Design, Synthesis and Activity Evaluation of Novel Bromodomain-Containing Protein 4 (BRD4) Small Molecule Inhibitor Based on ABBV-075

doi:10.6023/cjoc202007059

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (4): 1712-1721.DOI: 10.6023/cjoc202007059 Previous Articles Next Articles

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基于ABBV-075的新型溴结构域蛋白4 (BRD4)小分子抑制剂的设计、合成及活性评价

徐晨淏^a^,^b^,^c^,^d, 龚云鹏^a^,^b^,^c^,^d, 陈雅欣^a^,^b^,^c^,^d, 宋启梦^a^,^b^,^c^,^d, 李娇^a^,^b^,^c^,^d, 郑一超^a^,^b^,^c^,^d, 李雯^a^,^b^,^c^,^d^,^*(), 孙凯^a^,^b^,^c^,^d^,^*(), 刘宏民^a^,^b^,^c^,^d^,^*()

a 郑州大学药学院郑州 450001
b 郑州大学药物研究院郑州 450001
c 新药创制与药物安全性评价河南省协同创新中心郑州 450001
d 药物关键制备技术教育部重点实验室郑州 450001

收稿日期:2020-07-26 修回日期:2020-10-21 发布日期:2020-12-05
通讯作者: 李雯, 孙凯, 刘宏民
基金资助:
国家自然科学基金(81438005); 国家自然科学基金(81773562); 国家蛋白质重点研究项目基金(SQ2018YFE011359); 河南省重点研究项目基金(1611003110100)

Design, Synthesis and Activity Evaluation of Novel Bromodomain-Containing Protein 4 (BRD4) Small Molecule Inhibitor Based on ABBV-075

Chenhao Xu^a^,^b^,^c^,^d, Yunpeng Gong^a^,^b^,^c^,^d, Yaxin Chen^a^,^b^,^c^,^d, Qimeng Song^a^,^b^,^c^,^d, Jiao Li^a^,^b^,^c^,^d, Yichao Zheng^a^,^b^,^c^,^d, Wen Li^a^,^b^,^c^,^d^,^*(), Kai Sun^a^,^b^,^c^,^d^,^*(), Hongmin Liu^a^,^b^,^c^,^d^,^*()

a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
b Institute of Drug Discovery & Development, Zhengzhou University, Zhengzhou 450001
c Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001
d Key Laboratory of Technology of Drug Preparation, Ministry of Education, Zhengzhou 450001

Received:2020-07-26 Revised:2020-10-21 Published:2020-12-05
Contact: Wen Li, Kai Sun, Hongmin Liu
About author:
* Corresponding authors. E-mail: liwen@zzu.edu.cn;
E-mail: kaisun@zzu.edu.cn;
E-mail: liuhm@zzu.edu.cn
Supported by:
National Natural Science Foundation of China(81438005); National Natural Science Foundation of China(81773562); National Key Research Program of Proteins(SQ2018YFE011359); Key Research Program of Henan Province(1611003110100)

1. cjoc202007059辅助材料.pdf(1068KB)

Abstract

In order to discover novel bromodomain-containing protein 4 (BRD4) small molecule inhibitor, 16 compounds with 4 different nuclei based on ABBV-075 were designed and synthesized through scaffold hopping. The conditions of the Suzuki coupling reaction in the synthesis steps were optimized and the activity of all compounds against BRD4 was tested. The results indicated that compound N-(4-(2,4-difluorophenoxy)-3-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)- phenyl)ethanesulfonamide (15o) had 51% at concentration of 10 μmol/L with IC ₅₀ value of (16.39±1.20) μmol/L, possessing obvious BRD4 inhibitory activity. The molecular docking results showed that15oformed key hydrogen bonds with Asn433 and Asp381. The picture of superposed conformation of 15o and homolog of ABBV-075 exhibited the combination difference between them, explaining the reason of activity gap, which would provide excellent ideas for further study.

Key words: BRD4 inhibitor, ABBV-075, synthesis and optimization, bioactivity, molecular docking

Cite this article

Chenhao Xu, Yunpeng Gong, Yaxin Chen, Qimeng Song, Jiao Li, Yichao Zheng, Wen Li, Kai Sun, Hongmin Liu. Design, Synthesis and Activity Evaluation of Novel Bromodomain-Containing Protein 4 (BRD4) Small Molecule Inhibitor Based on ABBV-075[J]. Chinese Journal of Organic Chemistry, 2021, 41(4): 1712-1721.

