 2.17, 3.67, 1.17, and 4.2 for the mice treated with saline, 1 NPs, 5, 3 NPs + Light, and cisplatin, respectively (Figure S27B). The tumor coverage percentages of the lung surface were calculated to be 9.33%, 2.23%, 4.37%, 0.83%, and 5.51% for the mice treated with saline, 1 NPs, 5, 3 NPs + Light, and cisplatin, respectively (Figure S27C). In contrast to these groups, only one tumor nodule was visualized from the six lungs of mice that received the combinational treatment using 1 NPs + Light. The average tumor coverage on the lung surface was only 0.07%, indicating strong anti-metastatic efficacy of the PDT by 1 NPs.

Conclusions

In summary, we designed and synthesized two supramolecular metallacages using the coordination-driven self-assembly between porphyrin derivatives (3 and 4) and 120° bimetallic Pt (II) acceptors (5). The single crystal of 1 indicates that the formation of metallacages efficiently inhibits the intramolecular and intermolecular stacking interactions of the porphyrin motifs, leading to a higher ROS generation efficiency relative to the precursor. 1 NPs and 2 NPs were prepared by encapsulating the metallacages into the core of hydrophilic nanoparticles by using amphiphilic block polymer PEBP-b-PEG-cRGD, which enhances their colloidal stability and prolongs their circulation time. 1 NPs showed an IC50 value of 0.087 ± 0.009 μM upon light irradiation, which was significantly lower than those of the small molecule precursors. In vivo studies suggest that PDT 1 NPs exert tumor inhibition effects without recurrence and metastasis after a single treatment against orthotopic breast cancers and drug-resistant cancers. This research provides a promising strategy for efficient cancer treatment by modulating the properties of functional motifs using self-assembly.

Experimental section

General Procedures.

Compound 5,19 420 and PEBP-b-PEG-cRGD13c,11c were prepared according the reported literature. All reagents were purchased from Sigma-Aldrich, Matrix Scientific, Alfa Aesar and used without further purification. Column chromatography was conducted using basic Al2O3 (Brockman I, activity, 58 Å) or SiO2 (VWR, 40-60 μm, 60 Å) and the separated products were visualized by UV light. NMR spectra data were recorded on a 500-MHz Bruker Avance NMR spectrometer in CDCl3, DMSO-d6 with TMS as reference. ESI-MS was recorded with a Waters Synapt G2 tandem mass spectrometer, using solutions of 0.5 mg sample in 1 mL of DMSO/MeOH/Acetone (1:1:3, v/v) for complexes. The X-ray diffraction data were measured on Bruker D8 Venture PHOTON II CPAD system equipped with a Cu Kα INCOATEC ImuS micro-focus source (λ = 1.54178 Å). The TEM images of the drop cast samples were taken with a JEOL 2010 transmission electron microscope.

Synthesis of Complex 1: 3 (10.0 mg, 16.2 μmol) and 5 (43.4 mg, 32.4 μmol) were weighed accurately and dissolved in 2.5 mL DMSO, and the mixture was heated at 80 °C for 10 h. After cooling to room temperature, excessive amount of diethyl ether was added and a precipitate was formed, which was filtered and washed with diethyl ether, then dried in vacuo to get a dark brown solid (51.5mg, 96.4%). 1H NMR (500 MHz, DMSO-d6, 300 K, ppm) :δ 9.60 (m, 8H, Py-Ha), δ 9.33 (d, 8H, Py-Hb), δ 8.94 (m, 24H, Py-Hd, P-He), δ 8.28 (t, 8H, Py-Hc), δ 7.63 (d, 16H, Ph-H2), δ 7.20-7.30 (m, 16H, Ph-H1), δ −3.13 (s, 4H, P-Hf). 13C DEPTQ NMR (500 MHz, DMSO-d6, 300 K, ppm ) δ 194.01, 154.46, 153.24, 143.76, 142.94, 140.53, 137.29, 135.39, 131.93, 130.08, 128.92, 127.06, 122.01, 119.86, 115.42, 42.57, 41.80, 40.89, 12.65, 7.89. ESI-MS (m/z): 2049.2 [M-3OTf−]3+ (calcd m/z: 2049.2), 1500.9 [M-4OTf−]4+ (calcd m/z: 1500.9), 1170.7 [M-5OTf−]5+ (calcd m/z: 1170.7), 950.6 [M-6OTf−]6+ (calcd m/z: 950.6).

Synthesis of Complex 2: 4 (10 mg, 14.7 μmol) and 5 (39.4 mg, 29.4 μmol) were weighed accurately and dissolved in 2.5 mL DMSO, and the mixture was heated at 80 °C for 10 h. After cooling to room temperature, excessive amount of diethyl ether was added and a precipitate was formed, which was filtered and washed with diethyl ether, then dried in vacuo to get a dark purple solid (47.0 mg, 95.1%). 1H NMR (500 MHz, DMSO-d6, 300 K, ppm): δ 9.60 (s, 8H, Py-Ha), δ 9.29-9.30 (d, 8H, Py-Hb), δ 8.84-8.87 (m, 24H, Py-Hd, ZP-He), δ 8.22-8.25 (t, 8H, Py-Hc), δ 7.64 (d, 16H, Ph-H2), δ 7.21-7.32 (m, 16H, Ph-H1). 13C DEPTQ NMR (500 MHz, DMSO-d6, 300 K, ppm) δ 193.98, 154.08, 152.81, 150.01, 143.60, 142.80, 141.78, 137.27, 135.40, 132.49, 131.92, 130.10, 128.90, 126.72, 122.27, 119.71, 115.53, 41.81, 12.64, 7.88. ESI-MS (m/z): 2093.2 [M-3OTf−]3+ (calcd m/z: 2093.2), 1532.4 [M-4OTf−]4+ (calcd m/z: 1532.4), 1196.1 [M-5OTf−]5+ (calcd m/z: 1196.1), 971.8 [M-6OTf−]6+ (calcd m/z: 971.8).

Supplementary Material

Supporting Information

ACKNOWLEDGMENT

This work was supported by the Program for JLU Science and Technology Innovative Research Team and Natural Science Foundation of Jilin Province (20180101297JC), National Natural Science Foundation of China (51822306) and the National Key R&D Program of China (2016YFE0132700). P. J. S. thanks NIH (Grant R01 CA215157) for financial support.

Footnotes

Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.9b02775. Electronic Supplementary Information (ESI) available: Synthetic and characterization data (NMR, ESI-MS, in vitro and in vivo experiment).

The authors declare no competing financial interest.

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