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The bromoporphyrins as promising anti-tumor photosensitizers in vitro

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Abstract

The synthesis of ideal photosensitizers (PSs) is considered to be the most significant bottleneck in photodynamic therapy (PDT). To discover novel PSs with excellent photodynamic anti-tumor activities, a series of novel photosensitizers 5,15-diaryl-10,20-dibromoporphyrins (I1–6) were synthesized by a facile method. Compared with hematoporphyrin monomethyl ether (HMME) as the representative porphyrin-based photosensitizers, it is found that not only the longest absorption wavelength of all compounds was red-shifted to therapeutic window (660 nm) of photodynamic therapy, but also the singlet oxygen quantum yields were significantly increased. Furthermore, all compounds exhibited lower dark toxicity (except I2) and stronger phototoxicity (except I4) against Eca-109 tumor cells than HMME. Among them, I3 possessed the highest singlet oxygen quantum yield (ΦΔ = 0.205), the lower dark toxicity and the strongest phototoxicity (IC50 = 3.5 μM) in vitro. The findings indicated the compounds I3 had the potential to become anti-tumor agents for PDT.

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Abbreviations

PDT:

Photodynamic therapy

PSs:

Photosensitizers

ROS:

Reactive oxygen species

1O2 :

Singlet oxygen

TLC:

Thin-layer chromatography

NMR:

Nuclear magnetic resonance

MS:

Mass spectra

HMME:

Hematoporphyrin monomethyl ether

MB:

Methylene blue

DMSO:

Dimethyl sulfoxide

DMF:

Dimethylformamide

DPBF:

1, 3-Diphenylisobenzofuran

DDQ:

2, 3-Dicyano-5, 6-dichlorobenzoquinone

FBS:

Fetal bovine serum

PBS:

Phosphate buffered saline

MTT:

3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-terazolium bromide

References

  1. Sung, H., Ferlay, J., Siegel, R. L., et al. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71, 209–249.

    PubMed  Google Scholar 

  2. Ethirajan, M., Chen, Y., Joshi, P., et al. (2011). The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chemical Society Reviews, 40, 340–362.

    Article  CAS  PubMed  Google Scholar 

  3. Dabrowski, J. M., & Arnaut, L. G. (2015). Photodynamic therapy (PDT) of cancer: From local to systemic treatment. Photochemical & Photobiological Sciences, 14, 1765–1780.

    Article  CAS  Google Scholar 

  4. Gomez, S., Tsung, A., & Hu, Z. (2020). Current targets and bioconjugation strategies in photodynamic diagnosis and therapy of cancer. Molecules, 25, 4964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liao, P. Y., Gao, Y. H., Wang, X. R., et al. (2016). Tetraphenylporphyrin derivatives possessing piperidine group as potential agents for photodynamic therapy. Journal of Photochemistry and Photobiology B: Biology, 165, 213–219.

    Article  CAS  PubMed  Google Scholar 

  6. Liao, P. Y., Wang, X. R., Gao, Y. H., et al. (2016). Synthesis, photophysical properties and biological evaluation of beta-alkylaminoporphyrin for photodynamic therapy. Bioorganic & Medicinal Chemistry, 24, 6040–6047.

    Article  CAS  Google Scholar 

  7. Liao, P. Y., Wang, X. R., Zhang, X. H., et al. (2017). Synthesis of 2-morpholinetetraphenylporphyrins and their photodynamic activities. Bioorganic Chemistry, 71, 299–304.

    Article  CAS  PubMed  Google Scholar 

  8. Yu, W., Zhen, W., Zhang, Q., et al. (2020). Porphyrin-based metal-organic framework compounds as promising nanomedicines in photodynamic therapy. ChemMedChem, 15, 1766–1775.

    Article  CAS  PubMed  Google Scholar 

  9. Li, M. Y., Gao, Y. H., Zhang, J. H., et al. (2021). Synthesis and evaluation of novel fluorinated hematoporphyrin ether derivatives for photodynamic therapy. Bioorganic Chemistry, 107, 104528.

    Article  CAS  PubMed  Google Scholar 

  10. Knoll, J. D., & Turro, C. (2015). Control and utilization of ruthenium and rhodium metal complex excited states for photoactivated cancer therapy. Coordination Chemistry Reviews, 282–283, 110–126.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Plaetzer, K., Krammer, B., Berlanda, J., et al. (2009). Photophysics and photochemistry of photodynamic therapy: Fundamental aspects. Lasers in Medical Science, 24, 259–268.

