5-苄基-2-苯基嘧啶-4(3H)-酮类新型MEK抑制剂基于结构的设计与合成

doi:10.5246/jcps.2018.10.070

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (10): 686-695.DOI: 10.5246/jcps.2018.10.070

5-苄基-2-苯基嘧啶-4(3H)-酮类新型MEK抑制剂基于结构的设计与合成

李灿, 李宏月, 孙静, 席丹丹, 王超, 梁磊, 许凤荣, 牛彦^*, 徐萍^*

北京大学医学部药学院药物化学系, 北京 100191

收稿日期:2018-05-31 修回日期:2018-07-17 出版日期:2018-10-30 发布日期:2018-09-10
通讯作者: Tel.: +86-010-82802632, Fax: +86-010-82801117, E-mail: pingxu@bjmu.edu.cn; yanniu@bjmu.edu.cn
基金资助:
National Natural Science Fund of China (Grant No. 21172012), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20120001110010) and Beijing Natural Science Foundation of China (Grant No. 7162110).

Structure-based design and synthesis of 5-benzyl-2-phenylpyrimidin-4(3H)-one derivatives as novel MEK1 inhibitors

Can Li, Hongyue Li, Jing Sun, Dandan Xi, Chao Wang, Lei Liang, Fengrong Xu, Yan Niu^*, Ping Xu^*

Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2018-05-31 Revised:2018-07-17 Online:2018-10-30 Published:2018-09-10
Contact: Tel.: +86-010-82802632, Fax: +86-010-82801117, E-mail: pingxu@bjmu.edu.cn; yanniu@bjmu.edu.cn
Supported by:
National Natural Science Fund of China (Grant No. 21172012), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20120001110010) and Beijing Natural Science Foundation of China (Grant No. 7162110).

摘要/Abstract

摘要：

Ras/Raf/MEK/ERK通路在人类的多种肿瘤中均表现异常活化, 通过抑制MEK激酶阻断该通路是有效的癌症治疗策略。本文描述了5-苄基-2-苯基嘧啶-4(3H)-酮类作为新型MEK变构抑制剂骨架的设计与合成。所得目标化合物在Raf-MEK级联实验中表现出中等的MEK1抑制效力, 对接研究结果显示活性最好的化合物SJ3的结合模式与常见的二芳胺类抑制剂PD0325901的结合模式非常相似。这些结果为基于该新型母核结构的进一步设计和优化并最终获得成药性分子提供了有力的依据。

关键词: 5-苄基-2-苯基嘧啶-4(3H)-酮, MEK1 抑制剂, 对接

Abstract:

Previous studies have shown that Ras/Raf/MEK/ERK signaling pathway is up-regulated in almost all cancer cells. Blocking of this pathway by MEK inhibition is an efficient therapeutic approach of cancer. In the present study, we described the discovery of 5-benzyl-2-phenylpyrimidin-4(3H)-one as a novel skeleton of allosteric MEK inhibitor. All acquired target compounds exhibited modest potency to inhibit MEK1 in Raf-MEK cascading assay, and docking studies revealed that the binding mode of the most potent compound (SJ3) was very similar to that of the well known diarylamine-based inhibitor (PD0325901). The results provided valuable guidance for further optimizations on this novel scaffold to achieve druggable molecules.

Key words: 5-Benzyl-2-phenylpyrimidin-4(3H)-one, MEK1 inhibitor, Docking

中图分类号:

R916

Supporting:

李灿, 李宏月, 孙静, 席丹丹, 王超, 梁磊, 许凤荣, 牛彦, 徐萍. 5-苄基-2-苯基嘧啶-4(3H)-酮类新型MEK抑制剂基于结构的设计与合成[J]. 中国药学(英文版), 2018, 27(10): 686-695.

Can Li, Hongyue Li, Jing Sun, Dandan Xi, Chao Wang, Lei Liang, Fengrong Xu, Yan Niu, Ping Xu. Structure-based design and synthesis of 5-benzyl-2-phenylpyrimidin-4(3H)-one derivatives as novel MEK1 inhibitors[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(10): 686-695.

参考文献

[1] Roger, D. The mitogen-activated protein kinase signal transduction pathway. J. Biol. Chem. 1993, 268, 14553–14556.

[2] Wallace, M.B.; Adams, M.E.; Kanouni, T.; Mol, C.D.; Dougan, D.R.; Feher, V.A.; O’Connell, S.M.; Shi, L.; Halkowycz, P.; Dong, Q. Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 4156–4158.

[3] Duncan, K.E.; Chang, L.Y.; Patronas, M. MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity. Eye. 2015, 29, 1003–1012.

[4] Roskoski, R.Jr. ERK1/2 MAP kinases: Structure, function, and regulation. Pharmacol. Res. 2012, 66, 105–143.

