Synthesis and photodynamic effect of 3-substituted methyl pyropheophorbide-a derivatives as novel photodynamic therapeutic agents for cancer treatment

Tae Heon Lee; Hye Jeong Kim; Bo-Ra Lee; Sang Bong Lee; Da-Sol Lee; Ye Ri Han; Kil Soo Kim; Young Kyu Song; Young Key Shim; Su-Jin Park; Dong-Won Kim; Yong Hyun Jeon

Journal of Industrial and Engineering Chemistry, Vol.105, 513-519, January, 2022

DOI10.1016/j.jiec.2021.10.009 Export Citation

Synthesis and photodynamic effect of 3-substituted methyl pyropheophorbide-a derivatives as novel photodynamic therapeutic agents for cancer treatment

Tae Heon Lee¹, Hye Jeong Kim¹, Bo-Ra Lee², Sang Bong Lee³, Da-Sol Lee², Ye Ri Han⁴, Kil Soo Kim^{2, 3}, Young Kyu Song^{1, †}, Young Key Shim¹, Su-Jin Park⁵, Dong-Won Kim⁶, and Yong Hyun Jeon^{2, 7, †}

¹Research Center of Dr. i&B Co., DaeJeon, Republic of Korea
²Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Cheombok-ro Dong-gu Daegu, Republic of Korea
³College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
⁴New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Chembok-ro Dong-gu Daegu, Republic of Korea
⁵Woogene B&G Co., LTD., 230, Jeongmunsongsan-ro, Yanggam-myeon, Hwasung-si Gyonggi-do, Republic of Korea
⁶OSP Co., LTD., 11, Saneopdanji-ro 2-gil, Seongdong-myeon, Nonsan-si, Chungcheongnam-do, Republic of Korea
⁷Vaccine Commercialization Center, Gyeongbuk Institute for Bioindustry, 88, Saneodanjigil, pungsan-eup, Andong-si, Gyeongbuk, 36618, Republic of Korea

E-mail:,

The unique ability of chlorophyll derivatives to accumulate in tumor tissues and cause a photodynamic effect under laser radiation has been successfully used in photodynamic therapy (PDT). Previous research on modified peripheral substituents in chlorophyll showed that the presence and position of substituents in chlorin derivatives remarkably affect biological activities. Herein, we synthesized methyl pyropheophorbide-a (MPPa) derivatives, which are chlorophyll-a derivatives with heterocyclic aromatic substituents or pyrazole moieties on the peripheral positions. Then, we examined the PDT effects of these new derivatives in vitro and in vivo.

Keywords:Methyl pyropheophorbide-a (MPPa);Fluorescence dye;Photodynamic therapy (PDT);Tumor targeted imaging;Theranostics

[References]

Dougherty TJ, J. Clin. Laser Med. Sur., 20, 3 (2002)
Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q, JNCI-J. Natl. Cancer, 1(90), 889 (1998)
Zheng G, Potter WR, Camacho SH, Missert JR, Wang G, Bellnier DA, Henderson BW, Rodgers MA, Dougherty TJ, Pandey RK, J. Med. Chem., 44, 1540 (2001)
Bonnett R, Chem. Soc. Rev., 24, 19 (1995)
Firey PA, Rodgers MAJ, Photochem. Photobiol., 45, 535 (1987)
Rungta A, Zheng G, Missert JR, Potter WR, Dougherty TJ, Pandey RK, Bioorg. Med. Chem. Lett., 10, 1463 (2000)
Morgan A, Rampersaud A, Keck R, Selman S, Photochem. Photobiol., 46, 441 (1987)
Kobayashi M, Kise H, Tanielian C, et al., Electron Transfer from Nucleic Acid Base to Dyes in the Singlet Excited States, Springer, Tokyo, pp.572, 1997.
Grichine A, Feofanov A, Karmakova T, Kazachkina N, Pecherskih E, Yakubovskaya R, Mironov A, Egret-Charlier M, Vigny P, Photochem. Photobiol., 73, 267 (2001)
Brandis AS, Salomon Y, Scherz A, Chlorophyll Sensitizers in Photodynamic Therapy, Springer, Dordrecht, pp.461, 2006.
Pandey R, Sumlin A, Potter W, Bellnier D, Henderson B, Constantine S, Aoudia M, Rodgers M, Smith K, Dougherty T, Photochem. Photobiol., 63, 1751 (1996)
Pandey RK, Jagerovic N, Ryan JM, Dougherty TJ, Smith KM, Tetrahedron, 52, 5349 (1996)
Roeder B, Dressler C, Fuchs B, Hagemann R, Berlien HP, Nowak C, Moser JG, Proc. SPIE 2078, Photodyn. Ther. Cancer., 427 (1994).
Brandis AS, Salomon Y, Scherz A, Bacteriochlorophyll Sensitizers in Photodynamic Therapy, Springer, Dordrecht, pp.485, 2006.
Li G, Graham A, Chen Y, Dobhal MP, Morgan J, Zheng G, Kozyrev A, Oseroff A, Dougherty TJ, Pandey RK, J. Med. Chem., 46, 5349 (2003)
Qin JH, Zhang H, Sun P, Huang YD, Shen Q, Yang XG, Ma LF, Dalton Trans., 49, 17772 (2020)
Zhong Y, Li X, Chen J, Wang X, Wei L, Fang L, Kumar A, Zhang S, Liu J, Dalton Trans., 49, 11045 (2020)
Zhou Z, Li B, Shen C, Wu D, Fan H, Zhao J, Li H, Zeng Z, Luo Z, Ma L, Small, 16, 200417 (2020)
Liu W, Pan Y, Zhong Y, Li B, Ding Q, Xu H, Qiu Y, Ren F, Li B, Muddassir M, Chem. Eng. J., 412 (2021)
Ponomarev G, Pavlov VY, Konstantinov I, Timofeev V, Russ. J. Org. Chem., 39, 1683 (2003)
Gamage SA, Spicer JA, Rewcastle GW, Milton J, Sohal S, Dangerfield W, Mistry P, Vicker N, Charlton PA, Denny WA, J. Med. Chem., 45, 740 (2002)
Galindev O, Badraa N, Dalantai M, Sengee GI, Dorjnamjin D, Shim YK, Photochem. Photobiol. Sci., 7, 1273 (2008)

