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. 2023 Jun 6;8(24):21941–21947. doi: 10.1021/acsomega.3c01807

Long-Wavelength Absorbing Benzimidazolo-Chlorin for Enhanced Photodynamic Therapy

Huiqiang Wu †, Sooho Yeo †, Jiazhu Li ‡,*, Jinjun Wang §, Woo Kyoung Lee †,*, Il Yoon †,*
PMCID: PMC10285954  PMID: 37360422

Abstract

graphic file with name ao3c01807_0010.jpg

In this study, we condensed methyl pyropheophorbide-a (2) with 1,2-phenylenediamine to synthesize benzimidazolo-chlorin (3a) as an effective near-infrared photosensitizer (PS) with an absorption maximum of 730 nm. The ability of 3a to generate singlet oxygen, as well as its photodynamic effect on A549 and HeLa cells, was investigated. PS exhibited strong phototoxicity and negligible dark toxicity. Its structure was examined by UV–visible spectroscopy, nuclear magnetic resonance, and high-resolution fast atom bombardment mass spectrometry.

Introduction

Photodynamic therapy (PDT), a noninvasive and patient-friendly cancer treatment, has gained popularity in recent decades.1,2 PDT is now an extremely common treatment modality because of its high responsiveness and tumor-localizing treatment,3 which reduces long-term morbidity and sets PDT apart from many other cancer treatments, such as chemotherapy, radiotherapy, and tumor resection.

In general, irradiating the tumor site with a suitable wavelength4 can activate photosensitizers (PSs) that have selectively accumulated in the tumor tissue, causing a photochemical reaction, which results in the necrosis of the tumor tissue.5−7 It can only be applied to shallow tissues due to low penetration and the absorption of surrounding tissues.8 As a result, a key parameter of ideal PS is the absorption ability of light in the long-wavelength region, where sufficient tissue penetration by PS-activating light, known as the therapeutic window,9−12 can be achieved for overcoming the aforementioned shortcomings, resulting in deeper tumor treatment without side effects.

PSs can be modified via either chemical conjugation or physical coupling, which manipulates their chemical properties, such as absorbance, solubility, singlet oxygen (1O2), photogeneration quantum yield, and tissue penetration. Chlorin derivatives are chemically and thermally stable long-wavelength absorbing PSs with strong Soret and Q band absorption. For synthesizing these, it is important to use chlorophyll-a with various chemical modifications, such as a fused cyclopentanone structure (E ring), for increased long-wavelength absorption of PS, as shown in Scheme 1.13−18

Scheme 1. Synthetic Procedure of Benzimidazolo-Chlorin Isomers (3a and 3b) and Fused Quinoxaline (3c).

Scheme 1

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1O2 Photogeneration ability of compounds 3a, 3b, and 3c was evaluated by 1,3-diphenylisobenzofuran (DPBF) test, from which 3a was used for cell study (PDT activity). (a) Pyridine, H2O, N2, reflux, 8 h, 80%; (b) 1,2-Phenylenediamine, pyridine, trifluoroacetic acid, N2, reflux, 8 h, diazomethane (3a: 20%, 3b: 10%, 3c: 2.5%).

Benzimidazole, a key component of vitamin B12, is a benzoheterocyclic compound containing two nitrogen atoms. There have been numerous reports of benzimidazole derivatives with anticancer activity.19−21 Furthermore, benzimidazole is an effective chromophore that combines with chlorophyll-a and conjugates with porphyrin rings, increasing electron delocalization and causing a red-shift of the maximum absorption wavelength to synthesize long-wavelength absorbing PS.22,23

Pandey et al. recently reported benzimidazole-introduced chlorin derivatives by synthesizing methyl 132-oxopyropheophorbide-a (132-oxo-methyl pyropheophorbide a (MPPa)) via LiOH-promoted allomerization of PPa, followed by condensation of 132-oxo-MPPa with 1,2-phenylenediamine with an acid catalyst (two-step synthetic procedure).24

Furthermore, Pandey et al. synthesized benzimidazolo-bacterochlorin derivatives, which displayed red-shifted long-wavelength absorption in the near-infrared (NIR) region and were highly stable as potential PS candidates for PDT.25 In a previous study, we synthesized benzimidazolo-chlorin isomers 3a and 3b and fused them with quinoxaline 3c from methyl pheophorbide-a (MPa, 1) or MPPa (2) after a condensation reaction with 1,2-phenylenediamine.26

To the best of our knowledge, this is the first cell study on PDT using compound 3a. As a result, in this study, we revisited the synthesis of chlorin derivatives 3a, 3b, and 3c to develop a long-wavelength absorbing promising PS for enhanced PDT.