[5] Haura, E.B.; Ricart, A.D.; Larson, T.G.; Stella, P.J.; Bazhenova, L.; Miller, V.A.; Cohen, R.B.; Eisenberg, P.D.; Selaru, P.; Wilner, K.D.; Gadgeel, S.M. A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer. Clin. Cancer Res. 2010, 16, 2450–2457.

[6] Uehling, D.E.; Harris, P.A. Recent progress on MAP kinase pathway inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 4047–4056.

[7] Rice, K.D.; Aay, N.; Anand, N.K.; Blazey, C.M.; Bowles, O.J.; Bussenius, J.; Costanzo, S.; Curtis, J.K.; Defina, S.C.; Dubenko, L.; Engst, S.; Joshi, A.A.; Kennedy, A.R.; Kim, A.I.; Koltun, E.S.; Lougheed, J.C.; Manalo, J.C.; Martini, J.F.; Nuss, J. M.; Peto, C.J.; Tsang, T.H.; Yu, P.; Johnston, S. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med. Chem. Lett. 2012, 3, 416–421.

[8] Patel, Y.T.; Daryani, V.M.; Patel, P.; Zhou, D.; Fangusaro, J.; Carlile, D.J.; Martin, P.D.; Aarons, L.; Stewart, C.F. Population Pharmacokinetics of Selumetinib and Its Metabolite N-desmethyl-selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low-Grade Gliomas. CPT Pharmacometrics Syst. Pharmacol. 2017, 6, 305–314.

[9] Wang, C.; Zhang, H.; Xu, F.; Niu, Y.; Wu, Y.; Wang, X.; Peng, Y.; Sun, J.; Liang, L.; Xu, P. Substituted 3-benzylcoumarins as allosteric MEK1 inhibitors: design, synthesis and biological evaluation as antiviral agents. Molecules. 2013, 18, 6057–6091.

[10] Sun, J.; Niu, Y.; Wang, C.; Zhang, H.; Xie, B.; Xu, F.; Jin, H.; Peng, Y.; Liang, L.; Xu, P., Discovery of 3-benzyl-1,3-benzoxazine-2,4-dione analogues as allosteric mitogen-activated kinase kinase (MEK) inhibitors and anti-enterovirus 71 (EV71) agents. Bioorg. Med. Chem. 2016, 24, 3472–3482.

[11] Sun, J.; Niu, Y.; Xu, F.; Liang, L.; Wang, C.; Xu, P. Design, synthesis and biological evaluation of 3H-pyrano[2,3-d]pyrimidine-4,7-dionederivatives as MEK inhibitors. China Sci. Paper. 2015, 10, 2823–2829.

[12] Dong, Q.; Dougan, D.R.; Gong, X.; Halkowycz, P.; Jin, B.; Kanouni, T.; O'Connell, S.M.; Scorah, N.; Shi, L.; Wallace, M.B.; Zhou, F. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg. Med. Chem. Lett. 2011, 21, 1315–1319.

[13] El Kaim, L.; Grimaud, L.; Oble, J. New Ugi-Smiles-metathesis strategy toward the synthesis of pyrimidoazepines. J. Org. Chem. 2007, 72, 5835–5838.

[14] Zhang, X.; Raghavan, S.; Ihnat, M.; Hamel, E.; Zammiello, C.; Bastian, A.; Mooberry, S.L.; Gangjee, A. The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents. Bioorg. Med. Chem. 2015, 23, 2408–2423.

[15] Goldys, A.M.; Nunez, M.G.; Dixon, D.J. Creation through Immobilization: A New Family of High Performance Heterogeneous Bifunctional Iminophosphorane (BIMP) Superbase Organocatalysts. Org. Lett. 2014, 16, 6294–6297.

[16] Hagmann, W.K.; Basha, F.Z.; Hashimoto, M.; Frye, R.B.; Kojo, S.; Hecht, S.M. Chemistry of 2-substituted pyrimidines. Studies directed toward the synthesis of the pyrimidine moiety of bleomycin. J. Org. Chem. 1981, 46, 1413–1423.

[17] Fischmann, T.O.; Smith, C.K.; Mayhood, T.W.; Myers, J.E.; Reichert, P.; Mannarino, A.; Carr, D.; Zhu, H.; Wong, J.; Yang, R.S.; Le, H.V.; Madison, V.S. Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors. Biochemistry. 2009, 48, 2661–2674.

5-苄基-2-苯基嘧啶-4(3H)-酮类新型MEK抑制剂基于结构的设计与合成

Structure-based design and synthesis of 5-benzyl-2-phenylpyrimidin-4(3H)-one derivatives as novel MEK1 inhibitors

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