    Article  CAS  PubMed  Google Scholar 

  12. Leonidova, A., Pierroz, V., Rubbiani, R., et al. (2014). Photo-induced uncaging of a specific Re(I) organometallic complex in living cells. Chemical Science, 5, 4044–4056.

    Article  CAS  Google Scholar 

  13. Bacellar, I. O. L., & Baptista, M. S. (2019). Mechanisms of photosensitized lipid oxidation and membrane permeabilization. ACS Omega, 4, 21636–21646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Allison, R. R., & Sibata, C. H. (2010). Oncologic photodynamic therapy photosensitizers: a clinical review. Photodiagnosis and Photodynamic Therapy, 7, 61–75.

    Article  CAS  PubMed  Google Scholar 

  15. Liao, P., Zhang, X., Zhang, L., et al. (2016). Synthesis, characterization and biological evaluation of a novel biscarboxymethyl-modified tetraphenylchlorin compound for photodynamic therapy. RSC Advances, 6, 26186–26191.

    Article  CAS  Google Scholar 

  16. Szacilowski, K., Macyk, W., Matuszek, A. D., et al. (2005). Bioinorganic photochemistry: Frontiers and mechanisms. Chemical Reviews, 105, 2647–2694.

    Article  CAS  PubMed  Google Scholar 

  17. Kobayashi, H., Ogawa, M., Alford, R., et al. (2010). New strategies for fluorescent probe design in medical diagnostic imaging. Chemical Reviews, 110, 2620–2640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gomes, A. T. P. C., Neves, M. G. P. M. S., & Cavaleiro, J. A. S. (2018). Cancer, photodynamic therapy and porphyrin-type derivatives. Anais da Academia Brasileira de Ciências., 90, 993–1026.

    Article  CAS  PubMed  Google Scholar 

  19. Xu, D. Y. (2007). Research and development of photodynamic therapy photosensitizers in China. Photodiagnosis and Photodynamic Therapy, 4, 13–25.

    Article  CAS  PubMed  Google Scholar 

  20. Bonnett, R. (1995). Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chemical Society Reviews, 24, 19–33.

    Article  CAS  Google Scholar 

  21. Cheng, J., Liang, H., Li, Q., et al. (2010). Hematoporphyrin monomethyl ether-mediated photodynamic effects on THP-1 cell-derived macrophages. Journal of Photochemistry and Photobiology B: Biology, 101, 9–15.

    Article  CAS  PubMed  Google Scholar 

  22. Tsolekile, N., Nelana, S., & Oluwafemi, O. S. (2019). Porphyrin as diagnostic and therapeutic agent. Molecules, 24, 2669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ji, Z., Cheng, Z., Mori, H., et al. (2020). Synthesis and physicochemical properties of 2,7-disubstituted phenanthro[2,1-b:7,8-b’]dithiophenes. Molecules, 25, 3842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Banfi, S., Caruso, E., Buccafurni, L., et al. (2006). Comparison between 5,10,15,20-Tetraaryl- and 5,15-diarylporphyrins as photosensitizers: Synthesis, photodynamic activity, and quantitative structure-activity relationship modeling. Journal of Medicinal Chemistry, 49, 3293–3304.

    Article  CAS  PubMed  Google Scholar 

  25. Wiehe, A., Simonenko, E. J., Senge, M. O., et al. (2012). Hydrophilicity vs hydrophobicity—varying the amphiphilic structure of porphyrins related to the photosensitizer m-THPC. Journal of Porphyrins and Phthalocyanines, 05, 758–761.

    Article  Google Scholar 

  26. Zhu, W., Gao, Y. H., Liao, P. Y., et al. (2018). Comparison between porphin, chlorin and bacteriochlorin derivatives for photodynamic therapy: Synthesis, photophysical properties, and biological activity. European Journal of Medicinal Chemistry, 160, 146–156.

    Article  CAS  PubMed  Google Scholar 

  27. Maisch, T., Bosl, C., Szeimies, R. M., et al. (2005). Photodynamic effects of novel XF porphyrin derivatives on prokaryotic and eukaryotic cells. Antimicrobial Agents and Chemotherapy, 49, 1542–1552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Einzinger, M., Zhu, T., de Silva, P., et al. (2017). Shorter exciton lifetimes via an external heavy-atom effect: Alleviating the effects of bimolecular processes in organic light-emitting diodes. Advanced Materials, 29, 1701987.

