嘧啶并二氮(艹卓)类化合物作为L3MBTL3抑制剂的设计、合成与构效关系研究
收稿日期: 2016-07-01
修回日期: 2016-08-03
网络出版日期: 2016-08-12
基金资助
国家自然科学基金（No. 81072526）和吉林省科技发展计划重点（No. 20140309010YY）资助项目.
Design, Synthesis and Structure-Activity Relationship Study of Pyri-midine-Fused Diazepine Derivatives as L3MBTL3 Inhibitors
Received date: 2016-07-01
Revised date: 2016-08-03
Online published: 2016-08-12
Supported by
Project supported by the National Natural Science Foundation of China (No. 81072526) and the Science and Technology Development Plan of Jilin Province (No. 20140309010YY).
周皓 , 车鑫 , 鲍国臣 , 王娜 , 柏旭 . 嘧啶并二氮(艹卓)类化合物作为L3MBTL3抑制剂的设计、合成与构效关系研究[J]. 有机化学, 2016 , 36(12) : 2948 -2959 . DOI: 10.6023/cjoc201607001
Histone methylation is one of epigenetic marks and its deregulation is linked to many diseases. Malignant brain tumor (MBT) domain protein is one of proteins that could read methylated lysine (Kme) of histones. L3MBTL1, a representative member of the MBT family, is related to transcriptional repression, hematopoietic function and tumor formation. Developing a potent and selective inhibitor of L3MBTL1 can help explain the regulatory mechanisms and validate its drugability. Active compound 1 for L3MBTL3 from a library of pyrimidine-fused diazepines was initially obtained. By incorporating the structural features of reported binders, the structure-activity relationship (SAR) studies were conducted, which led to four novel L3MBTL3 inhibitors with IC50 values under 1 μmol·L-1.
Key words： pyrimidine-fused diazepine; L3MBTL3; inhibitor; SAR study
Brueckner, B.; Garcia Boy, R.; Siedlecki, P.; Musch, T.; Kliem, H. C.; Zielenkiewicz, P.; Suhai, S.; Wiessler, M.; Lyko, F. Cancer Res. 2005, 65(14), 6305
[2] Kubicek, S.; O'sullivan, R. J.; August, E. M.; Hickey, E. R.; Zhang, Q.; Teodoro, M. L.; Rea, S.; Mechtler, K.; Kowalski, J. A.; Homon, C. A.; Kelly, T. A.; Jenuwein, T. Mol. Cell 2007, 25(3), 473.
[3] Manel, E. Carcinogenesis 2010, 31(1), 27.
[4] Zhang, Y.; Reinberg, D. Genes Dev. 2001, 15(18), 2343.
[5] Maurer-Stroh, S.; Dickens, N. J.; Hughes-Davies, L.; Kouzarides, T.; Eisenhaber, F.; Ponting, C. P. Trends Biochem. Sci. 2003, 28(2), 69.
[6] Nady, N.; Krichevsky, L.; Zhong, N.; Duan, S.; Tempel, W.; Amaya, M. F.; Ravichandran, M.; Arrowsmith, C. H. J. Mol. Biol. 2012, 423(5), 702.
[7] Northcott, P. A.; Nakahara, Y.; Wu, X.; Feuk, L.; Ellison, D. W.; Croul, S.; Mack, S.; Kongkham, P. N.; Peacock, J.; Dubuc, A.; Ra, Y. S.; Zilberberg, K.; Mcleod, J.; Scherer, S. W.; Sunil Rao, J.; Eberhart, C. G.; Grajkowska, W.; Gillespie, Y.; Lach, B.; Grundy, R.; Pollack, I. F.; Hamilton, R. L.; Van Meter, T.; Carlotti, C. G.; Boop, F.; Bigner, D.; Gilbertson, R. J.; Rutka, J. T.; Taylor, M. D. Nat. Genet. 2009, 41(4), 465.
[8] Satoko, A.; Toru, M. EMBO J. 2005, 24(10), 1863.
[9] James, L. I.; Barsyte-Lovejoy, D.; Zhong, N.; Krichevsky, L.; Korboukh, V. K.; Herold, J. M.; Macnevin, C. J.; Norris, J. L.; Sagum, C. A.; Tempel, W.; Marcon, E.; Guo, H.; Gao, C.; Huang, X. P.; Duan, S.; Emili, A.; Greenblatt, J. F.; Kireev, D. B.; Jin, J.; Janzen, W. P.; Brown, P. J.; Bedford, M. T.; Arrowsmith, C. H.; Frye, S. V. Nat. Chem. Biol. 2013, 9(3), 184.
[10] James, L. I.; Korboukh, V. K.; Krichevsky, L.; Baughman, B. M.; Herold, J. M.; Norris, J. L.; Jin, J.; Kireev, D. B.; Janzen, W. P.; Arrowsmith, C. H.; Frye, S. V. J. Med. Chem. 2013, 56(18), 7358
[11] Camerino, M. A.; Zhong, N.; Dong, A.; Dickson, B. M.; James, L. I.; Baughman, B. M.; Norris, J. L.; Kireev, D. B.; Janzen, W. P.; Arrowsmith, C. H.; Frye, S. V. Med. Chem. Commun. 2013, 4(11), 1501.
[12] Baughman, B. M.; Pattenden, S. G.; Norris, J. L.; James, L. I.; Frye, S. V. ACS Chem. Biol. 2016, 11(3), 722.
[13] Xiang, J.; Wen, D.; Xie, H.; Dang, Q.; Bai, X. J. Comb. Chem. 2010, 12(4), 503.
[14] West, L. E.; Roy, S.; Lachmi-Weiner, K.; Hayashi, R.; Shi, X. B.; Appella, E.; Kutateladze, T. G.; Gozani, O. J. Biol. Chem. 2010, 285(48), 37725.
[15] Eryilmaz, J.; Pan, P.; Amaya, M. F.; Allali-Hassani, A.; Dong, A.; Adams-Cioaba, M. A.; Mackenzie, F.; Vedadi, M.; Min, J. PLoS One 2009, 4(10), e7274.
[16] Yap, K. L.; Li, S.; Munoz-Cabello, A. M.; Raguz, S.; Zeng, L.; Mujtaba, S.; Gil, J.; Walsh, M. J.; Zhou, M. M. Mol. Cell 2010, 38(5), 662.
[17] Ditacchio, L.; Le, H. D.; Vollmers, C.; Hatori, M.; Witcher, M.; Secombe, J.; Panda, S. Science 2011, 333(6051), 1881.
[18] Reader, J. C.; Leng, Q.; Rassool, F. V.; Ning, Y. Leukemia Res. 2010, 34(8), 1094.
[19] Botuyan, M. V.; Lee, J.; Ward, I. M.; Kim, J. E.; Thompson, J. R.; Chen, J.; Mer, G. Cell 2006, 127(7), 1361.
[20] Wigle, T. J.; Herold, J. M.; Senisterra, G. A.; Vedadi, M.; Kireev, D. B.; Arrowsmith, C. H.; Frye, S. V.; Janzen, W. P. J. Biomol. Screening 2010, 15(1), 62.
/
| 〈 |
|
〉 |