Results and Discussion

Synthesis and Characterization of Benzimidazolo-Chlorin Derivatives

In this study, we modified Pandey et al.’s24 and our lab’s26 previous synthetic methods. Benzimidazolo-chlorins were synthesized from MPa 1 followed by a deacetylation and reduction reaction at the 132 position, as shown in Scheme 1. In the mixture of the three products, 3a was the major compound (20% yield), followed by 3b (10% yield) and 3c (only 2.5% yield); this method differs slightly from our previous work.26,27

The two isomers 3a and 3b displayed quite different UV–vis absorption ranges (such as 730 and 714 nm of λmax, respectively) (Figure 1), which was the same as previously reported by Pandey et al. and our lab.24,26,27 When compared to 3a and 3b, compound 3c had a lower wavelength absorption of λmax at 708 nm. As a result, 3a exhibited a highly red-shifted λmax of 62 nm compared to that of MPPa 2. Particularly, Pandey et al. confirmed the two isomer structures of 3a and 3b using single-crystal X-ray structures.24

Figure 1.

Figure 1

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UV–vis absorption spectra of 2 and 3a–3c. The concentration of the compound in each sample is 10 μM (CH2Cl2, 25 °C).

Benzimidazolo-chlorin 3a was characterized by 1H-NMR spectroscopy (Figure S1), in which four new proton signals on the benzimidazole unit at 7.5–9.0 ppm in CDCl3 appeared, indicating the successful formation of the benzimidazole ring in 3a. The 13C-NMR spectrum displayed all 40 carbon signals, demonstrating the distinct structure of 3a (Figure S2). Furthermore, high-resolution fast atom bombardment mass spectrometry (HRFAB MS) analysis confirmed the formation of 3a (calcd for [M + H]+ 651.3084; found 651.3086) (Figure S3). The fluorescence emission spectra (excitation wavelength, 730 nm) of 2 and 3a revealed considerable fluorescence activity of the chlorins, with 3a exhibiting a higher red-shift in the NIR region (745 nm) than 2 (675 nm, Figure 2). The significantly red-shifted UV–vis absorption and fluorescence emission observed between 2 and 3a could be attributed to the rigid conjugation of the benzene ring and imidazole ring, resulting in extended electron delocalization (Figure 3).

Figure 2.

Figure 2

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Fluorescence emission spectra of 2 and 3a. The concentration of the compound in each sample is 20 μM (DMSO, 25 °C).

Figure 3.

Figure 3

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Energy-minimized ball-and-stick models of (a) 2 and (b) 3a.

1O2 Photogeneration Study Using 1,3-Diphenylisobenzofuran (DPBF)

The relative photodynamic effect of chlorin derivatives was evaluated through 1O2 photogeneration ability using DPBF as a selective 1O2 acceptor in the absence of tumor cells. In this study, we used two different LED lights (590–710 and 735–785 nm) to exhibit different activity effects depending on the absorption wavelength ranges of chlorins. The longer-wavelength LED having a 735–785 nm range is suitable for benzimidazolo-chlorin 3a (λmax of 730 nm) for generating enhanced 1O2 photogeneration (Figures 4 and S4). In irradiation using a shorter-wavelength LED (590–710 nm), 3a displayed better 1O2 photogeneration compared with 2 and methylene blue (MB), which is a standard 1O2 sensitizer. When irradiated with a longer-wavelength LED (735–785 nm), 3a demonstrated more 1O2 photogeneration than when exposed to a shorter-wavelength LED, while 2 and MB showed almost no 1O2 photogeneration. Additionally, 3b and 3c exhibited comparable 1O2 photogeneration using a shorter-wavelength LED (Figure S5). This indicates an absorption wavelength-dependent 1O2 photogeneration for each PS molecule. We, therefore, selected 3a as a suitable PS for further cell study in PDT based on its highest absorption wavelength of λmax as well as 1O2 photogeneration.

