Synthesis and Evaluation of 3-(Indol-3-yl)-4-(pyrazolo[3,4- c]pyridazin-3-yl)maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors

doi:10.6023/cjoc202010045

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (5): 1991-2000.DOI: 10.6023/cjoc202010045 Previous Articles Next Articles

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3-(吲哚-3-基)-4-(吡唑并[3,4-c]哒嗪-3-基)马来酰亚胺脱氢类异柠檬酸酶-1突变体高效抑制剂的合成与评价

许萌^a, 高燊原^a, 曾源煦^a, 高安慧^b, 高立信^b, 许磊^b, 周宇波^b, 高建荣^a, 叶青^a^,^*(), 李佳^b^,^*()

a 浙江工业大学化学工程学院杭州 310032
b 中国科学院上海药物研究所上海 201203

收稿日期:2020-11-30 修回日期:2021-01-21 发布日期:2021-02-22
通讯作者: 叶青, 李佳
作者简介:
† 共同第一作者.
基金资助:
浙江省自然科学基金(LY18H300009); 中国博士后科学基金(2014M550256); 药物研究国家重点实验室(SIMM1601KF-04); 国家自然科学基金(8150131067)

Synthesis and Evaluation of 3-(Indol-3-yl)-4-(pyrazolo[3,4- c]pyridazin-3-yl)maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors

Meng Xu^a, Shenyuan Gao^a, Yuanxu Zeng^a, Anhui Gao^b, Lixin Gao^b, Lei Xu^b, Yubo Zhou^b, Jianrong Gao^a, Qing Ye^a^,^*(), Jia Li^b^,^*()

a College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203

Received:2020-11-30 Revised:2021-01-21 Published:2021-02-22
Contact: Qing Ye, Jia Li
About author:
* Corresponding authors. E-mail: yeqing1975@zjut.edu.cn;
E-mail: jli@simm.ac.cn
† These authors contributed equally to this work.
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)

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Abstract

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.

Key words: 3-(indol-3-yl)-4-(pyrazolo[3,4-c]pyridazin-3-yl)maleimide, mutant isocitrate dehydrogenase-1 (R132H) inhibitor, synthesis, biological activity

Cite this article

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.

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References 28

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Entry	Pd-cat	Solvent	Temp./℃	Pd-cat/mol%	Additive	Yield^b/%
1^c	Pd(PPh₃)₂Cl₂	PhMe	100	15	LiCl	76.9
2	Pd(PPh₃)₄	PhMe	100	15	LiCl	69.9
3	PdCl₂(dppf)	PhMe	100	15	LiCl	56.2
4	Pd(PPh₃)₂Cl₂	PhMe	100	15	CsF	68.3
5	Pd(PPh₃)₂Cl₂	PhMe	100	15	—	39.3
6	Pd(PPh₃)₂Cl₂	DMF	100	15	LiCl	22.9
7	Pd(PPh₃)₂Cl₂	1,4-Dioxane	100	15	LiCl	94.5
8	Pd(PPh₃)₂Cl₂	CH₃CN	100	15	LiCl	Trace
9	Pd(PPh₃)₂Cl₂	1,4-Dioxane	100	10	LiCl	77.6
10	Pd(PPh₃)₂Cl₂	1,4-Dioxane	100	5	LiCl	61.5
11	Pd(PPh₃)₂Cl₂	1,4-Dioxane	90	15	LiCl	63.7

Entry	Pd-cat	Solvent	Temp./℃	Pd-cat/mol%	Additive	Yield^b/%
1^c	Pd(PPh₃)₂Cl₂	PhMe	100	15	LiCl	76.9
2	Pd(PPh₃)₄	PhMe	100	15	LiCl	69.9
3	PdCl₂(dppf)	PhMe	100	15	LiCl	56.2
4	Pd(PPh₃)₂Cl₂	PhMe	100	15	CsF	68.3
5	Pd(PPh₃)₂Cl₂	PhMe	100	15	—	39.3
6	Pd(PPh₃)₂Cl₂	DMF	100	15	LiCl	22.9
7	Pd(PPh₃)₂Cl₂	1,4-Dioxane	100	15	LiCl	94.5
8	Pd(PPh₃)₂Cl₂	CH₃CN	100	15	LiCl	Trace
9	Pd(PPh₃)₂Cl₂	1,4-Dioxane	100	10	LiCl	77.6
10	Pd(PPh₃)₂Cl₂	1,4-Dioxane	100	5	LiCl	61.5
11	Pd(PPh₃)₂Cl₂	1,4-Dioxane	90	15	LiCl	63.7

Compd.	R¹	R²	R³	R⁴	IC₅₀±SE^a/ (nmol?L^–1)
9a	H		Me	H	148±46
9b	6-Br		Me	H	31±2
9c	6-F		Me	H	127±53
9d	5-F		Me	H	84±31
9e	6-Me		Me	H	42±12
9f	6-Br		Et	H	37±3
9g	6-Br		n-Bu	H	76±3
9h	6-Br	H	Me	H	1495±258
9i	6-Br		Me	Me	351±23
8b	6-Br		Me	Ph	≥10000
AG-120					199±81

Compd.	R¹	R²	R³	R⁴	IC₅₀±SE^a/ (nmol?L^–1)
9a	H		Me	H	148±46
9b	6-Br		Me	H	31±2
9c	6-F		Me	H	127±53
9d	5-F		Me	H	84±31
9e	6-Me		Me	H	42±12
9f	6-Br		Et	H	37±3
9g	6-Br		n-Bu	H	76±3
9h	6-Br	H	Me	H	1495±258
9i	6-Br		Me	Me	351±23
8b	6-Br		Me	Ph	≥10000
AG-120					199±81

Compd.	IC₅₀/(μmol?L^–1)
9b	≥10
9d	≥10
9e	≥10
9f	≥10
9g	≥10

3-(吲哚-3-基)-4-(吡唑并[3,4-c]哒嗪-3-基)马来酰亚胺脱氢类异柠檬酸酶-1突变体高效抑制剂的合成与评价

Synthesis and Evaluation of 3-(Indol-3-yl)-4-(pyrazolo[3,4- c]pyridazin-3-yl)maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors

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