Synthesis and Anti-tumor Evaluation of Novel C-37 Modified Derivatives of Gambogic Acid
Xiang Li
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Search for more papers by this authorXiaojin Zhang
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Search for more papers by this authorCorresponding Author
Haopeng Sun
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China, Tel.: 0086-025-83271351; Fax: 0086-025-83271351Search for more papers by this authorLei Zhang
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Search for more papers by this authorYuan Gao
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
Search for more papers by this authorJinxin Wang
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Search for more papers by this authorQinglong Guo
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
Search for more papers by this authorCorresponding Author
Qidong You
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China, Tel.: 0086-025-83271351; Fax: 0086-025-83271351Search for more papers by this authorXiang Li
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Search for more papers by this authorXiaojin Zhang
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Search for more papers by this authorCorresponding Author
Haopeng Sun
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China, Tel.: 0086-025-83271351; Fax: 0086-025-83271351Search for more papers by this authorLei Zhang
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Search for more papers by this authorYuan Gao
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
Search for more papers by this authorJinxin Wang
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Search for more papers by this authorQinglong Guo
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
Search for more papers by this authorCorresponding Author
Qidong You
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China, Tel.: 0086-025-83271351; Fax: 0086-025-83271351Search for more papers by this authorAbstract
Gambogic acid (GA, 1), the most prominent representative of Garcinia natural products, has been reported to be a promising anti-tumor agent. In order to further explore the structure-activity relationship of GA and discover novel GA derivatives as anti-tumor agents, 17 novel C-37 modified derivatives of GA were synthesized and evaluated for their in vitro anti-tumor activities against A549, HCT-116, BGC-823, HepG2 and MCF-7 cancer cell lines. Among them, 11 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 8 was almost 5–10 folds more active than GA against A549 and BGC-823 cell lines with the IC50 values of 0.12 µmol·L−1 and 0.57 µmol·L−1, respectively. Chemical modification at C-37 position of GA by introducing of hydrophilic amines could lead to increased activity and improved drug-like properties. These findings will enhance our understanding of the structure-activity relationship (SAR) of GA and lead to the discovery of novel GA derivatives as potential anti-tumor agents.
Supporting Information
Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors.
| Filename | Description |
|---|---|
| cjoc_201100693_sm_suppl.pdf1.1 MB | suppl |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Auterhoff, H.; Frauendorf, H.; Liesenklas, W.; Schwandt, C.. Arch. Pharm., 1962, 295, 833.
- 2 Kumar, P.; Baslas, R. K.. Herba Hungarica, 1980, 19, 81.
- 3
Yates, P.;
Karmarkar, S. S.;
Rosenthal, D.;
Stout, G. H.;
Stout, V. F..
Tetrahedron Lett.,
1963,
4,
1623.
10.1016/S0040-4039(01)90882-2 Google Scholar
- 4 Weakley, T. J. R.; Cai, S. X.; Zhang, H. Z.; Keana, J. F. W.. J. Chem. Crystllogr., 2001, 31, 501.
- 5 Wu, Z. Q.; Guo, Q. L.; You, Q. D.; Zhao, L.; Gu, H. Y.. Biol. Pharm. Bull., 2004, 27, 1769.
- 6 Zhang, H. Z.; Kasibhatla, S.; Wang, J.; Herich, J.; Guastella, J.; Tseng, B.; Drewe, J.; Cai, S. X.. Bioorg. Med. Chem., 2004, 12, 309.
- 7 Zhao, L.; Zhen, C.; Wu, Z. Q.; Hu, R.; Zhou, C. L.; Guo, Q. L.. Drug Chem. Toxicol., 2010, 33, 86.
- 8 Zhao, L.; Guo, Q. L.; You, Q. D.; Wu, Z. Q.; Gu, H. Y.. Biol. Pharm. Bull., 2004, 27, 998.
- 9 Li, Q.; Cheng, H.; Zhu, G.; Yang, L.; Zhou, A.; Wang, X.; Fang, N.; Xia, L.; Su, J.; Wang, M.; Peng, D.; Xu, Q.. Biol. Pharm. Bull., 2010, 33, 415.
- 10 Chantarasriwong, O.; Batova, A.; Chavasiri, W.; Theodorakis, E. A.. Chem. Eur. J., 2010, 16, 9944.
