苯磺酰哌嗪类化合物的合成及活性研究

doi:10.6023/cjoc202409007

有机化学 ›› 2025, Vol. 45 ›› Issue (7): 2406-2415.DOI: 10.6023/cjoc202409007 上一篇下一篇

研究论文

苯磺酰哌嗪类化合物的合成及活性研究

刘江钰^a^,^†, 刘洪涛^b^,^c^,^†, 巫晔翔^d, 张国盛^a, 王玉杰^a, 张煜皓^d, 雷丽娟^d, 许艳妮^d^,^*(), 李文燕^a^,^*()

^a 河北师范大学化学与材料科学学院河北省有机功能分子重点实验室石家庄 050024
^b 河北医科大学第一医院药剂科石家庄 050000
^c 河北省人民医院临床医学研究中心石家庄 050017
^d 中国医学科学院医药生物技术研究所国家新药(微生物)筛选实验室北京 100050

收稿日期:2024-11-08 修回日期:2025-02-28 发布日期:2025-03-07
作者简介:
^† 共同第一作者
基金资助:
河北省自然科学基金(H2022307031); 河北省自然科学基金(H2024205002); 河北省科技厅省级重点实验室绩效补助经费(22567622H)

Synthesis and Activity of Benzenesulfonyl Piperazines

Jiangyu Liu^a, Hongtao Liu^b^,^c, Yexiang Wu^d, Guosheng Zhang^a, Yujie Wang^a, Yuhao Zhang^d, Lijuan Lei^d, Yanni Xu^d^,^*(), Wenyan Li^a^,^*()

^a Hebei Key Laboratory of Organic Functional Molecules, College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang 050024
^b Department of Pharmacy, the First Hospital of Hebei Medical University, Shijiazhuang 050000
^c Clinical Medical Research Center, Hebei General Hospital, Shijiazhuang 050017
^d National Laboratory for Screening of New Drugs (Microbial), Institute of Medical Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050

Received:2024-11-08 Revised:2025-02-28 Published:2025-03-07
Contact: *E-mail: xuyanniwendeng@hotmail.com; wyli8512@mail.hebtu.edu.cn
About author:
^† These authors contributed equally to this work
Supported by:
Natural Science Foundation of Hebei Province(H2022307031); Natural Science Foundation of Hebei Province(H2024205002); Project of Science and Technology Department of Hebei Province(22567622H)

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摘要/Abstract

腺嘌呤核苷三磷酸(ATP)结合盒转运蛋白A1 (ABCA1)是胆固醇逆转运(RCT)中介导巨噬细胞胆固醇和其它亲脂性物质外流的关键蛋白, 是RCT的起始和限速步骤. 提高ABCA1的表达水平有利于抑制和延缓动脉粥样硬化(AS), 合成了一类含有苯磺酰哌嗪骨架的化合物, 并对其ABCA1上调表达活性进行了评价. 其中5-[4-(2,6-二氯苯磺酰基)-1-哌嗪甲基]-2-呋喃甲酸(4b)和2-[4-(2,6-二氯苯磺酰基)-1-哌嗪基]噻唑-5-甲酸(4c)对ABCA1的最高上调表达率可达308%和223%, EC₅₀值分别为0.03和0.008 μmol/L, 是良好的ABCA1上调表达剂. 同时对此类化合物的构效关系也进行了简单的总结.

关键词: 动脉粥样硬化, 腺嘌呤核苷三磷酸(ATP)结合盒转运蛋白A1 (ABCA1), ABCA1上调表达剂, 苯磺酰哌嗪

Adenosine triphosphate (ATP) binding cassette transporter A1 (ABCA1) is a critical transporter that mediates cellular cholesterol and other lipophilic substances efflux from macrophages in reverse cholesterol transport (RCT). ABCA1 is the initiation and rate-limiting step of RCT. Therefore, increasing the expression level of ABCA1 is beneficial to inhibit and delay atherosclerosis (AS). ABCA1 expression up-regulator is expected to be a new method for the treatment of AS. A class of compounds containing benzenesulfonyl piperazine skeleton were synthesized and their up-regulated expression activities of ABCA1 were evaluated based on ABCA1-promoter-luc-HepG2 stable transfection cell model. Among them, 5-(4-(2,6- dichlorophenylsulfonyl)-1-piperazinomethyl)-2-furancarboxylic acid (4b) and 2-(4-(2,6-dichlorophenylsulfonyl)-1-piperazi- nyl)thiazole-5-carboxylic acid (4c) had the highest up-regulated expression rates of 308% and 223%, and the EC₅₀ values were 0.03 and 0.008 μmol/L, respectively. They were good up-regulated expression agents of ABCA1. The structure-activity relationship of these compounds was also briefly summarized.