Figure 4.

Figure 4

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Remaining of DPBF (%, in DMSO) at 418 nm after photoirradiation using two LEDs (590–710 and 735–785 nm, total light dose of each LED: 2 J/cm2; irradiation time: 15 min) without PSs (DPBF only, 50 μM) or the presence of PSs (1 μM) (without cells).

Cellular Uptake and Localization in Mitochondria and Lysosome

The successful cellular uptake and localization of 3a in A549 and HeLa cells were confirmed by fluorescence images of 3a using confocal laser scanning microscopy (CLSM, Figure 5).28 CLSM images exhibited that 3a displayed high mitochondria-targeted accumulation (Figure 5a), resulting in orange color in merged images and inducing mitochondria-mediated apoptosis to destroy the cancer cells.29 And 3a has low lysosome accumulation (Figure 5b), resulting in weak yellow color in merged images.

Figure 5.

Figure 5

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(a) Confocal images of 3a (red) and mitochondria (green) in A549 and HeLa cells. (b) Confocal images of 3a (red) and lysosome (green) in A549 and HeLa cells. Cells were treated with 3a (5 μM) for 24 h post incubation by imaging with CLSM. Scale bar: 20 μm.

We conducted further quantitative evaluation of different organelle accumulations of 3a for the signal colocalization using Pearson’s correlation coefficient (PCC)30 (Figure 6). For the mitochondria, PCC values were higher (0.520 and 0.733 in A549 and HeLa cells, respectively) than those in lysosome (0.265 and 0.267 in A549 and HeLa cells, respectively), indicating high mitochondria targeting (about 2–3 times) and low accumulation in lysosomes.

Figure 6.

Figure 6

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(a) Colocalization of 3a (red) and mitochondria (green) in A549 and HeLa cells. (b) Colocalization of 3a (red) and lysosome (green) in A549 and HeLa cells. PCC was calculated from the region of merged images (white line). The 2D intensity histogram and relative intensity are shown.

Cell Viabilities for Photocytotoxicity and Dark Cytotoxicity

The photocytotoxicity and dark toxicity of 2 and 3a were evaluated in A549 and HeLa cells via the WST-8 assay at a range of 0.50–5.0 μM (Figure 7 and Tables S2–S5). Compounds 2 and 3a demonstrated negligible dark toxicity, indicating their suitable biocompatibility. Upon irradiation with the longer-wavelength LED (735–785 nm, total light dose 2 J/cm2), 3a showed excellent photoactivity with half-maximum inhibitory concentration (IC50, black dashed line in Figure 7) of 4.0 and 3.4 μM against A549 and HeLa cells, respectively. However, 2 exhibited negligible photoactivity. These results are consistent with 1O2 photogeneration shown in Figure 4.

Figure 7.

Figure 7

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In vitro cell viability of 2 and 3a in (a) A549 cells and (b) HeLa cells. Cell viability results in the dark (dash line) and irradiation of 735–785 nm (total light dose: 2 J/cm2; irradiation time: 15 min) (solid line). PS concentration range: 0–5.0 μM.

Conclusions

To develop a long-wavelength (NIR) absorbing PS, we revisited the synthesis of benzimidazolo-chlorin isomers 3a and 3b and fused them with quinoxaline 3c derived through a one-step reaction between MPPa 2 and 1,2-phenylenediamine. Among the mixture of three products, 3a has several advantages, including the following: (i) the major compound in the mixture; (ii) the longest absorption wavelength of λmax at 730 nm; and (iii) the highest 1O2 photogeneration. As a result, we evaluated 3a in further cell studies. Long-wavelength absorbing benzimidazolo-chlorin 3a displayed negligible dark toxicity and excellent phototoxicity, with an IC50 of 4.0 and 3.4 μM against A549 and HeLa cells, respectively, which might be attributed to cellular uptake followed by mitochondrial-targeting-mediated apoptosis for destroying tumor cells. This study will be useful in developing the design and synthesis of long-wavelength absorbing PS with high 1O2 photogeneration and no dark toxicity, in addition to mitochondrial-targeting PS-mediated apoptosis for enhanced PDT.

