CN109453161A - α-，β-和γ-倒捻子素作为LSD1抑制剂在药物中的应用 - Google Patents

α-，β-和γ-倒捻子素作为LSD1抑制剂在药物中的应用 Download PDF

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CN109453161A
CN109453161A CN201811559375.6A CN201811559375A CN109453161A CN 109453161 A CN109453161 A CN 109453161A CN 201811559375 A CN201811559375 A CN 201811559375A CN 109453161 A CN109453161 A CN 109453161A
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mangostin
lsd1
inhibitor
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柳继锋
郑超
郑一超
马天放
李芳�
温婷羽
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Zhengzhou University
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Abstract

本发明属于药物化学领域，具体涉及α‑，β‑和γ‑倒捻子素作为新的组蛋白赖氨酸特异性去甲基化酶1（LSD1）抑制剂的应用。将其作为LSD1抑制剂可以用于预防和治疗与组蛋白去甲基化酶LSD1的活动相关的疾病和症状，特别是与反常基因转录，细胞分化和增值相关的疾病，如肿瘤等疾病。其结构式如下：

Description

α-，β-和γ-倒捻子素作为LSD1抑制剂在药物中的应用
技术领域
本发明涉及药物化学领域，具体涉及α-，β-和γ-倒捻子素作为新的组蛋白赖氨酸特异性去甲基化酶1(LSD1)抑制剂的应用。
背景技术
藤黄科藤黄属植物山竹(Garcinia mangostana L.)的果壳是东南亚地区的民间传统用药，常用于治疗痢疾、扭伤、伤寒、溃疡、皮肤感染等症。通过本领域技术人员已知的适当方法可从中分离得到α-，β-和γ-倒捻子素(mangostin)等xanthone类成分。目前主要用于抗真菌、抗细菌、抗肿瘤、疟疾、唾液酸苷酶抑制剂及芳香酶抑制剂。目前尚未有α-，β-和γ-倒捻子素(mangostin)作为LSD1抑制剂的相关报道。
恶性肿瘤严重影响着人们的身体健康，据世界卫生组织统计，全世界每年新确诊的肿瘤患者在1000万以上，给国家和社会造成沉重的负担，其中寻找高效低毒、可选择性杀伤或抑制肿瘤细胞的新作用机制的靶点明确的新型抗肿瘤药物已成为抗肿瘤药物研发的重要方向。组蛋白赖氨酸特异性去甲基化酶1(Histone Lysine Specific Demethylase 1,LSD1)是第一个被发现的组蛋白赖氨酸去甲基化酶(Y.Shi et al,Cell,2004,29,941-953)。目前研究发现LSD1与肿瘤、病毒性感染、代谢疾病、炎症等疾病的发生发展均有密切的关系。LSD1对胃癌、前列腺癌、乳腺癌等多种恶性肿瘤均过度表达并异常激活，导致抑癌基因沉默。因此，抑制LSD1活性或下调表达量可有效抑制肿瘤的生长、侵袭和转移，是当前抗肿瘤药物研究的热点靶标。如苯环丙胺类LSD1抑制剂可用于治疗白血病(Zhang YC etal,Med Res Rev,2015,35 1032-1071)；在水痘带状疱疹病毒和单纯疱疹病毒感染的人细胞中，降低LSD1的表达量或者抑制其活性，可以降低病毒mRNA和病毒蛋白的表达量(LiangYet al,PLOS Pathog,2011,7,e10021184)等。由此可见，通过开发新型，高活性的以LSD1为作用靶点的抑制剂，对于研究LSD1的生物学功能，开发新型抗肿瘤、抗病毒、抗炎等疾病的治疗药物，具有十分重要的意义。
发明内容
本发明一方面在于提供α-，β-和γ-倒捻子素或其药学上可接受的盐作为LSD1抑制剂的用途。
本发明另一方面在于提供α-，β-和γ-倒捻子素或其药学上可接受的盐作为LSD1抑制剂在制备预防或治疗LSD1异常表达引起的疾病的药物中的应用。
为实现本发明目的，本发明通过活性筛选，运用活性追踪及现代分离鉴定手段从山竹中分离得到α-，β-和γ-倒捻子素(mangostin)，经进一步活性测试发现其可作为对LSD1活性有较好抑制效果的抑制剂，可以用于与组蛋白去甲基化酶的活性相关的疾病和症状的预防和治疗中。在一些实施方式中，所述LSD1异常表达引起的疾病，包括但不限于肿瘤和病毒性感染疾病。
本发明所述的倒捻子素化学结构式如下：
其中R1为CH3或H，R2为CH3或H。
α-，β-和γ-倒捻子素(mangostin)化学结构式如下：
本发明预期α-，β-和γ-倒捻子素(mangostin)“药学上可接受的盐”也具有相同的活性。通常，例如通过将游离酸或碱形式的这些化合物与化学计算量适当的碱或酸在水中或在有机溶剂中或者两者的混合物中制备。通常，非水性介质如乙醚，乙酸乙酯，乙醇，异丙醇或乙腈是优选的。酸加成盐的实例包括无机酸加成盐，例如乙酸盐，马来酸盐，富马酸盐，柠檬酸盐，草酸盐，琥珀酸盐，酒石酸盐，苹果酸盐和对甲苯磺酸盐等。碱加盐的实例包括无机盐如钠，钾，钙，铵，镁，铝和锂盐，以及有机碱，如乙二胺，乙醇胺，N,N-二烷基乙醇胺，三乙醇胺，葡糖胺和碱性氨基酸盐。
本发明创新点在于：通过实验证实了天然产物α-，β-和γ-倒捻子素对于LSD1的抑制作用，可以作为LSD1抑制剂或以此为靶点治疗或预防与此相关的疾病和症状，特别是与反常基因转录、细胞分化和增值等相关疾病提供良好的应用前景。
具体实施方式
为了理解本发明，下面以实施例进一步对本发明实质内容进行说明，但本发明的内容并不局限于此。
实施例1：α-，β-和γ-倒捻子素(mangostin)LSD1抑制活性测定1.实验方法：样品为本发明从山竹分离得到的天然产物α-，β-和γ-倒捻子素(mangostin)(分离方法参见SakagamiY.etal,Phytomedicine,2005,12(3):203-208)；样品储备液：称取3-5mg样品置于1.5mL EP管中，然后用DMSO配制成浓度是20mM的溶液，4摄氏度保存放置，实验时根据所需浓度用DMSO稀释。将待测样品与LSD1蛋白于室温孵化后，加入LSD1反应底物H3K4me2并孵育反应，最后加入荧光染料Amplex和辣根过氧化酶HRP室温孵育，在酶标仪上激发光530nm，发射光590nm检测荧光数值：
实验结果采用SPSS软件计算IC50值。
2.实验结果如下表-1所示
a数据表示为：平均值±标准差；b n.t.:表示未测定。