Key words: atherosclerosis, adenosine triphosphate (ATP) binding cassette transporter A1 (ABCA1), ABCA1 up-regulated expression agent, benzenesulfonyl piperazine

引用此文

刘江钰, 刘洪涛, 巫晔翔, 张国盛, 王玉杰, 张煜皓, 雷丽娟, 许艳妮, 李文燕. 苯磺酰哌嗪类化合物的合成及活性研究[J]. 有机化学, 2025, 45(7): 2406-2415.

Jiangyu Liu, Hongtao Liu, Yexiang Wu, Guosheng Zhang, Yujie Wang, Yuhao Zhang, Lijuan Lei, Yanni Xu, Wenyan Li. Synthesis and Activity of Benzenesulfonyl Piperazines[J]. Chinese Journal of Organic Chemistry, 2025, 45(7): 2406-2415.

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图/表 7

图1. 苯磺酰哌嗪类化合物的结构

Figure 1. Structures of benzenesulfonyl piperazines

图式1. 化合物3a~3j和4a~4f的合成

Scheme 1. Synthesis of compounds 3a~3j and 4a~4f Reaction conditions: (i) pyridine, THF; (ii) TFA, DCM; (iii) TEA, DCM; (iv) Cs2CO3, DMF, 120 ℃; (v) THF, 10% NaOH, EtOH, 60 ℃.

图式2. 化合物7a~7f, 8a~8e的合成

Scheme 2. Synthesis of compounds 7a~7f, 8a~8e Reaction conditions: (i) Pd(OAc)2, BINAP, Cs2CO3, toluene, 100 ℃; (ii) THF, conc. H2SO4, NBS, －25 ℃/NCS, 40 ℃; (ⅲ) DCM, TFA, r.t.; (ⅳ) 2,6-dichlorobenzene sulfonyl chloride or 2,6-difluorobenzene sulfonyl chloride, THF, pyridine; (ⅴ) THF, aq. NaOH (ω=10%), EtOH, 60 ℃.

Compd.	Highest up-regulated expression rate/%	EC₅₀/(μmol•L^－1)
3a	105±8	—
3b	142±5	—
3c	129±3	—
3d	210±2	0.40±0.14
3e	198±1	0.15±0.09
3f	179±6	0.58±0.21
3g	137±4	—
3h	145±3	—
3i	150±1	—
3j	117±2	—
4a	182±1	4.19±0.17
4b	308±1	0.03±0.01
4c	223±1	0.008±0.001
4d	201±6	0.17±0.06
4e	227±5	0.11±0.04
4f	140±4	—
7a	169±3	10.18±0.18
7b	179±2	17.54±0.39
7c	172±8	6.98±0.11
7d	212±2	11.47±0.32
7e	203±4	4.89±0.71
7f	145±7	—
8a	146±2	—
8b	129±3	—
8c	164±2	32.25±1.86
8d	215±1	0.14±0.03
8e	210±5	3.73±0.19
6i	200±6	0.41±0.05

表1. 目标化合物的ABCA1上调表达活性

Table 1. ABCA1 upregulatory activity of target compounds

图2. 化合物4b和4c对RAW264.7细胞中ABCA1 mRNA表达的影响

Figure 2. Effects of compounds 4b and 4c on ABCA1 mRNA expression in RAW264.7 cells

图3. 化合物4b和4c对RAW264.7细胞胆固醇流出的影响

Figure 3. Effects of compounds 4b and 4c on cholesterol efflux in RAW264.7 cells

图4. 化合物4b和4c的油红O染色实验

Figure 4. Oil red O staining experiment of compounds 4b and 4c

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苯磺酰哌嗪类化合物的合成及活性研究

Synthesis and Activity of Benzenesulfonyl Piperazines

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