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Fig. & Tab. 13

References 26

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Entry	Catalyst	Ligand	Base	Solvent	T/℃	Time/h	Yield^a/%
1	Pd₂(dba)₃	X-Phos	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
2	Pd₂(dba)₃	X-Phos	Cs₂CO₃	DMSO	90	6	0
3	Pd₂(dba)₃	X-Phos	Cs₂CO₃	DMF	90	6	0
4	Pd₂(dba)₃	X-Phos	K₃PO₄	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
5	Pd₂(dba)₃	X-Phos	Na₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
6	Pd₂(dba)₃	PPh₃	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
7	Pd(OAc)₂	X-Phos	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
8	Pd(OAc)₂	PPh₃	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
9	Pd(dppf)Cl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
10	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	30
11	(dtbpf)PdCl₂	None	K₃PO₄	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	12
12	(dtbpf)PdCl₂	None	Na₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	10
13	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	12	40
14	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	24	40
15	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane	90	12	0
16	(dtbpf)PdCl₂	None	Cs₂CO₃	DMSO	90	12	0
17	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	30	12	0
18	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	60	12	0

Entry	Catalyst	Ligand	Base	Solvent	T/℃	Time/h	Yield^a/%
1	Pd₂(dba)₃	X-Phos	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
2	Pd₂(dba)₃	X-Phos	Cs₂CO₃	DMSO	90	6	0
3	Pd₂(dba)₃	X-Phos	Cs₂CO₃	DMF	90	6	0
4	Pd₂(dba)₃	X-Phos	K₃PO₄	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
5	Pd₂(dba)₃	X-Phos	Na₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
6	Pd₂(dba)₃	PPh₃	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
7	Pd(OAc)₂	X-Phos	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
8	Pd(OAc)₂	PPh₃	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
9	Pd(dppf)Cl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	0
10	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	30
11	(dtbpf)PdCl₂	None	K₃PO₄	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	12
12	(dtbpf)PdCl₂	None	Na₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	6	10
13	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	12	40
14	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	90	24	40
15	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane	90	12	0
16	(dtbpf)PdCl₂	None	Cs₂CO₃	DMSO	90	12	0
17	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	30	12	0
18	(dtbpf)PdCl₂	None	Cs₂CO₃	1,4-Dioxane/H₂O (V∶V=4∶1)	60	12	0

Compd.	R¹	Inhibition/% at 10 μmol/L	IC₅₀^a/(μmol?L^–1)
15a	H	23	—
15b	2,4-F₂	5	—
15c	3-CH₃	20	—
15d	4-CH₃	3	—
15e	3-OCH₃	5	–
15f	4-F	20	–
(+)-JQ1			0.070±0.001

Compd.	R¹	Inhibition/% at 10 μmol/L	IC₅₀^a/(μmol?L^–1)
15a	H	23	—
15b	2,4-F₂	5	—
15c	3-CH₃	20	—
15d	4-CH₃	3	—
15e	3-OCH₃	5	–
15f	4-F	20	–
(+)-JQ1			0.070±0.001

Compd.	R¹	Inhibition/% at 10 μmol/L	IC₅₀^a/ (μmol?L^–1)	Compd.	R¹	Inhibition/% at 10 μmol/L	IC₅₀^a/ (μmol?L^–1)
15g	H	12	–	15m	H	5	—
15h	3-F	13	–	15n	2,4-F₂	35	—
15i	4-F	25	—	15o	2,4-F₂	51	16.39±1.20
15j	4-CN	5	—	15p	2,4-F₂	24	—
15k	H	28	—	(+)-JQ1			0.070±0.001
15l	H	31	—

基于ABBV-075的新型溴结构域蛋白4 (BRD4)小分子抑制剂的设计、合成及活性评价

Design, Synthesis and Activity Evaluation of Novel Bromodomain-Containing Protein 4 (BRD4) Small Molecule Inhibitor Based on ABBV-075

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