    Article  Google Scholar 

  29. Gan, S., Hu, S., Li, X. L., et al. (2018). Heavy atom effect of bromine significantly enhances exciton utilization of delayed fluorescence luminogens. ACS Applied Materials & Interfaces, 10, 17327–17334.

    Article  CAS  Google Scholar 

  30. Zou, J., Yin, Z., Ding, K., et al. (2017). BODIPY derivatives for photodynamic therapy: Influence of configuration versus heavy atom effect. ACS Applied Materials & Interfaces, 9, 32475–32481.

    Article  CAS  Google Scholar 

  31. Erbas, S., Gorgulu, A., Kocakusakogullari, M., et al. (2009). Non-covalent functionalized SWNTs as delivery agents for novel Bodipy-based potential PDT sensitizers. Chemical Communications, 33, 4956–4958.

    Article  Google Scholar 

  32. Batat, P., Cantuel, M., Jonusauskas, G., et al. (2011). BF2-azadipyrromethenes: Probing the excited-state dynamics of a NIR fluorophore and photodynamic therapy agent. Journal of Physical Chemistry A, 115, 14034–14039.

    Article  CAS  PubMed  Google Scholar 

  33. Xiao, W., Wang, P., Ou, C., et al. (2018). 2-Pyridone-functionalized Aza-BODIPY photosensitizer for imaging-guided sustainable phototherapy. Biomaterials, 183, 1–9.

    Article  CAS  PubMed  Google Scholar 

  34. Xu, Y., Zhao, M., Zou, L., et al. (2018). Highly stable and multifunctional Aza-BODIPY-based phototherapeutic agent for anticancer treatment. ACS Applied Materials & Interfaces, 10, 44324–44335.

    Article  CAS  Google Scholar 

  35. Chen, D., Tang, Q., Zou, J., et al. (2018). pH-Responsive PEG-doxorubicin-encapsulated Aza-BODIPY nanotheranostic agent for imaging-guided synergistic cancer therapy. Advanced Healthcare Materials, 7, 1701272.

    Article  Google Scholar 

  36. Čížková, M., Cattiaux, L., Mallet, J.-M., et al. (2018). Electrochemical switching fluorescence emission in rhodamine derivatives. Electrochimica Acta, 260, 589–597.

    Article  Google Scholar 

  37. Dumoulin, F., Durmuş, M., Ahsen, V., et al. (2010). Synthetic pathways to water-soluble phthalocyanines and close analogs. Coordination Chemistry Reviews, 254, 2792–2847.

    Article  CAS  Google Scholar 

  38. Kwitniewski, M., Juzeniene, A., Ma, L. W., et al. (2009). Diamino acid derivatives of PpIX as potential photosensitizers for photodynamic therapy of squamous cell carcinoma and prostate cancer: In vitro studies. Journal of Photochemistry and Photobiology B: Biology, 94, 214–222.

    Article  CAS  PubMed  Google Scholar 

  39. Serra, V. V., Zamarrón, A., Faustino, M., et al. (2010). New porphyrin amino acid conjugates: Synthesis and photodynamic effect in human epithelial cells. Bioorganic & Medicinal Chemistry, 18, 6170–6178.

    Article  CAS  Google Scholar 

  40. Tamiaki, H., Isoda, Y., Tanaka, T., et al. (2014). Synthesis of chlorophyll-amino acid conjugates as models for modification of proteins with chromo/fluorophores. Bioorganic & Medicinal Chemistry, 22, 1421–1428.

    Article  CAS  Google Scholar 

  41. Wang, H. M., Jiang, J. Q., Xiao, J. H., et al. (2008). Porphyrin with amino acid moieties: A tumor photosensitizer. Chemico-Biological Interactions, 172, 154–158.

    Article  CAS  PubMed  Google Scholar 

  42. Meng, Z., Yu, B., Han, G., et al. (2016). Chlorin p6-based water-soluble amino acid derivatives as potent photosensitizers for photodynamic therapy. Journal of Medicinal Chemistry, 59, 4999–5010.

    Article  CAS  PubMed  Google Scholar 

  43. Allison, R. R., Downie, G. H., Cuenca, R., et al. (2004). Photosensitizers in clinical PDT. Photodiagnosis and Photodynamic Therapy, 1, 27–42.

