Preview

Fine Chemical Technologies

Advanced search

Amino acid derivatives of natural chlorins as a platform for the creation of targeted photosensitizers in oncology

https://doi.org/10.32362/2410-6593-2020-15-6-16-33

Full Text:

Abstract

Objectives. This study aims to obtain the amino acid derivatives of chlorophyll a and bacteriochlorophyll a for the targeted delivery of pigments to tumor foci. This will increase biocompatibility and, as a result, reduce toxic side effects. In addition to photodynamic efficiency, an additional cytotoxic effect is expected for the obtained conjugates of photosensitizers (PSs) with amino acids. This is owing to the participation of the latter in intracellular biochemical processes, including interaction with the components of the glutathione antioxidant system, leading to the vulnerability of tumor cells to oxidative stress.

Methods. In this work, we have implemented the optimization of the structure of a highly efficient infrared PS based on O-propyloxim-N-propoxybacteriopurpurinimide (DPBP), absorbing at 800 nm and showing photodynamic efficacy for the treatment of deep-seated and pigmented tumors, by introducing L-lysine, L-arginine, methionine sulfoximine (MSO), and buthionine sulfoximine (BSO) methyl esters. The structure of the obtained compounds was proved by mass spectrometry and nuclear magnetic resonance spectroscopy, and the photoinduced cytotoxicity was studied in vitro on the HeLa cell line.

Results. Conjugates of DPBP with amino acids and their derivatives, such as lysine, arginine, MSO, and BSO have been prepared. The chelating ability of DPBP conjugate with lysine was shown, and its Sn(IV) complex was obtained.

Conclusions. Biological testing of DPBP with MSO and BSO showed a 5–6-fold increase in photoinduced cytotoxicity compared to the parent DPBP PS. Additionally, a high internalization of pigments by tumor cells was found, and the dark cytotoxicity (in the absence of irradiation) of DPBP-MSO and DPBP-BSO increased fourfold compared to the initial DPBP compound. This can be explained by the participation of methionine derivatives in the biochemical processes of the tumor cell.

About the Authors

A. F. Mironov
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Andrei F. Mironov, Dr. of Sci. (Chemistry), Professor, N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry; Scopus Author ID 55968884300

86, Vernadskogo pr., Moscow, 119571



P. V. Ostroverkhov
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Petr V. Ostroverkhov, Postgraduate Student, Assistant of the N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry; Scopus Author ID 57194061159

86, Vernadskogo pr., Moscow, 119571



S. I. Tikhonov
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Sergei I. Tikhonov, Assistant of the N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry

86, Vernadskogo pr., Moscow, 119571



V. A. Pogorilyy
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Viktor A. Pogorilyy, Postgraduate Student, Assistant of the N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry; Scopus Author ID 57201999616

86, Vernadskogo pr., Moscow, 119571



N. S. Kirin
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Nikita S. Kirin, Postgraduate Student, Assistant of the N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry; Researcher ID ААА-7238-2020

86, Vernadskogo pr., Moscow, 119571



O. O. Chudakova
Institute of Fundamental Problems of Biology, Russian Academy of Sciences
Russian Federation

Olga O. Chudakova, Junior Researcher; Reseacher ID Т-8560-2018

2, ul. Institutskaya, Pushchino, Moscow oblast, 142290



A. A. Tsygankov
Institute of Fundamental Problems of Biology, Russian Academy of Sciences
Russian Federation

Аnatolii А. Tsygankov, Dr. of Sci. (Biology), Head of the Laboratory of Biotechnology and Physiology of Phototrophic Organisms, Director; Scopus Author ID 7102020614, ResearcherID K-6541-2013

2, ul. Institutskaya, Pushchino, Moscow oblast, 142290



M. A. Grin
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Mikhail A. Grin, Dr. of Sci. (Chemistry), Professor, Head of the N.A. Preobrazhensky Department of Chemistry and Technology of Biologically Active Compounds, Medicinal and Organic Chemistry; Scopus Author ID 6603356480

86, Vernadskogo pr., Moscow, 119571



References

1. Rakesh K.P., Darshini N., Manukumar H.M., Vivek H.K., Eissa M.Y.H., Prasanna D.S., Mallesha N. Xanthone. Conjugated аmino аcids as potential anticancer and DNA binding agents: molecular docking, cytotoxicity and SAR studies. Anticancer Agents Med. Chem. 2018;18(15):2169-2177. https://doi.org/10.2174/1871520618666180903105256