Experimental Section

Materials

Chlorophyll-a paste was purchased from Shandong Lanmo Biotech Co., Ltd. (Shandong, China). Pyridine, dichloromethane, acetone, hydrochloric acid (35.0–37.0%), trifluoroacetic acid, urea, diethyl ether, and dimethyl sulfoxide were supplied by SAMCHUN (Pyeongtaek, Korea). Silica gel powder (SL–110–60 Å) was purchased from SK Chemicals Co., Ltd. (Gyeonggi-do, Korea). 1,2-Phenylenediamine, methylene blue (MB), and 1,3-diphenylisobenzofuran (DPBF) were purchased from Tokyo Chemical Industry, Ltd. (Tokyo, Japan). Methylamine hydrochloride was purchased from Sigma-Aldrich (St. Louis, MO). Sulfuric acid and potassium hydroxide were supplied from Duksan Pure Chemical Co. (Ansan-si, Korea). Dulbecco’s modified Eagle’s Medium, and Roswell Park Memorial Institute 1640 Medium were supplied from GenDPOT (Barker, TX). Fetal bovine serum (FBS) and streptomycin–penicillin were purchased from BioWest (Nuaillé, France). The cancer cell lines (A549 and HeLa) were purchased from the Korea Cell Line Bank (Seoul, Korea). WST-8 Cell Viability Assay Kit was supplied from Quanti-Max (Biomax, Gyeonggi-do, South Korea). 4′,6-Diamidino-2-phenylindole and MitoSpy Orange CMTMRos were supplied from BioLegend (San Diego, California). LysoTracker Green DND-26 was supplied from Invitrogen (Massachusetts). All compounds are 99–98% pure by HPLC analysis.

1O2 Photogeneration Study

DPBF was used to detect the formation of 1O2. DPBF solution in DMSO (50 μM) was prepared in the dark using the following: DPBF only (50 μM, control sample) as a control group, MB (1 μM, containing DPBF), 2 (1 μM, containing DPBF), and 3a (1 μM, containing DPBF). The samples were irradiated (2 J/cm2) with LED for 15 min, after which the absorbance of each sample was measured at 418 nm using a fluorescence multidetection reader.

Synthesis of MPPa (2)

MPa, 1 (5 g), was dissolved in 200 mL of pyridine and 5 mL of water, refluxed for 9 h under N2, and then put into a diluted hydrochloric acid aqueous solution (1%). The solvent was evaporated under vacuum, and pure 2 (3.5 g) was obtained by recrystallization from dichloromethane and methanol. UV–vis (CH2Cl2) λmax (log ε): 371.0 (4.44), 391.9 (4.44), 395.3 (4.44), 419.3 (4.44), 476.4 (3.61), 507.5 (4.00), 539.0 (3.91), 610.2 (3.86), 668.2 (4.37).

Synthesis of Benzimidazolochlorophyll-a Methyl Ester (3a)