    Article  CAS  PubMed  Google Scholar 

  44. Kessel, D. (1989). Determinants of photosensitization by mono-L-aspartyl chlorin e6. Photochemistry and Photobiology, 49, 447–452.

    Article  CAS  PubMed  Google Scholar 

  45. Gregory, W., Roberts, F., Shiau, Y., et al. (1988). In Vitro Characterization of monoaspartyl chlorin e6 and diaspartyl chlorin e6 for photodynamic therapy. JNCI Journal of the National Cancer Institute, 80, 330–336.

    Article  Google Scholar 

  46. Le, N. A., Babu, V., Spingler, B., et al. (2021). Photostable platinated bacteriochlorins as potent photodynamic agents. Journal of Medicinal Chemistry, 64(10), 6792–6801.

    Article  CAS  PubMed  Google Scholar 

  47. De Pinillos Bayona, A. M., Mroz, P., Thunshelle, C., et al. (2017). Design features for optimization of tetrapyrrole macrocycles as antimicrobial and anticancer photosensitizers. Chemical Biology & Drug Design, 89, 192–206.

    Article  Google Scholar 

  48. Donuru, V. R., Vegesna, G. K., Velayudham, S., et al. (2009). Synthesis and optical properties of red and deep-red emissive polymeric and copolymeric BODIPY dyes. Chemical Biology & Drug Design, 21, 2130–2138.

    CAS  Google Scholar 

  49. Zhang, L. J., Bian, J., Bao, L. L., et al. (2014). Photosensitizing effectiveness of a novel chlorin-based photosensitizer for photodynamic therapy in vitro and in vivo. Journal of Cancer Research and Clinical Oncology, 140, 1527–1536.

    Article  CAS  PubMed  Google Scholar 

  50. Wolfgang, S., & Röder, B. (1998). Singlet oxygen quantum yields of different photosensitizers in polar solvents and micellar solutions. Journal of Porphyrins and Phthalocyanines, 2(2), 145–158.

    Article  Google Scholar 

  51. Wei, T., Hao, X., Kopelman, R., et al. (2005). Photodynamic characterization and in vitro application of methylene blue-containing nanoparticle platforms. Photochemistry and Photobiology, 81, 242–249.

    Article  Google Scholar 

  52. Misra, R., Kumar, R., Chandrashekar, T. K., et al. (2006). 22π smaragdyrin molecular conjugates with aromatic phenylacetylenes and ferrocenes: Syntheses, electrochemical, and photonic properties. Journal of the American Chemical Society, 128, 16083–16091.

    Article  CAS  PubMed  Google Scholar 

  53. Fujino, S., Yamaji, M., Okamoto, H., et al. (2017). Systematic investigations on fused pi-system compounds of seven benzene rings prepared by photocyclization of diphenanthrylethenes. Photochemical & Photobiological Sciences, 16, 925–934.

    Article  CAS  Google Scholar 

  54. Pellicciari, R., Liscio, P., Giacche, N., et al. (2018). Alpha-amino-beta-carboxymuconate-epsilon-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD(+)) Biosynthesis. Journal of Medicinal Chemistry, 61, 745–759.

    Article  CAS  PubMed  Google Scholar 

  55. Travelli, C., Aprile, S., Rahimian, R., et al. (2017). Identification of novel triazole-based nicotinamide phosphoribosyltransferase (NAMPT) inhibitors endowed with antiproliferative and antiinflammatory activity. Journal of Medicinal Chemistry, 60, 1768–1792.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded by the National Natural Science Foundation of China (No. 21977016) and Foundation of Shanghai Science & Technology Committee (No. 20430730900, 20490740400, 21430730100).

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Authors and Affiliations

  1. Department of Pharmacy, Huadong Hospital, Fudan University, Shanghai, 200040, China

    Man-Yi Li, Yi-Jia Yan & Zhi-Long Chen

  2. Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, 201620, China

    Man-Yi Li, Le Mi, Tabbisa Namulinda, Xing-Ping Zhou & Zhi-Long Chen

  3. Shanghai Xianhui Pharmaceutical Co., Ltd., Shanghai, 201620, China

    Yi-Jia Yan

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Li, MY., Mi, L., Namulinda, T. et al. The bromoporphyrins as promising anti-tumor photosensitizers in vitro. Photochem Photobiol Sci 22, 427–439 (2023). https://doi.org/10.1007/s43630-022-00326-9

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