Citation: Guan Daokun, Sun Shaofeng, Chen Jing, He Zuopeng, Kong Xiangkai, Wang Ningning, Yao Jianwen, Wang Hongbo. Synthesis and Evaluation of Antitumor Activity of Sorafenib Derivatives Possessing Diphenylamine and Thiourea Structures[J]. Chinese Journal of Organic Chemistry, ;2018, 38(6): 1414-1421. doi: 10.6023/cjoc201802005 shu

Synthesis and Evaluation of Antitumor Activity of Sorafenib Derivatives Possessing Diphenylamine and Thiourea Structures

Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University, Yantai 264005

Corresponding author: Yao Jianwen, jwyao@ytu.edu.cn Wang Hongbo, hongbowangwt@gmail.com
Received Date: 2 February 2018
Revised Date: 22 March 2018
Available Online: 13 June 2018
Fund Project: the Key Technology Development Plan of Yantai City 2017ZH075the Key Research Project of Shandong Province 2017GSF18177the National Natural Science Foundation of 81728020Project supported by the National Natural Science Foundation of China (No. 81728020), the Key Research Project of Shandong Province (No. 2017GSF18177), and the Key Technology Development Plan of Yantai City (No. 2017ZH075)

Figures(4)

17 novel sorafenib derivatives possessing diphenylamine and thiourea structures were designed and synthesized using 2-picolinic acid and substituted anilines as raw materials. The structures of the target compounds were all characterized by NMR and HRMS. In addition, the in vitro antiproliferation activity of the target compounds was studied in human colon cancer cell HCT116, human breast cancer cell line MDA-MB-231, human prostate cancer cell line PC-3 and mouse melanoma cell line B16BL6. The results showed that 1-(4-chloro-3-trifluoromethylphenyl)-3-(4-(2-(isopropylcarbamoyl)pyridine-4-amino)phenyl)thiourea (9g) had better inhibitory activity against four cell lines than the positive drug sorafenib, and 1-(3-trifluoromethyl-4-chlorophenyl)-3-{4-[2-(methylcarbamoyl)pyridine-4-amino]phenyl}thiourea (9b) and 1-(3-trifluoro-methyl-4-fluorophenyl)-3-{4-[2-(isopropylcarbamoyl)pyridine-4-amino]phenyl}thiourea (9j) had better inhibitory activity against MDA-MB-231, PC-3 and B16BL6 cell lines. The molecular docking of the active small molecule 9j was further studied, and its binding mode with the active site of the 3-D crystal structure (5HI2) of B-Raf receptor was discussed, which provided a useful reference for the design and synthesis of novel sorafenib derivatives in the future.
- B-Raf,
- molecular docking,
- an-titumor activity,
- diphenylamine and thiourea,
- sorafenib derivatives
1. [1]
  Robert, R. J. Biochem. Biophys. Res. Commun. 2010, 399, 313. doi: 10.1016/j.bbrc.2010.07.092
2. [2]
  Rawan, A.; Rachel, H.; Sophia, E.; Elia, S.; Jacob, B. Oncotarget 2016, 7, 18694.
3. [3]
  Huang, T. G.; Michael, K.; Zhuge, J.; Zhong, M. H.; Liu, D. L. J. Hematol. Oncol. 2013, 6, 30. doi: 10.1186/1756-8722-6-30
4. [4]
  Yang, Y. S.; Zhang, F.; Tang, D. J.; Yang, Y. H.; Zhu, H. L. Plos One 2014, 9, 1.
5. [5]
