CN111592513A - 一种倍半萜化合物用作lsd1抑制剂和制备抗肿瘤药物的医药用途 - Google Patents
一种倍半萜化合物用作lsd1抑制剂和制备抗肿瘤药物的医药用途 Download PDFInfo
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Abstract
本发明公开了一种倍半萜化合物用作LSD1抑制剂和制备抗肿瘤药物的医药用途。本发明发现3种倍半萜化合物atractylenolide V、8β‑methoxyatractylenolide、8β‑ethoxyasterolid为有效的LSD1抑制剂。组蛋白去甲基化酶在多种肿瘤中扮演着致癌蛋白的角色，而LSD1作为第1个被确认的酶在包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤等多种肿瘤中高表达并对其生长、转移和侵袭起着重要作用，因此LSD1是理想的抗肿瘤药物作用靶点，本发明发现的LSD1抑制剂具有开发成抑制肿瘤生长、转移和侵袭药物的前景。
Description
技术领域
本发明属于医药领域，涉及已知化合物新用途，具体涉及一种倍半萜化合物用作LSD1抑制剂和制备抗肿瘤药物的医药用途。
背景技术
组蛋白赖氨酸特异性去甲基化酶1(histone lysine specific demethylase 1，LSD1)是一个黄素腺嘌呤二核苷酸(FAD)依赖的氨基氧化酶，能够特异性去除组蛋白H3K4和H3K9的单、双甲基化。最新研究表明，组蛋白去甲基化酶在多种肿瘤中扮演着致癌蛋白的角色，而LSD1作为第1个被确认的酶在多种肿瘤的发生和发展中起着促进作用，因此LSD1是一个比较理想的抗肿瘤药物作用靶点。利用RNA干扰技术和小分子LSD1抑制剂调节LSD1的表达量和活性，能够控制肿瘤细胞的增殖、转移和侵袭。同时，由于LSD1在多种肿瘤中高表达，靶向LSD1的抗肿瘤治疗方案表现出较高的选择性和较低的毒副作用。因此，LSD1可能成为表观遗传学抗肿瘤药物的新靶点[参考文献：抗肿瘤药物新靶点:表观遗传组蛋白赖氨酸特异性去甲基化酶1，国际药学研究杂志，2014年2月第41卷第1期]。
LSD1对多种疾病的发生起着重要作用，用RNAi或小分子抑制剂抑制组蛋白去甲基化酶的表达或活性，能够抑制肿瘤的生长和转移。因此，设计并合成选择性强、高效、低毒的去甲基化酶抑制剂是治疗癌症的新途径[参考文献：抗肿瘤药物新靶点:表观遗传组蛋白赖氨酸特异性去甲基化酶1，国际药学研究杂志，2014年2月第41卷第1期]。
总之，LSD1在多种其他肿瘤中高表达并对其生长、转移和侵袭起着重要作用，包括胃癌[Magerl C,Ellinger J,Braunschweig T,et al.H3K4 Dimethylation inhepatocellular carcinoma is rare compared with other hepatobiliary andgastrointestinal carcinomas and correlates with expression of the methylaseAsh2 and the demethylase LSD1.Hum Pathol,2010]、结肠癌[Hayami S,Kelly JD,ChoHS,et al.Overexpression of LSD1 contributes to human carcinogenesis throughchromatin regulation in various cancers.Int J Cancer,2011]、膀胱癌[Hayami S,Kelly JD,Cho HS,et al.Overexpression of LSD1 contributes to humancarcinogenesis through chromatin regulation in various cancers.Int J Cancer,2011]、食管癌[Chen C,Zhao M,Yin N,et al.Abnormal histone acetylation andmethylation levels in esophageal squamous cell carcinomas.Cancer Invest,2011]、急性粒细胞白血病[Lokken AA,Zeleznik-Le NJ.Breaking the LSD1/KDM1Aaddiction:therapeutic targeting of the epigenetic modifier in AML.CancerCell,2012]和成视网膜细胞瘤[Yokoyama A,Takezawa S,Schule R,etal.Transrepressive function of TLX requires the histone demethylase LSD1.MolCell Biol,2008]等，而用RNAi技术降低LSD1的表达，或用小分子LSD1抑制剂调控LSD1的活性能够抑制肿瘤细胞的生长和转移[参考文献：抗肿瘤药物新靶点:表观遗传组蛋白赖氨酸特异性去甲基化酶1，国际药学研究杂志，2014年2月第41卷第1期]。文献还公开了LSD1与前列腺癌、乳腺癌、神经母细胞瘤的关系[LSD1及与肿瘤关系研究进展，中国肿瘤2010年第19卷第9期]。
