Chinese Journal of Organic Chemistry >
Synthesis and Evaluation of 3-(Indol-3-yl)-4-(pyrazolo[3,4- c]pyridazin-3-yl)maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors
Received date: 2020-11-30
Revised date: 2021-01-21
Online published: 2021-02-22
Supported by
Natural Science Foundation of Zhejiang Province(LY18H300009); Postdoctoral Science Foundation of China(2014M550256); State Key Laboratory of Drug Research(SIMM1601KF-04); National Natural Science Foundation of China(8150131067)
A series of novel 3-(indol-3-yl)-4-(pyrazolo[3,4-c]pyridazin-3-yl)maleimides were synthesized and evaluated for their inhibitory activity against mutant isocitrate dehydrogenase-1 (R132H). Most compounds exhibited potent potency to IDH1-R132H. Among them, compound9bwas the most promising IDH1-R132H inhibitor with IC50 values of 31 nmol/L and could significantly inhibit the production of 2-HG in human brain astroblastoma cells with mutant isocitrate dehydrogenase-1 （R132H). Preliminary structure-activity relationship and molecular modeling studies were discussed based on the experimental data obtained.
Meng Xu , Shenyuan Gao , Yuanxu Zeng , Anhui Gao , Lixin Gao , Lei Xu , Yubo Zhou , Jianrong Gao , Qing Ye , Jia Li . Synthesis and Evaluation of 3-(Indol-3-yl)-4-(pyrazolo[3,4- c]pyridazin-3-yl)maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors[J]. Chinese Journal of Organic Chemistry, 2021 , 41(5) : 1991 -2000 . DOI: 10.6023/cjoc202010045
| [1] | Dang, L.; White, D. W.; Gross, S.; Bennett, B. D.; Bittinger, M. A.; Driggers, E. M.; Fantin, V. R.; Jang, H. G.; Jin, S. Nature 2009, 462, 739. |
| [2] | Yan, H.; Parsons, D. W.; Jin, G. L.; McLendon, R.; Rasheed, B. A.; Yuan, W. S.; Kos, I.; Batinic-Haberlen, I.; Jones, S.; Riggins, G. J.; Friedman, H.; Friedman, A.; Reardon, D.; Herndon, J.; Kinzler, K. W.; Velculescu, V. E.; Vogelstein, B.; Bigner, D. D. N. Engl. J. Med. 2009, 360, 765. |
| [3] | Dang, L.; Jin, S.; Su, S. M. Trends Mol. Med. 2010, 16, 387. |
| [4] | Green, A.; Beer, P. N. Engl. J. Med. 2010, 362, 369. |
| [5] | Kao, H. W.; Liang, D. C.; Wu, J. H.; Kuo, M. C.; Wang, P. N.; Yang, C. P.; Shih, Y. S.; Lin, T. H.; Huang, Y. H. Neoplasia 2014, 16, 481. |
| [6] | Gross, S.; Cairns, R. A.; Minden, M. D.; Driggers, E. D.; Bittinger, M. A.; Jang, H. G.; Sasaki, M.; Jin, S. F.; Schenkein, D. P.; Su, S. M.; Dang, L.; Fantin, V. R.; Mak, T. W. J. Exp. Med. 2010, 207, 339. |
| [7] | Zhang, Y.; Wei, H.; Tang, K.; Lin, D.; Zhang, C.; Mi, Y.; Wang, L.; Wang, C.; Wang, M. Genet. Test. Mol. Biomarkers 2012, 16, 991. |
| [8] | Wang, X. L.; Liu, Y. H.; Jiang, J. H. Mod. Chin. Doct. 2020, 58, 15. (in Chinese). |
| [8] | (王晓丽, 刘永华, 江锦红, 中国现代医生, 2020, 58, 15.) |
| [9] | Lin, C.-C.; Hou, H. A.; Chou, W. C.; Kuo, Y.-Y.; Liu, C. Y.; Chen, C. Y.; Lai, Y. J.; Teng, M. H.; Huang, C. F. Am. J. Hematol. 2014, 89, 137. |
| [10] | Patnaik, M.-M.; Hanson, C. A.; Hodnefield, J. M.; Lasho, T. L.; Finke, C. M.; Knudson, R. A.; Ketterling, R. P.; Pardanani, A. Leukemia 2012, 26, 101. |
| [11] | Ghiam, A. F.; Cairns, R. A.; Thoms, J.; Pra, A. D.; Ahmed, O.; Meng, A.; Mak, T. W. Oncogen 2011, 31, 3826. |
| [12] | Li, Y.; Ma, L. Chin. J. Med. Imaging 2020, 28, 142. (in Chinese). |
| [12] | (李锐, 马林, 中国医学影像学杂, 2020, 28, 142.) |
| [13] | Kaneko, M. K.; Liu, X.; Oki, H.; Ogasawara, S.; Nakamura, T.; Saidoh, N.; Tsujimoto, Y.; Matsuyama, Y.; Uruno, A.; Sugawara, M.; Tsuchiya, T.; Yamakawa, M.; Yamamoto, M.; Takagi, M.; Kato, Y. Cancer Sci. 2014, 105, 744. |
| [14] | Deng, H. M.; Duan, H. X. J. Clin. Hepatol. 2020, 36, 2856. (in Chinese). |