  Wagle, N.; Van Allen, E. M.; Treacy, D. J.; Frederick, D. T.; Cooper, Z. A.; Taylor-Weiner, A.; Rosenberg, M.; Goetz, E. M.; Sullivan, R. J.; Farlow, D. N.; Friedrich, D. C.; Anderka, K.; Perrin, D.; Johannessen, C. M.; McKenna, A.; Cibulskis, K.; Kryukov, G.; Hodis, E.; Lawrence, D. P.; Fisher, S.; Getz, G.; Gabriel, S. B.; Carter, S. L.; Flaherty, K. T.; Wargo, J. A.; Garraway, L. A. Cancer Discovery 2014, 4, 61. doi: 10.1158/2159-8290.CD-13-0631
6. [6]
  Rauch, J.; O'Neill, E.; Mack, B.; Matthias, C.; Munz, M.; Kolch, W.; Gires, O. Cancer Res. 2010, 70, 1679. doi: 10.1158/0008-5472.CAN-09-2740
7. [7]
  Shi, H.; Moriceau, G.; Kong, X.; Lee, M. K.; Lee, H.; Koya, R. C.; Ng, C.; Chodon, T.; Scolyer, R. A.; Dahlman, K. B.; Sosman, J. A.; Kefford, R. F.; Long, G. V.; Nelson, S. F.; Ribas, A.; Lo, R. S. Nat Commun. 2012, 3, 724. doi: 10.1038/ncomms1727
8. [8]
  Vasbinder, M. M.; Aquila, B.; Augustin, M.; Chen, H.; Cheung, T.; Cook, D.; Drew, L.; Fauber, B. P.; Glossop, S.; Grondine, M.; Hennessy, E.; Johannes, J.; Lee, S.; Lyne, P.; Mortl, M.; Omer, C.; Palakurthi, S.; Pontz, T.; Read, J.; Sha, L.; Shen, M.; Steinbacher, S.; Wang, H.; Wu, A.; Ye, M. J. Med. Chem. 2013, 56, 1996. doi: 10.1021/jm301658d
9. [9]
  Tang, J.; Hamajima, T.; Nakano, M.; Sato, H.; Dickerson, S. H.; Lackey, K. E. Bioorg. Med. Chem.Lett. 2008, 18, 4610. doi: 10.1016/j.bmcl.2008.07.019
10. [10]
  Wilhelm, S. M.; Adnane, L.; Newell, P.; Villanueva, A.; Llovet, J. M.; Lynch, M. Mol. Cancer Ther. 2008, 7, 3129. doi: 10.1158/1535-7163.MCT-08-0013
11. [11]
  Ambrosini, G.; Cheema, H. S.; Seelman, S.; Teed, A.; Sambol, E. B.; Singer, S.; Schwartz, G. K. Mol. Cancer Ther. 2008, 7, 890. doi: 10.1158/1535-7163.MCT-07-0518
12. [12]
  Hong, D. S.; Cabanillas, M. E.; Wheler, J.; Naing, A.; Tsimberidou, A. M.; Ye, L.; Waguespack, S. G.; Hernandez, M.; El Naggar, A. K.; Bidyasar, S.; Wright, J.; Sherman, S. I.; Kurzrock, R. J. Clin. Endocrinol. Metab. 2011, 96, 997. doi: 10.1210/jc.2010-1899
13. [13]
  Adnane, L.; Trail, P. A.; Taylor, I.; Wilhelm, S. M. Method Enzymol. 2006, 407, 597. doi: 10.1016/S0076-6879(05)07047-3
14. [14]
  Jean, G. W.; Mani, R. M.; Jaffry, A.; Khan, S. A. Clin. Rev. Educ. 2016, 2, 529.
15. [15]
  Gedaly, R.; Angulo, P.; Hundley, J.; Daily, M. F.; Chen, C.; Koch, A.; Evers, B. M. Anticancer Res. 2010, 30, 4951.
16. [16]
  Richetta, A. G.; Maiani, E.; Carboni, V.; Carlomagno, V.; Cimillo, M.; Mattozzi, C.; Calvieri, S. Eur. J. Dermatol. 2012, 55, 1082.
17. [17]
  Justin D.; Vijay G.; Wang X. D.; Laurence H. H.; Gary A. F. Bioorg. Med. Chem. 2010, 18, 292. doi: 10.1016/j.bmc.2009.10.055
18. [18]
  Yao, J.; Chen, J.; He, Z.; Sun, W.; Xu, W. Bioorg. Med. Chem. 2012, 20, 2923. doi: 10.1016/j.bmc.2012.03.018
19. [19]
  Kong, X.; Yao, Z.; He, Z.; Xu, W.; Yao, J. MedChemComm 2015, 6, 867. doi: 10.1039/C4MD00536H
20. [20]
  Scott, A. F.; Daniel, M. W.; Aysxegül, Ö.; Matthew, J. W. C. K.; Yin, J. P.; Ivana, Y.; Gabriele, S.; John, D. M.; Juliann, C.; Philip, J. S.; Lee, A. A.; Yan, J. B.; Kyung, S.; Georgia, H.; Charles, E.; Christine, Y.; Andrey, S. S.; Gerard, M.; Nicholas, J. S.; Sarah, G. H.; Shiva, M. Cancer Cell 2016, 29, 477. doi: 10.1016/j.ccell.2016.02.010