2. Sun J., Wei Q., Zhou Y., Wang J., Liu Q., Xu H. A systematic analysis of FDA-approved anticancer drugs. BMC Syst. Biol. 2017;11(s5):87. https://doi.org/10.1186/s12918-017-0464-7

3. Girasolo M., Rubino S., Portanova P., Calvaruso G., Ruisi G., Stocco G. New organotin(IV) complexes with L-Arginine, Nα - t -Boc-L-Arginine and L-AlanylL-Arginine: Synthesis, structural investigations and cytotoxic activity. Journal of Organometallic Chemistry. 2010;695(4):609-618. https://doi.org/10.1016/j.jorganchem.2009.11.002

4. Mody T.D. Pharmaceutical development and medical applications of porphyrin-type macrocycles. J. Porphyr. Phthalocyanines. 2000;4(4):362-367. https://doi.org/10.1002/(SICI)1099-1409(200006/07)4:4%3C362::AID-JPP250%3E3.0.CO;2-Z

5. Pandey R.K. Recent advances in photodynamic therapy. J. Porphyr. Phthalocyanines. 2000;4(4):368-373. https://doi.org/10.1002/(SICI)1099-1409(200006/07)4:4%3C368::AID-JPP244%3E3.0.CO;2-6

6. Zheng W., Zhao Y., Luo Q., Zhang Y., Wu K., Wang F. Multi-targeted anticancer agents. Curr. Top. Med. Chem. 2017;17:3084-3098. https://doi.org/10.2174/1568026617666170707124126

7. Stevens M., Frobisher C., Hawkins M., Jenney M., Lancashire E., Reulen R., Taylor A., Winter D. The British childhood cancer survivor study: objectives, methods, population structure, response rates and initial descriptive information. Pediatr. Blood Cancer. 2008;50:1018-1025. https://doi.org/10.1002/pbc.21335

8. He R., Finan B., Mayer J.P., DiMarchi R.D. Peptide conjugates with small molecules designed to enhance efficacy and safety. Molecules. 2019;24:11-14. https://doi.org/10.3390/molecules24101855

9. Hoppenz P., Els-Heindl S., Beck-Sickinger A.G. Peptide-drug conjugates and their targets in advanced cancer therapies. Front. Chem. 2020;8:1-24. https://doi.org/10.3389/fchem.2020.00571

10. Calvaresi E.C., Hergenrother P.J. Glucose conjugation for the specific targeting and treatment of cancer. Chem. Sci. 2013;4:2319-2333. https://doi.org/10.1039/c3sc22205e

11. Hossain F., Andreana P.R. Developments in carbohydrate-based cancer therapeutics. Pharmaceuticals. 2019;12(2):84. https://doi.org/10.3390/ph12020084

12. Posocco B., Dreussi E., De Santa J., Toffoli G., Abrami M., Musiani F., Grassi M., Farra R., Tonon F., Grassi G., Dapas B. Polysaccharides for the delivery of antitumor drugs. Materials (Basel). 2015;8(5):2569-2615. https://doi.org/10.3390/ma8052569

13. Zhang L., Sui C., Yang W., Luo Q. Amino acid transporters: Emerging roles in drug delivery for tumortargeting therapy. Asian J. Pharm. Sci. 2020;15(2):192-206. https://doi.org/10.1016/j.ajps.2019.12.002

14. Lu Y., Wang W., Wang J., Yang C., Mao H., Fu X., Wu Y., Cai J., Han J., Xu Z., Zhuang Z., Liu Z., Hu H., Chen B. Overexpression of arginine transporter CAT-1 is associated with accumulation of L-arginine and cell growth in human colorectal cancer tissue. PLoS One. 2013;8(9):1-8. https://doi.org/10.1371/journal.pone.0073866

15. Facon T., Mary J.Y., Hulin C., Benboubker L., Attal M., Pegourie B., Renaud M., Harousseau J.L., Guillerm G., Chaleteix C., Dib M., Voillat L., Maisonneuve H., Troncy J., Dorvaux V., Monconduit M., Martin C., Casassus P., Jaubert J., Jardel H., Doyen C., Kolb B., Anglaret B., Grosbois B., Yakoub-Agha I., Mathiot C., Avet-Loiseau H. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370(9594):1209-18. https://doi.org/10.1016/S0140-6736(07)61537-2

16. Spanswick V.J., Lowe H.L., Newton C., Bingham J.P., Bagnobianchi A., Kiakos K., Craddock C., Ledermann J.A., Hochhauser D., Hartley J.A. Evidence for different mechanisms of “unhooking” for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples. BMC Cancer. 2012;12(1):1-13. https://doi.org/10.1186/1471-2407-12-436