[1] Dougherty TJ, J. Clin. Laser Med. Sur., 20, 3 (2002)

[2] Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q, JNCI-J. Natl. Cancer, 1(90), 889 (1998)

[3] Zheng G, Potter WR, Camacho SH, Missert JR, Wang G, Bellnier DA, Henderson BW, Rodgers MA, Dougherty TJ, Pandey RK, J. Med. Chem., 44, 1540 (2001)

[4] Bonnett R, Chem. Soc. Rev., 24, 19 (1995)

[5] Firey PA, Rodgers MAJ, Photochem. Photobiol., 45, 535 (1987)

[6] Rungta A, Zheng G, Missert JR, Potter WR, Dougherty TJ, Pandey RK, Bioorg. Med. Chem. Lett., 10, 1463 (2000)

[7] Morgan A, Rampersaud A, Keck R, Selman S, Photochem. Photobiol., 46, 441 (1987)

[8] Kobayashi M, Kise H, Tanielian C, et al., Electron Transfer from Nucleic Acid Base to Dyes in the Singlet Excited States, Springer, Tokyo, pp.572, 1997.

[9] Grichine A, Feofanov A, Karmakova T, Kazachkina N, Pecherskih E, Yakubovskaya R, Mironov A, Egret-Charlier M, Vigny P, Photochem. Photobiol., 73, 267 (2001)

[10] Brandis AS, Salomon Y, Scherz A, Chlorophyll Sensitizers in Photodynamic Therapy, Springer, Dordrecht, pp.461, 2006.

[11] Pandey R, Sumlin A, Potter W, Bellnier D, Henderson B, Constantine S, Aoudia M, Rodgers M, Smith K, Dougherty T, Photochem. Photobiol., 63, 1751 (1996)

[12] Pandey RK, Jagerovic N, Ryan JM, Dougherty TJ, Smith KM, Tetrahedron, 52, 5349 (1996)

[13] Roeder B, Dressler C, Fuchs B, Hagemann R, Berlien HP, Nowak C, Moser JG, Proc. SPIE 2078, Photodyn. Ther. Cancer., 427 (1994).

[14] Brandis AS, Salomon Y, Scherz A, Bacteriochlorophyll Sensitizers in Photodynamic Therapy, Springer, Dordrecht, pp.485, 2006.

[15] Li G, Graham A, Chen Y, Dobhal MP, Morgan J, Zheng G, Kozyrev A, Oseroff A, Dougherty TJ, Pandey RK, J. Med. Chem., 46, 5349 (2003)

[16] Qin JH, Zhang H, Sun P, Huang YD, Shen Q, Yang XG, Ma LF, Dalton Trans., 49, 17772 (2020)

[17] Zhong Y, Li X, Chen J, Wang X, Wei L, Fang L, Kumar A, Zhang S, Liu J, Dalton Trans., 49, 11045 (2020)

[18] Zhou Z, Li B, Shen C, Wu D, Fan H, Zhao J, Li H, Zeng Z, Luo Z, Ma L, Small, 16, 200417 (2020)

[19] Liu W, Pan Y, Zhong Y, Li B, Ding Q, Xu H, Qiu Y, Ren F, Li B, Muddassir M, Chem. Eng. J., 412 (2021)

[20] Ponomarev G, Pavlov VY, Konstantinov I, Timofeev V, Russ. J. Org. Chem., 39, 1683 (2003)

[21] Gamage SA, Spicer JA, Rewcastle GW, Milton J, Sohal S, Dangerfield W, Mistry P, Vicker N, Charlton PA, Denny WA, J. Med. Chem., 45, 740 (2002)

[22] Galindev O, Badraa N, Dalantai M, Sengee GI, Dorjnamjin D, Shim YK, Photochem. Photobiol. Sci., 7, 1273 (2008)