21. [21]
  Harry, S. M.; Melvin, L. Heterocycl. Basic Comd. 1954, 20, 285.
22. [22]
  Wei, L.; Xin, Z.; Lu, D.; Limin, S.; Chen, X. M.; Ping, G.; Sun, T. M. Molecules 2011, 16, 5134.
1. [1]
  Jing WU , Puzhen HUI , Huilin ZHENG , Pingchuan YUAN , Chunfei WANG , Hui WANG , Xiaoxia GU . Synthesis, crystal structures, and antitumor activities of transition metal complexes incorporating a naphthol-aldehyde Schiff base ligand. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2422-2428. doi: 10.11862/CJIC.20240278
2. [2]
  Zhi Zhou , Yu-E Lian , Yuqing Li , Hui Gao , Wei Yi . New Insights into the Molecular Mechanism Behind Clinical Tragedies of “Cephalosporin with Alcohol”. University Chemistry, 2025, 40(3): 42-51. doi: 10.12461/PKU.DXHX202403104
3. [3]
  Jianfeng Yan , Yating Xiao , Xin Zuo , Caixia Lin , Yaofeng Yuan . Comprehensive Chemistry Experimental Design of Ferrocenylphenyl Derivatives. University Chemistry, 2024, 39(4): 329-337. doi: 10.3866/PKU.DXHX202310005
4. [4]
  Ping Song , Nan Zhang , Jie Wang , Rui Yan , Zhiqiang Wang , Yingxue Jin . Experimental Teaching Design on Synthesis and Antitumor Activity Study of Cu-Pyropheophorbide-a Methyl Ester. University Chemistry, 2024, 39(6): 278-286. doi: 10.3866/PKU.DXHX202310087
5. [5]
  Xiaotong LU , Pan ZHANG , Zijie ZHAO , Lei HUANG , Hongwei ZUO , Lili LIANG . Antitumor and antibacterial activities of pyridyl Schiff base indium and dysprosium complexes. Chinese Journal of Inorganic Chemistry, 2025, 41(8): 1523-1532. doi: 10.11862/CJIC.20250073
6. [6]
  Yanglin Jiang , Mingqing Chen , Min Liang , Yige Yao , Yan Zhang , Peng Wang , Jianping Zhang . Experimental and Theoretical Investigations of Solvent Polarity Effect on ESIPT Mechanism in 4′-N,N-diethylamino-3-hydroxybenzoflavone. Acta Physico-Chimica Sinica, 2025, 41(2): 2309027-0. doi: 10.3866/PKU.WHXB202309027
7. [7]
  Xiaofei Liu , He Wang , Li Tao , Weimin Ren , Xiaobing Lu , Wenzhen Zhang . Electrocarboxylation of Benzylic Phosphates and Phosphinates with Carbon Dioxide. Acta Physico-Chimica Sinica, 2024, 40(9): 2307008-0. doi: 10.3866/PKU.WHXB202307008
8. [8]
  Yonghui ZHOU , Rujun HUANG , Dongchao YAO , Aiwei ZHANG , Yuhang SUN , Zhujun CHEN , Baisong ZHU , Youxuan ZHENG . Synthesis and photoelectric properties of fluorescence materials with electron donor-acceptor structures based on quinoxaline and pyridinopyrazine, carbazole, and diphenylamine derivatives. Chinese Journal of Inorganic Chemistry, 2024, 40(4): 701-712. doi: 10.11862/CJIC.20230373
9. [9]
  Yikai Wang , Xiaolin Jiang , Haoming Song , Nan Wei , Yifan Wang , Xinjun Xu , Cuihong Li , Hao Lu , Yahui Liu , Zhishan Bo . Thickness-Insensitive, Cyano-Modified Perylene Diimide Derivative as a Cathode Interlayer Material for High-Efficiency Organic Solar Cells. Acta Physico-Chimica Sinica, 2025, 41(3): 2406007-0. doi: 10.3866/PKU.WHXB202406007