17. Baker A., Kanofsky J.R., Quenching of singlet oxygen by biomolecules from L1210 leukemia cells. Photochem. Photobiol. 1992;55(4):523-8. https://doi.org/10.1111/j.1751-1097.1992.tb04273.x

18. Moan J. On the diffusion length of singlet oxygen in cells and tissues. J. Photochem. Photobiol. B Biol. 1990;6(3):343-347. https://doi.org/10.1016/1011-1344(90)85104-5

19. Grin M., Mironov A., Shtil A. Bacteriochlorophyll a and its derivatives: chemistry and perspectives for cancer therapy. Anticancer. Agents Med. Chem. 2012;8(6):683-697. https://doi.org/10.2174/1871520610808060683

20. Mironov A.F., Grin M.A., Pantushenko I.V., Ostroverkhov P.V., Ivanenkov Y.A., Filkov G.I., Plotnikova E.A., Karmakova T.A., Starovoitova A.V., Burmistrova N.V., Yuzhakov V.V., Romanko Y.S., Abakumov M.A., Ignatova A.A., Feofanov A.V., Kaplan M.A., Yakubovskaya R.I., Tsigankov A.A., Majouga A.G. Synthesis and Investigation of photophysical and biological properties of novel s-containing bacteriopurpurinimides. J. Med. Chem. 2017;60(24):10220-10230. https://doi.org/10.1021/acs.jmedchem.7b00577

21. Kessel D. Subcellular targets for photodynamic therapy: Implications for initiation of apoptosis and autophagy. J. Natl. Compr. Cancer Netw. 2012;2(02):56-59. https://doi.org/10.6004/jnccn.2012.0177

22. Kang J.H., Ko Y.T. Dual-selective photodynamic therapy with a mitochondria-targeted photosensitizer and fiber optic cannula for malignant brain tumors. Biomater. Sci. 2019;7(7):2812-2825. https://doi.org/10.1039/c9bm00403c

23. Morgan J., Oseroff A.R. Mitochondria-based photodynamic anti-cancer therapy. Adv. Drug Deliv. Rev. 2001;49(1-2):71-86. https://doi.org/10.1016/S0169-409X(01)00126-0

24. Thomas A.P., Palanikumar L., Jeena M.T., Kim K., Ryu J.H. Cancer-mitochondria-targeted photodynamic therapy with supramolecular assembly of HA and a water soluble NIR cyanine dye. Chem. Sci. 2017;8:8351-8356. https://doi.org/10.1039/c7sc03169f

25. Mahalingam S.M., Ordaz J.D., Low P.S. Targeting of a photosensitizer to the mitochondrion enhances the potency of photodynamic therapy. ACS Omega. 2018;3(6): 6066-6074. https://doi.org/10.1021/acsomega.8b00692

26. Rosenbach-Belkin V., Chen L., Fiedor L., Tregub I., Pavlotsky F., Brumfeld V., Salomon Y., Scherz A. Serine conjugates of chlorophyll and bacteriochlorophyll: Photocytotoxicity in vitro and tissue distribution in mice bearing melanoma tumors. Photochem. Photobiol. 1996;64(1):174-181. https://doi.org/10.1111/j.1751-1097.1996.tb02439.x

27. Brandis A.S., Salomon Y., Scherz A. Chlorophyll Sensitizers in Photodynamic Therapy. In: Grimm B., Porra R.J., Rüdiger W., Scheer H. (eds). Chlorophylls and Bacteriochlorophylls. Advances in Photosynthesis and Respiration, vol 25. Dordrecht: Springer, 2006, 461-483. https://doi.org/10.1007/1-4020-4516-6_32

28. Hargus J., Fronczek F., Vicente M., Smith K. Mono-(L)-aspartylchlorine-e6 . Photochemistry and Photobiology. 2007;83:1006-1015. https://doi.org/10.1111/j.1751-1097.2007.00092.x

29. Jinadasa R.G.W., Hu X., Grac M., Vicente H., Smith K.M. Syntheses and cellular investigations of 173 -, 152 -, and 131 -amino acid derivatives of chlorin e6. J. Med. Chem. 2011;54(21):7464-7476. https://doi.org/10.1021/jm2005139

30. Serra V.V., Zamarron A., Faustino M.A.F., La Cruz M.C.I.D., Blázquez A., Rodrigues J.M.M., Neves M.G.P.M.S., Cavaleiro J.A.S., Juarranz A., Sanz-Rodríguez F. New porphyrin amino acid conjugates: Synthesis and photodynamic effect in human epithelial cells. Bioorganic Med. Chem. 2010;18(16):6170-6178.