Claims (2)

1.通式如下的倒捻子素 (Mangostin) 或其药学上可接受的盐及可药用载体或赋型剂的药物用途，其特征在于，将其作为活性成分用于 LSD1 抑制剂类药物的制备；
其中R1为CH3或H，R2 为CH3或H。
2.根据权利1要求所述的倒捻子素 (Mangostin) 或其药学上可接受的盐及可药用载体或赋型剂的药物用途，其特征在于，式（I）的化合物为 α -，β - 和γ - 倒捻子素(Mangostin)：
。
CN201811559375.6A 2018-12-20 2018-12-20 α-，β-和γ-倒捻子素作为LSD1抑制剂在药物中的应用 Pending CN109453161A (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409310A (zh) * 2020-12-18 2021-02-26 许昌学院 一种具有lsd1抑制活性的化合物、制备方法及应用
CN115737632A (zh) * 2022-12-16 2023-03-07 北京中医药大学 Lsd1抑制剂在抗急性髓性白血病药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150250824A1 (en) * 2014-03-07 2015-09-10 The Research Foundation For The State University Of New York Methods and compositions for expansion of stem cells and other cells
CN106045862A (zh) * 2015-04-10 2016-10-26 上海迪诺医药科技有限公司 环丙胺类螺(杂)环化合物、其药物组合物及应用
CN106176713A (zh) * 2016-08-24 2016-12-07 雷闽湘 α－山竹黄酮的新用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150250824A1 (en) * 2014-03-07 2015-09-10 The Research Foundation For The State University Of New York Methods and compositions for expansion of stem cells and other cells
CN106045862A (zh) * 2015-04-10 2016-10-26 上海迪诺医药科技有限公司 环丙胺类螺(杂)环化合物、其药物组合物及应用
CN106176713A (zh) * 2016-08-24 2016-12-07 雷闽湘 α－山竹黄酮的新用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHAO HAN: "Bioactivity evaluation of natural product α-mangostin as a novel xanthone-based lysine-specific demethylase 1 inhibitor to against tumor metastasis", 《BIOORGANIC CHEMISTRY》 *
张卫明: "《一带一路经济植物》", 30 November 2017 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409310A (zh) * 2020-12-18 2021-02-26 许昌学院 一种具有lsd1抑制活性的化合物、制备方法及应用
CN112409310B (zh) * 2020-12-18 2023-04-21 许昌学院 一种具有lsd1抑制活性的化合物、制备方法及应用
CN115737632A (zh) * 2022-12-16 2023-03-07 北京中医药大学 Lsd1抑制剂在抗急性髓性白血病药物中的应用
CN115737632B (zh) * 2022-12-16 2024-02-23 北京中医药大学 Lsd1抑制剂在抗急性髓性白血病药物中的应用

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