- 11 Palempalli, U. D.; Gandhi, U.; Kalantari, P.; Vunta, H.; Narayan, V.; Ravindran, A.; Prabhu, K. S.. Biochem. J., 2009, 419, 401.
- 12 Zhao, Q.; Yang, Y.; Yu, J.; You, Q. D.; Zeng, S.; Gu, H. Y.; Lu, N.; Qi, Q.; Liu, W.; Wang, X. T.; Guo, Q. L.. Cancer Lett., 2008, 262, 2230.
- 13 Yu, J.; Guo, Q. L.; You, Q. D.; Zhao, L.; Gu, H. Y.; Yang, Y.; Zhang, H. W.; Tan, Z.; Wang, X.. Carcinogenesis, 2007, 28, 632.
- 14 Lu, N.; Yang, Y.; You, Q. D.; Ling, Y.; Gao, Y.; Gu, H. Y.; Zhao, L.; Wang, X. T.; Guo, Q. L.. Cancer Lett., 2007, 258, 80.
- 15 Yi, T.; Yi, Z.; Cho, S. G.; Luo, J.; Pandey, M. K.; Aggarwal, B. B.; Liu, M.. Cancer Res., 2008, 68, 1843.
- 16 Wang, J.; Zhao, Q.; Qi, Q.; Gu, H. Y.; Rong, J. J.; Mu, R.; Zou, M. J.; Tao, L.; You, Q. D.; Guo, Q. L.. J. Cell Biochem., 2011, 112, 509.
- 17 Pandey, M. K.; Sung, B.; Ahn, K. S.; Kunnumakkara, A. B.; Chaturvedi, M. M.; Aggarwa, B. B.. Blood, 2007, 110, 3517.
- 18 Chen, J.; Gu, H. Y.; Lu, N.; Yang, Y.; Liu, W.; Qi, Q.; Rong, J. J.; Wang, X. T.; You, Q. D.; Guo, Q. L.. Life Sci., 2008, 83, 103.
- 19 Zhang, L.; Yi, Y.; Chen, J.; Sun, Y.; Guo, Q.; Zheng, Z.; Song, S.. Biochem. Biophys. Res. Commun., 2010, 403, 282.
- 20 Li, C. L.; Lu, N.; Qi, Q.; Li, F. N.; Ling, Y.; Chen, Y.; Qin, Y. S.; Li, Z. Y.; Zhang, H. W.; You, Q. D.; Guo, Q. L.. Biochem. Pharmacol., 2011, 82, 1873.
- 21 Wang, X. J.; Lu, N.; Yang, Q.; Gong, D. D.; Lin, C. J.; Zhang, S. L.; Xi, M. Y.; Gao, Y.; Wei, L. B.; Guo, Q. L.; You, Q. D.. Eur. J. Med. Chem., 2011, 46, 1280.
- 22 Zhang, H. Z.; Kasibhatla, S.; Wang, Y.; Herich, J.; Guastella, J.; Tseng, B.; Drewe, J.; Cai, S. X.. Bioorg. Med. Chem., 2004, 12, 309.
- 23 Jang, S. W.; Okada, M.; Sayeed, L.; Xiao, G.; Stein, D.; Jin, P.; Ye, K.. Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 16329.
- 24 Cai, S. X.; Zhang, H. Z.; Kasibhatla, S.; Gaeta, F. C., US 2003078292 Chem. Abstr., 2000, 133, 150415.
- 25 Tseng, B.; Sirisoma, N.; Sudath; Cai, S. X.; Zhang, H. Z.; Kasibhatla, S.; Ollis, K. P.; Drewe, J., WO 2004002428 Chem. Abstr., 2004, 140, 87676.
- 26 Wang, J. X.; Zhao, L.; Hu, Y.; Guo, Q. L.; Zhang, L.; Wang, X. J.; Li, N. G.; You, Q. D.. Eur. J. Med. Chem., 2009, 44, 2611.
- 27 Wang, J. X.; Ma, J. H.; You, Q. D.; Zhao, L.; Wang, F.; Li, C.; Guo, Q. L.. Eur. J. Med. Chem., 2010, 45, 4343.
- 28 Ollis, W. D.; Ramsay, M. V. J.; Sutherland, I. O.; Mongkolsuk, S.. Tetrahedron, 1965, 21, 1453.
- 29 Carmichael, J.; DeGraff, W. G.; Gazdar, A. F.; Minna, J. D.; Mitchell, J. B.. Cancer Res., 1987, 47, 936.