2 (170 mg, 0.302 mmol) was dissolved in pyridine (15 mL), 1,2-phenylenediamine hydrochloride (65 mg) was added, and trifluoroacetic acid (0.5 mL) was injected into the solution. The reaction mixture was refluxed for 8 h, and the progress was monitored by thin-layer chromatography. The reaction solution was extracted using water and CH2Cl2 (500 mL). The organic layer was then dried over sodium sulfate, filtered, and removed under vacuum. The residue was treated with CH2N2 for 5 min and chromatographed on silica (eluent, toluene/acetone = 10:1), and the product was separated as a red-brown band (40 mg, yield 20%). UV–vis (CH2Cl2) λmax (log ε): 377.8 (3.54), 427.2 (4.34), 487.3 (3.41), 516.0 (3.43), 557.2 (3.87), 668.8 (3.54) 730.7 (4.13). 1H-NMR (500 MHz, CDCl3) δ 9.33 (s, 1H, 10H), 9.22 (s, 1H, 5H), 8.95–8.87 (m, 1H, Ar-Hd), 8.75 (s, 1H, 20H), 8.05 (d, 1H, Ar-Ha), 7.99 (dd, J = 17.8, 11.5 Hz, 1H 31H), 7.65–7.56 (m, 2H, Ar-Hb+c), 6.51–6.18 (m, 2H, 32H), 5.62 (dd, J = 9.1, 2.6 Hz, 1H, 18H), 4.57 (q, J = 7.4 Hz, 1H, 17H), 3.80 (s, 3H, 12H), 3.54 (d, J = 10.3 Hz, 5H, 81H + 173H), 3.50 (s, 3H, 71H), 3.11 (s, 3H, 21H), 2.98 (dd, J = 15.4, 10.3, 4.7 Hz, 1H 171), 2.75–2.52 (m, 2H, 171H + 172H), 2.23 (tdd, J = 12.2, 8.8, 3.7 Hz, 1H, 172H), 2.02 (d, J = 7.4 Hz, 3H, 181H), 1.70 (t, J = 7.6 Hz, 3H, 82H), 1.59–1.37 (m, 1H, NH). HRFAB MS: calcd for C37H41N5O4 [M + H]+ 651.3084; found, 651.3086.

Cellular Culture

HeLa (human cervical carcinoma) and A549 (human breast adenocarcinoma) cells were used in this study. The cells were cultured in DMEM and RPMI-1640 supplemented with 10% FBS and 1% antibiotics (streptomycin–penicillin) at 37 °C under a 5% humidified CO2. The cells were collected by centrifugation, resuspended in the medium, and detected.

Cellular Uptake

To study the cellular uptake of PS, the cells were seeded in a confocal dish (2 × 104 cells) and incubated for 24 h. Subsequently, the cells were incubated for 24 h with free PS (5 μM). The cells were washed with PBS and stained with MitoTracker Orange and DAPI for 15 min. Images of the cells were acquired using a highly sensitive CLSM.

Cell Viability

A549 and HeLa cells were cultured in a suitable cell media at 37 °C in a 5% humidified CO2 atmosphere. The cells were seeded into 48-well plates and incubated with different concentrations of 3a for 24 h. After incubation, the cells were exposed to LED light irradiation for 15 min under 735–785 nm (for the dark toxicity experiment, LED light irradiation is not required), followed by an additional incubation of 24 h in the same conditions. The standard WST-8 assay (100 μL, 1:10 dilution of media) was used to measure cell viability for 1 h post incubation, and the results were expressed as a percentage of live cells relative to control cells.

Acknowledgments

This research was supported by the National Research Foundation of Korea (NRF) grant, the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE, Korea, NRF-2020R1I1A1A01060632), and the Korean government (MSIT) (NRF-2020R1F1A1070571).

Glossary

Abbreviations Used

PDT

photodynamic therapy

PS

photosensitizer

1O2

singlet oxygen

MPPa

methyl pyropheophorbide-a

NIR

near-infrared

MPa

methyl pheophorbide-a

DPBF

1,3-diphenylisobenzofuran

MB

methylene blue

DMSO

dimethyl sulfoxide

CLSM

confocal laser scanning microscopy

PCC

Pearson’s correlation coefficient

FBS

fetal bovine serum

PBS

phosphate-buffered saline

DMEM

Dulbecco’s modified Eagle’s medium

RPMI

Roswell Park Memorial Institute 1640 Medium

DAPI

4′,6-diamidino-2-phenylindole

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c01807.

  • Experimental procedures, table of absorbance of PSs, images of DPBF experiments, 1H-NMR and 13C-NMR spectra, HRFAB mass spectrum of 3a, and table of cell viability of PSs (PDF)

Author Contributions

Conceptualization was done by H.W., J.L., W.K.L., and I.Y.; methodology was done by H.W., S.Y., and J.W.; resource gathering was done by W.K.L. and I.Y.; writing and original draft preparation were done by H.W. and I.Y.; funding acquisition was done by W.K.L. and I.Y.; and supervision was done by J.L., W.K.L., and I.Y. All authors have read and agreed to the published version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ao3c01807_si_001.pdf (637.2KB, pdf)

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