10. [10]
  Jiahao Zeng , Hui Chao . 诱导程序性细胞死亡的金属抗肿瘤药物研究. University Chemistry, 2025, 40(6): 145-159. doi: 10.12461/PKU.DXHX202406019
11. [11]
  Jian Li , Yu Zhang , Rongrong Yan , Kaiyuan Sun , Xiaoqing Liu , Zishang Liang , Yinan Jiao , Hui Bu , Xin Chen , Jinjin Zhao , Jianlin Shi . Highly Efficient, Targeted, and Traceable Perovskite Nanocrystals for Photoelectrocatalytic Oncotherapy. Acta Physico-Chimica Sinica, 2025, 41(5): 100042-0. doi: 10.1016/j.actphy.2024.100042
12. [12]
  Jichao XU , Ming HU , Xichang CHEN , Chunhui WANG , Leichen WANG , Lingyi ZHOU , Xing HE , Xiamin CHENG , Su JING . Construction and hydrogen peroxide-activated chemodynamic activity of ferrocene?benzoselenadiazole conjugate. Chinese Journal of Inorganic Chemistry, 2025, 41(8): 1495-1504. doi: 10.11862/CJIC.20250144
13. [13]
  Hanxue LIU , Shijie LI , Meng REN , Xuling XUE , Hongke LIU . Design and antitumor properties of dehydroabietic acid functionalized cyclometalated iridium(Ⅲ) complex. Chinese Journal of Inorganic Chemistry, 2025, 41(8): 1483-1494. doi: 10.11862/CJIC.20250031
14. [14]
  Linjie ZHU , Xufeng LIU . Synthesis, characterization and electrocatalytic hydrogen evolution of two di-iron complexes containing a phosphine ligand with a pendant amine. Chinese Journal of Inorganic Chemistry, 2025, 41(5): 939-947. doi: 10.11862/CJIC.20240416
15. [15]
  Siran Wang , Yinuo Wang , Yilong Zhao , Dazhen Xu . Advances in the Application and Preparation of Rhodanine and Its Derivatives. University Chemistry, 2025, 40(5): 318-327. doi: 10.12461/PKU.DXHX202407033
16. [16]
  Jia-He Li , Yu-Ze Liu , Jia-Hui Ma , Qing-Xiao Tong , Jian-Ji Zhong , Jing-Xin Jian . 洛芬碱衍生物的合成、化学发光与重金属离子检测. University Chemistry, 2025, 40(6): 230-237. doi: 10.12461/PKU.DXHX202407080
17. [17]
  Zhongyan Cao , Shengnan Jin , Yuxia Wang , Yiyi Chen , Xianqiang Kong , Yuanqing Xu . Advances in Highly Selective Reactions Involving Phenol Derivatives as Aryl Radical Precursors. University Chemistry, 2025, 40(4): 245-252. doi: 10.12461/PKU.DXHX202405186
18. [18]
  Ruiqin Feng , Ye Fan , Yun Fang , Yongmei Xia . Strategy for Regulating Surface Protrusion of Gold Nanoflowers and Their Surface-Enhanced Raman Scattering. Acta Physico-Chimica Sinica, 2024, 40(4): 2304020-0. doi: 10.3866/PKU.WHXB202304020
19. [19]
  Manman Jin , Zhiguo Lv , Qingtao Niu . Teaching Reformation and Case Study for “Chemical Process Development and Design” Based on “Just-in-Time” Dynamic and Accurate Matching Industrial Needs. University Chemistry, 2024, 39(11): 108-116. doi: 10.12461/PKU.DXHX202403030
20. [20]
  Jiying Liu , Zehua Li , Wenjing Zhang , Donghui Wei . Molecular Orbital and Nucleus-Independent Chemical Shift Calculations for C₆H₆ and B₁₂H₁₂^2-: A Computational Chemistry Experiment. University Chemistry, 2025, 40(3): 186-192. doi: 10.12461/PKU.DXHX202406085

Get Citation

PDF

XML

Metrics

PDF Downloads(11)
Abstract views(1334)
HTML views(149)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142