α-亚甲基-γ-丁内酯类GPR52拮抗剂的设计与合成研究

doi:10.6023/cjoc202303005

摘要/Abstract

GPR52是一种孤儿G蛋白偶联受体, 在纹状体中高度表达, 与神经退行性疾病亨廷顿舞蹈症(HD)的发生相关. 变异亨廷顿蛋白(mHTT)的蓄积是亨廷顿舞蹈症的主要发病原因. 通过拮抗GPR52活性降低mHTT的水平是一种有潜力的新型治疗手段. 通过高通量筛选, 发现天然产物E7作为共价拮抗剂对GPR52具有一定的抑制作用(IC₅₀=12.0 μmol/L). 本工作通过保留关键母核α-亚甲基-γ-丁内酯, 对E7进行结构简化并改造, 设计合成了34个新型α-亚甲基-γ-丁内酯衍生物, 其中(±)-4-甲氧基苯甲酸-[(2S,3R)-4-甲亚基-5-氧亚基-2-(噻吩-2-基)四氢呋喃-3-基]甲基酯(10m)对GPR52具有较好的拮抗活性(IC₅₀=0.58 μmol/L). 同时, 初步确定了此类新型GPR52拮抗剂的构效关系, 并验证了α-亚甲基-γ-丁内酯母核的必要性.

关键词: 亨廷顿舞蹈症, G蛋白偶联受体, GPR52, α-亚甲基-γ-丁内酯, 拮抗剂

GPR52 is an orphan G protein-coupled receptor, which is highly expressed in the striatum and associated with Huntingdon’s disease (HD), a neurodegenerative disease. HD is caused by the accumulation of mutant Huntingdon’s protein (mHTT). Reduction of mHTT level by inhibition of GPR52 is a novel potential method of HD therapy. Through high throughput screening, the natural product E7 was found as a covalent antagonist against GPR52 (IC₅₀=12.0 μmol/L). In this study, the structure of E7 was simplified and the α-methylene-γ-butyrolactone moiety was retained. And 34 novel α-methylene-γ-butyro- lactone derivatives were designed and synthesized, of which (±)-((2S,3R)-4-methylene-5-oxo-2-(thiophen-2-yl)-tetrahydro- furan-3-yl)methyl 4-methoxybenzoate (10m) showed most potent antagonistic activity against GPR52 (IC₅₀=0.58 μmol/L). Meanwhile, the structure-activity relationship was determined preliminarily and the necessary of α-methylene-γ- butyrolactone moiety was verified.

Key words: Huntingdon’s disease, G protein-coupled receptor, GPR52, α-methylene-γ-butyrolactones, antagonist

引用此文

沈冬杭, 李鑫, 郭世猛, 谢欣, 南发俊. α-亚甲基-γ-丁内酯类GPR52拮抗剂的设计与合成研究[J]. 有机化学, 2023, 43(11): 3916-3929.

Donghang Shen, Xin Li, Shimeng Guo, Xin Xie, Fajun Nan. Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52[J]. Chinese Journal of Organic Chemistry, 2023, 43(11): 3916-3929.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 9