31. Wang A., Zhou R., Zhou L., Sun K., Jiang J., Wei S. Positively charged phthalocyanine-arginine conjugates as efficient photosensitizer for photodynamic therapy. Bioorganic Med. Chem. 2017;25(17):1643-1651. https://doi.org/10.1016/j.bmc.2017.01.029

32. Meng S., Xu Z., Hong G., Zhao L., Zhao Z., Guo J., Ji H., Liu T. Synthesis, Characterization and in Vitro Photodynamic Antimicrobial Activity of Basic Amino AcidPorphyrin Conjugates. European Journal of Medicinal Chemistry. 2015;92:35-48. https://doi.org/10.1016/j.ejmech.2014.12.029

33. Lu S.C. Regulation of glutathione synthesis. Mol. Aspects Med. 2009;30(1-2):42-59. https://doi.org/10.1016/j.mam.2008.05.005

34. Singh S., Khan A.R., Gupta A.K. Role of glutathione in cancer pathophysiology and therapeutic interventions. J. Exp. Ther. Oncol. 2012;9(4):303-16.

35. Grin M.A., Pogorilyy V.A., Noev A.N., Tikhonov S.I., Majouga A.G., Mironov A.F. Bacteriochlorophyll a derivatives with sulfur-containing amino acids as promising photosensitizers for cancer PDT. Macroheterocycles. 2018;11:89-94. https://doi.org/10.6060/mhc180176p

36. Gielen M. Organotin compounds and their therapeutic potential: a report from the Organometallic Chemistry Department of the Free University of Brussels. Applied Organometallic Chemistry. 2002;16(9):481-494. https://doi.org/10.1002/aoc.331

37. Gielen M. Tin-based antitumour drugs. Coordination Chemistry Reviews. 1996;151:41-51. https://doi.org/10.1016/S0010-8545(96)90193-9

38. Gielen M., Biesemans M., Willem R. Organotin compounds: from kinetics to stereochemistry and antitumour activities. Applied organometallic chemistry. 2005;19(4):440-450. https://doi.org/10.1002/aoc.771

39. Bregadze V.I., Glazun S.A. Metal-containing carboranes with antitumor activity. Russian Chemical Bulletin. 2007;56(4):643-659.

40. Montero D., Tachibana C., Rahr Winther J., Appenzeller-Herzog C., Intracellular glutathione pools are heterogeneously concentrated. Redox Biol. 2013;1(1):508-513. https://doi.org/10.1016/j.redox.2013.10.005


Supplementary files

1. Synthesis of the conjugate of dipropoxybacteriopurpurinimide with methyl ester of L-methionine sulfoximine and L-(S,R)-butionine sulfoximine
Subject
Type Research Instrument
View (247KB)    
Indexing metadata
2. This is to certify that the paper titled Amino acid derivatives of natural chlorins as a platform for the creation of targeted photosensitizers in oncology commissioned to us by Andrei F. Mironov, Petr V. Ostroverkhov, Sergei I. Tikhonov, Viktor A. Pogorilyy, Nikita S. Kirin, Olga O. Chudakova, Аnatolii А. Tsygankov, Mikhail A. Grin. has been edited for English language and spelling by Enago, an editing brand of Crimson Interactive Inc.
Subject CERTIFICATE OF EDITING
Type Other
View (281KB)    
Indexing metadata
  • The modification of PS molecules by amino acids, on the one hand, increases the hydrophilicity of pigments, and, on the other hand, improves the selectivity of their accumulation in tumor tissues, since amino acids are involved in numerous intracellular processes, including the accelerated proliferation of tumor cells.
  • In the present study, several conjugates of O-propyloxime-N-propoxybacteriopurpurinimide (DPBP) with amino acids and their derivatives were obtained. The chelating ability of the DPBP-lysine conjugate was shown, and the Sn(IV) complex was obtained. Biological tests were performed, and the high photoinduced cytotoxicity of DPBP derivatives with MSO and BSO was shown.

For citation:


Mironov A.F., Ostroverkhov P.V., Tikhonov S.I., Pogorilyy V.A., Kirin N.S., Chudakova O.O., Tsygankov A.A., Grin M.A. Amino acid derivatives of natural chlorins as a platform for the creation of targeted photosensitizers in oncology. Fine Chemical Technologies. 2020;15(6):16-33. https://doi.org/10.32362/2410-6593-2020-15-6-16-33

Views: 66


ISSN 2410-6593 (Print)
ISSN 2686-7575 (Online)