| [14] | (邓海敏, 段华新, 临床肝胆病杂志, 2020, 36, 2856.) |
| [15] | Grassian, A. R.; Pagliarini, R. Curr. Opin. Gastroenterol. 2014, 30, 295. |
| [16] | Yang, H.; Ye, D.; Guan, K.; Xiong, Y. Clin. Cancer Res. 2012, 18, 5562. |
| [17] | Xu, W.; Yang, H.; Liu, Y.; Yang, Y.; Wang, P.; Kim, S. H.; Ito, S.; Yang, C.; Wang, P.; Xiao, M, T.; Liu, L. X.; Jiang, W. Q.; Liu, J.; Zhang, J. Y.; Wang, B.; Frye, S.; Zhang, Y.; Xu, Y, H.; Lei, Q. Y.; Guan, K. L.; Zhao, S. M.; Xiong, Y.; Cancer Cell 2011, 19, 17. |
| [18] | Janeta, P. M.; Rene?, M.; Lemieux, E. A.; Jeffrey, O.; Saunders, F. G.; Salituro, J. T.; Giovanni, C.; Zhen, W. C.; Ding, Z.; Da, W. C.; Ping, C.; Kimberly, S.; Erica, T.; Fang, W.; Muriel, D.; David, V.; Penard, L.; Cyril, Q.; Veronique, S.; Stephane, D. B.; Stefan, G.; Lenny, D.; Hua, Y.; Luke, U.; Yue, C.; Hyeryun, K.; Sheng, F. J.; Zhi, W. G.; Gui, Y.; Zhi, Y. L.; Xiao, B. L.; Cheng, F.; Li, P. Y.; Andrew, O.; Lee, S.; Scott, B.; Shin, S. M.; Katharine, Y. ACS Med. Chem. Lett. 2018, 9, 300. |
| [19] | Cho, Y. S.; Levell, J. R.; Liu, G.; Caferro, T.; Sutton, J.; Shafer, C. M.; Costales, A.; Manning, J. R.; Zhao, Q.; Sendzik, M.; Shultz, M.; Chenail, G.; Dooley, J.; Villalba, B.; Farsidjani, A.; Chen, J.; Kulathila, R.; Xie, X.; Dodd, S.; Gould, T.; Liang, G.; Heimbach, T.; Slocum, K.; Firestone, B.; Pu, M.; Pagliarini, R.; Growney, J. D. ACS Med. Chem. Lett. 2017, 8, 1116. |
| [20] | Rehwinkel, H.; Panknin, O.; Ring, S.; Anlauf, S.; Siebeneicher, H.; Nguyen, D. WO 2015121210, 2015. |
| [21] | Hu, Y.-Y.; Gao, A. H.; Liao, H.-H.; Zhang, M.-M.; Xu, G. Y.; Gao, L. X.; Xu, L.; Zhu, B. Y.; Gao, J. R.; Ye, Q.; Li, A. Arch. Pharm. 2018,e1800039. |
| [22] | Liu, X. Q.; Hu, Y.-Y.; Gao, A.; Xu, M.; Gao, L.; Xu, L.; Zhou, Y.; Gao, J. R.; Ye, Q.; Li, J. Bioorg. Med. Chem. 2019, 27, 589. |
| [23] | Wang, S. Y.; Guo, X. B. Chin. J. Org. Chem. 1989, 9, 124. (in Chinese). |
| [23] | (王昭煜, 郭秀斌, 有机化学, 1989, 9, 124.) |
| [24] | Xiao, F.; Luo, Y.; Lü, W.; Tang, J. Chin. J. Org. Chem. 2010, 30, 311. (in Chinese). |
| [24] | (肖锋, 罗宇, 吕伟, 汤杰, 有机化学, 2010, 30, 311.) |
| [25] | Zhao, S. M.; Lin, Y.; Xu, W.; Jiang, W. Q.; Zha, Z. Y.; Wang, P.; Yu, W.; Li, Z. Q.; Gong, L.-L.; Peng, Y. J.; Ding, J. P.; Lei, Q. Y.; Guan, K. L.; Xiong, Y. Science 2009, 324, 261. |
| [26] | Ward, P. S.; Patel, J.; Wise, D. R.; Abdel-Wahab, O.; Bennett, B. D.; Coller, H. A.; Cross, J. R.; Fantin, V. R.; Hedvat, C. V.; Perl, A. E.; Rabinowitz, J. D.; Carroll, M.; Su, S. M.; Sharp, K. A.; Levine, R. L.; Thompson, C. B. Cancer Cell 2010, 17, 225. |
| [27] | Noushmehr, H.; Weisenberger, D. J.; Diefes, K.; Phillips, H. S.; Pujara, K.; Berman, B. P.; Pan, F.; Pelloski, C. E.; Sulman, E. P.; Bhat, K. P.; Verhaak, R. G. W.; Hoadley, K. A.; Hayes, D. N.; Perou, C. M.; Schmidt, H. K.; Ding, L.; Wilson, R. K.; Berg, V. D.; Shen, H.; Bengtsson, H.; Neuvial, P.; Cope, L. M.; Buckley, J.; Herman, J. G.; Baylin, S. B.; Laird, P. W.; Aldape, K. Cancer Cell. 2010, 17, 510. |
| [28] | Okoye-Okafor, U. C.; Bartholdy, B.; Cartier, J.; Gao, E. N.; Pietrak, B.; Rendina, A. R.; Rominger, C.; Quinn, C.; Smallwood, A.; Wiggall, K. J.; Reif, A. J.; Schmidt, S. J.; Qi, H, W.; Zhao, H. Z.; Joberty, G.; Faelth-Savitski, M.; Bantscheff, M.; Drewes, G.; Duraiswami, C.; Brady, P.; Groy, A.; Narayanagari, S. R.; Antony-Debre, I.; Mitchell, H. R.; Kao, Y. R.; Christopeit, M.; Carvajal, L.; Barreyro, L.; Paietta, E.; Makishima, H.; Will, B.; Concha, N.; Adams, N. D.; Schwartz, B.; McCabe, M. T.; Maciejewski, J.; Verma, A.; Steidl, U. Nat. Chem. Biol. 2015, 11, 878. |
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