参考文献 17

[1]	The Huntington’s Disease Collaborative Research Group Cell 1993, 72, 971. doi: 10.1016/0092-8674(93)90585-E
[2]	Richfield, E. K.; Maguire-Zeiss, K. A.; Vonkeman, H. E.; Voorn, P. Ann. Neurol. 1995, 38, 852. pmid: 8526457
[3]	Harper, S. Q.; Staber, P. D.; He, X.; Eliason, S. L.; Martins, I. H.; Mao, Q.; Yang, L.; Kotin, R. M.; Paulson, H. L.; Davidson, B. L. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 5820. doi: 10.1073/pnas.0501507102
[4]	Rodriguez-Lebron, E.; Denovan-Wright, E. M.; Nash, K.; Lewin, A. S.; Mandel, R. J. Mol. Ther. 2005, 12, 618.
[5]	DiFiglia, M.; Sena-Esteves, M.; Chase, K.; Sapp, E.; Pfister, E.; Sass, M.; Yoder, J.; Reeves, P.; Pandey, R. K.; Rajeev, K. G.; Manoharan, M.; Sah, D. W.; Zamore, P. D.; Aronin, N. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 17204. doi: 10.1073/pnas.0708285104
[6]	Kordasiewicz, H. B.; Stanek, L. M.; Wancewicz, E. V.; Mazur, C.; McAlonis, M. M.; Pytel, K. A.; Artates, J. W.; Weiss, A.; Cheng, S. H.; Shihabuddin, L. S.; Hung, G.; Bennett, C. F.; Cleveland, D. W. Neuron 2012, 74, 1031. doi: 10.1016/j.neuron.2012.05.009 pmid: 22726834
[7]	Caron, N. S.; Dorsey, E. R.; Hayden, M. R. Nat. Rev. Drug Discovery 2018, 17, 729. doi: 10.1038/nrd.2018.133
[8]	Wang, N.; Gray, M.; Lu, X.-H.; Cantle, J. P.; Holley, S. M.; Greiner, E.; Gu, X.-F.; Shirasaki, D.; Cepeda, C.; Li, Y.-Q.; Dong, H.-W.; Levine, M. S.; Yang, X. W. Nat. Med. 2014, 20, 536. doi: 10.1038/nm.3514 pmid: 24784230
[9]	Li, Z.-Y.; Wang, C.; Wang, Z.-Y.; Zhu, C.-G.; Li, J.; Sha, T.; Ma, L.-X.; Gao, C.; Yang, Y.; Sun, Y.-M.; Wang, J.; Sun, X.-L.; Lu, C.-Q.; Difiglia, M.; Mei, Y.-A.; Ding, C.; Luo, S.-Q.; Dang, Y.-J.; Ding, Y.; Fei, Y.-Y.; Lu, B.-X. Nature 2019, 575, 203. doi: 10.1038/s41586-019-1722-1
[10]	Baldo, B.; Weiss, A.; Parker, C. N.; Bibel, M.; Paganetti, P.; Kaupmann, K. J. Biol. Chem. 2012, 287, 1406. doi: 10.1074/jbc.M111.294801
[11]	Zhang, S.; Binari, R.; Zhou, R.; Perrimon, N. Genetics 2010, 184, 1165. doi: 10.1534/genetics.109.112516
[12]	Yao, Y.-W.; Cui, X.-T.; Al-Ramahi, I.; Sun, X.-L.; Li, B.; Hou, J.-P.; Difiglia, M.; Palacino, J.; Wu, Z.-Y.; Ma, L.-X.; Botas, J.; Lu, B.-X. Elife 2015, 4, e05449. doi: 10.7554/eLife.05449
[13]	Song, H.-K.; Li, H.-X.; Guo, S.-M.; Pan, Y.-Y.; Fu, Y.-H.; Zhou, Z.-J.; Li, Z.-Y.; Wen, X.; Sun, X.-L.; He, B.-Q.; Gu, H.-F.; Zhao, Q.; Wang, C.; An, P.; Luo, S.-Q.; Hu, Y.-H.; Xie, X.; Lu, B.-X. Brain 2018, 141, 1782. doi: 10.1093/brain/awy081
[14]	Wang, C.-C.; Zhang, Y.-F.; Guo, S.-M.; Zhao, Q.; Zeng, Y.-P.; Xie, Z-C.; Xie, X.; Lu, B.-X.; Hu, Y.-H. J. Med. Chem. 2021, 64, 941. doi: 10.1021/acs.jmedchem.0c01133
[15]	Ma, M.-N.; Guo, S.-M.; Lin, X.; Li, S.-S; Wu, Y.-R.; Zeng, Y.-P.; Hu, Y.-H.; Zhao, S.-W.; Xu, F.; Xie, X.; Shui, W.-Q. ACS Chem. Biol. 2020, 15, 3275. doi: 10.1021/acschembio.0c00867
[16]	Lagoutte, R.; Serba, C.; Abegg, D.; Hoch, D. G.; Adibekian, A.; Winssinger, N. Nat. Commun. 2016, 7, 12470 doi: 10.1038/ncomms12470 pmid: 27539788
[17]	Lin, X.; Li, M.-Y.; Wang, N.-D.; Wu, Y.-R.; Luo, Z.-P.; Guo, S.-M; Han, G.-W.; Li, S.-B.; Yue, Y.; Wei, X.-H.; Xie, X.; Chen, Y.; Zhao, S.-W.; Wu, J.; Lei, M.; Xu, F. Nature 2020, 579, 152 doi: 10.1038/s41586-020-2019-0

Compd.	IC₅₀/(μmol•L^–1)	Compd.	IC₅₀/(μmol•L^–1)
7a	1.73±0.09	8a	3.77±0.15
7b	0.67±0.18	8b	2.20±0.35
7c	3.99±0.35	8c	1.55±0.22
7d	1.53±0.22	8d	3.95±0.31
E7	11.89

Compd.	IC₅₀/(μmol•L^–1)	Compd.	IC₅₀/(μmol•L^–1)
7a	1.73±0.09	8a	3.77±0.15
7b	0.67±0.18	8b	2.20±0.35
7c	3.99±0.35	8c	1.55±0.22
7d	1.53±0.22	8d	3.95±0.31
E7	11.89

Compd.	IC₅₀/(μmol•L^–1)	Compd.	R³	IC₅₀/(μmol•L^–1)
7b	0.67±0.18	10m		0.58±0.09
10a	20.8±2.4	10n		3.79±0.82
10b	19.5±3.3	10o		2.02±0.48
10c	6.50±0.91	10p		3.75±0.29
10d	10.4±1.8	10q		4.55±1.20
10e	3.54±0.92	10r		1.33±0.22
10f	4.00±1.1	10s		1.44±0.20
10g	1.44±0.21	10t		4.85±0.59
10h	1.66±0.42	10u		2.43±0.09
10i	2.35±0.17	10v		5.15±0.31
10j	5.33±0.63	10w		3.76±1.10
10k	4.72±0.28	10x		8.59±1.00
10l	5.03±0.26	E7	—	11.89

Compd.	IC₅₀/(μmol•L^–1)	Compd.	R³	IC₅₀/(μmol•L^–1)
7b	0.67±0.18	10m		0.58±0.09
10a	20.8±2.4	10n		3.79±0.82
10b	19.5±3.3	10o		2.02±0.48
10c	6.50±0.91	10p		3.75±0.29
10d	10.4±1.8	10q		4.55±1.20
10e	3.54±0.92	10r		1.33±0.22
10f	4.00±1.1	10s		1.44±0.20
10g	1.44±0.21	10t		4.85±0.59
10h	1.66±0.42	10u		2.43±0.09
10i	2.35±0.17	10v		5.15±0.31
10j	5.33±0.63	10w		3.76±1.10
10k	4.72±0.28	10x		8.59±1.00
10l	5.03±0.26	E7	—	11.89

Comp.	X	R³	IC₅₀/(μmol•L^–1)
7b			0.67±0.18
12a			NA
10m			0.58±0.09
12b			NA