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

doi:10.6023/cjoc202007059

有机化学 ›› 2021, Vol. 41 ›› Issue (4): 1712-1721.DOI: 10.6023/cjoc202007059 上一篇下一篇

研究论文

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)

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摘要/Abstract

为发现新型溴结构域蛋白4 (BRD4)小分子抑制剂, 基于ABBV-075, 通过骨架跃迁, 设计并合成4种不同母核, 共16个化合物. 优化了合成步骤中Suzuki偶联反应条件, 并测试了化合物对BRD4的抑制活性. 结果表明, N-(4-(2,4-二氟氧代苯基)-3-(4-氧代-4,5-二氢-3H-吡咯并[2,3-d]嘧啶-2-基)苯基)乙磺酰胺(15o)的抑制率在10 μmol/L达到了51%, IC ₅₀=(16.39±1.20) μmol/L, 具有明显的BRD4抑制活性. 分子对接结果表明,15o可与Asn433和Asp381形成关键氢键, 其与ABBV-075同源物的叠合图显示了二者结合模式的差异. 阐明了化合物15o与ABBV-075活性差异的原因, 为进一步发现高活性BRD4抑制剂提供设计思路.

关键词: BRD4抑制剂, ABBV-075, 合成与优化, 生物活性, 分子对接

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

引用此文

徐晨淏, 龚云鹏, 陈雅欣, 宋启梦, 李娇, 郑一超, 李雯, 孙凯, 刘宏民. 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[J]. 有机化学, 2021, 41(4): 1712-1721.

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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图/表 13

图1. 代表性的BRD4抑制剂

Figure 1. Representative BRD4 inhibitors

图式1. 基于ABBV-075的BRD4抑制剂设计思路

Scheme 1. Design of BRD4 inhibitor based on ABBV-075

图式2. 化合物3的合成

Scheme 2. Synthesis of compound 3 Reagents and conditions: (a) CH3NH2?H2O, 1,4-dioxane, 80 ℃, 8 h, 90%; (b) NaNO2, AcOH, H2O, 0~5 ℃, 1 h, 55%

图式3. 化合物7a~7f的合成

Scheme 3. Synthesis of compounds 7a~7f Reagents and conditions: (a) ethanesulfonyl chloride, DMAP, pyridine, DCM, 25 ℃, 8 h, 80%; (b) appropriate phenol, Cs2CO3, DMSO, 100 ℃, 2 h, 85%~90%; (c) Fe, NH4Cl, THF/EtOH/H2O (V∶V∶V=2∶2∶1), 100 ℃, 2 h, 75%~80%

图式4. 化合物12a~12e的合成

Scheme 4. Synthesis of compounds 12a~12e Reagents and conditions: (a) appropriate phenol, Cs2CO3, DMSO, 100 °C, 2 h, 80%~90%; (b) Fe, NH 4Cl, THF/EtOH/H2O (V∶V∶V=2∶2∶1), 100 °C, 2 h, 70%~80%; (c) ethanesulfonyl chloride, DMAP, pyridine, DCM, 25 °C, 8 h, 85%~90%; (d) bis(pinacolato)diboron, Pd(dppf)Cl2, AcOK, 1,4-dioxane, N2, 100 °C, 2 h, 90%~95%

图式5. 化合物14a, 14b的合成与化合物14c的结构

Scheme 5. Synthesis of compounds 14a, 14b and the structure of 14c Reagents and conditions: (a) NaOH, H2O, 100 ℃, 12 h, 85%~90%

图式6. 化合物15a~15f的合成

Scheme 6. Synthesis of compounds 15a~15f Reagents and conditions: (a) HCl, EtOH/1,4-dioxane (V∶V=1∶1), 90 ℃, 8 h, 39%~47%

图式7. 化合物15g~15j的合成

Scheme 7. Synthesis of compounds 15g~15j Reagents and conditions: (a) Pd2(dba)3, X-Phos, K3PO4, 1,4-dio- xane/H2O (V∶V=4∶1), N2, 90 °C, 6 h, 41%~47%

图式8. 化合物15k~15p的合成

Scheme 8. Synthesis of compounds 15k~15p Reagents and conditions: (a) (dtbpf)PdCl2, K3PO4, 1,4-dioxane/H2O (V∶V=4∶1), N2, 90 ℃ 12 h, 35%~40%.

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

表1. 化合物15k的反应条件筛选与优化

Table 1. Screening and optimization of reaction conditions of compound 15k

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

表2. 化合物15a~15f的BRD4抑制活性

Table 2. BRD4 inhibitory activities of compounds 15a~15f

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	—

表3. 化合物15g~15p的BRD4抑制活性

Table 3. BRD4 inhibitory activities of compounds 15g~15p

图2. (A) ABBV-075同源物与BRD4结合模式图(PDB/ 5UVX)、(B)化合物15o与BRD4可能的结合模式图、(C) ABBV-075同源物与15o在蛋白空腔内的叠合图和(D) ABBV-075同源物(Ki=2.4 nmol/L)

Figure 2. (A) Binding mode of homolog of ABBV-075 in BRD4 (PDB:5UVX), (B) putative binding mode of 15o in BRD4, (C) the superposed conformation of 15o (blue) and homolog of ABBV-075 (pink) with BRD4 and (D) Homolog of Abbv-075 (Ki=2.4 nmol/L)

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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

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

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