近年来相关药物在多种肿瘤治疗中的应用也进一步证实LSD1作为药物靶点的适用性。应用传统小分子化合物调节LSD1的活性来调节肿瘤的发生和发展是目前LSD1抑制剂研究的热点方向。但目前发现的LSD1抑制剂对酶的抑制活性差，选择性低。因此，亟需设计合成高效、高选择性小分子LSD1抑制剂。
发明内容
本发明的目的在于克服现有技术的不足，提供一种倍半萜化合物用作LSD1抑制剂和制备抗肿瘤药物的医药用途。
本发明上述目的通过如下技术方案实现：
一种如下化学结构的倍半萜化合物：
上述化合物用于制备LSD1抑制剂药物的医药用途。
上述化合物用于制备抑制肿瘤生长的药物的医药用途。
进一步地，所述肿瘤包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤。
上述化合物用于制备抑制肿瘤转移的药物的医药用途。
进一步地，所述肿瘤包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤。
上述化合物用于制备抑制肿瘤侵袭的药物的医药用途。
进一步地，所述肿瘤包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤。
有益效果：
本发明发现，atractylenolide V、8β-methoxyatractylenolide、8β-ethoxyasterolid为有效的LDS1抑制剂。本领域技术人员知道，组蛋白去甲基化酶在多种肿瘤中扮演着致癌蛋白的角色，而LSD1作为第1个被确认的酶在包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤等多种肿瘤中高表达并对其生长、转移和侵袭起着重要作用，因此LSD1是一个比较理想的抗肿瘤药物作用靶点。LSD1抑制剂atractylenolide V、8β-methoxyatractylenolide、8β-ethoxyasterolid具有开发成抑制肿瘤生长、转移和侵袭药物的前景。
附图说明
图1为4种测试倍半萜化合物的化学结构式；
图2为不同浓度倍半萜对LSD1蛋白的抑制率曲线，其中：a、b、c、d依次为倍半萜化selina-4(14),7(11)-dien-8-one、atractylenolide V、8β-methoxyatractylenolide、8β-ethoxyasterolid对LSD1蛋白的抑制率曲线。
具体实施方式
下面结合附图和实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
一、实验材料
化学结构式如图1所示，HPLC纯度不低于98％。
硫酸卡那霉素、琼脂粉、胰蛋白胨、酵母提取物、氯化钠、十二水合磷酸氢二钠、咪唑、PET-28b-LSD1截断体质粒、BL21(DE)3感受态菌株、Ni-NTA亲和层析柱、IPTG、0.45μm滤头、HEPES、Amplex Red、HRP、H3K4me2多肽、96孔黑孔板、SDS、无水乙醇、溴酚兰、过硫酸铵、TEMED、Tris、Tricine、蛋白分子量Marker、考马斯亮蓝、冰醋酸。
二、实验方法
利用基因克隆的方法将LSD1活性区域的基因序列连到pET-28b载体上后，取2μL载体溶液加入感受态BL21(DE)3菌株中，遇冷混匀，冰上放置30min，42℃热击90s，冰上放置5min后加入800μL LB培养基37℃200rpm/min复苏1-2h。于LK固体培养基上涂布，37℃培养箱内过夜培养，挑取单菌落扩大培养，即为已克隆进质粒的BL21(DE)3-PET-28b-LSD1菌株，于150mL LK液体培养基内37℃200rpm扩大培养BL21(DE)3-PET-28b-LSD1菌株至菌液OD值0.6-0.8时，用0.25mM IPTG20℃下诱导表达12-14h，收集菌体，超声破碎后冷冻离心收集上清液利用亲和层析、离子交换柱采用不同浓度的NPI溶液流经镍柱纯化LSD1蛋白，对纯化后得到的蛋白溶液进行SDS-PAGE电泳后对凝胶进行考马斯亮蓝染色鉴定LSD1条带。酶活性检测采用监测中间产物的方法，将化合物、5nM LSD1重组蛋白、50nM FAD和待测化合物室温孵育10min，加入25mM底物H3K4me2在37℃反应30min，之后，加入过氧化物酶(5.5U/mL)和20nMAmplex Red常温反应10min后，在激发波长530nm和发射光590nm处检测荧光值，根据荧光值计算化合物的抑制率，根据不同浓度的抑制率计算各化合物对LSD1蛋白抑制作用的IC50值。同时设空白和阳性对照，阳性药为gsk2879552。
三、实验结果
阳性药gsk2879552以及4种倍半萜化合物selina-4(14),7(11)-dien-8-one、atractylenolide V、8β-methoxyatractylenolide、8β-ethoxyasterolid对LSD1蛋白抑制作用的IC50值分别为0.1、77.54、32.62、27.07、16.44μM，selina-4(14),7(11)-dien-8-one对LSD1蛋白的抑制作用较弱，atractylenolide V、8β-methoxyatractylenolide、8β-ethoxyasterolid对LSD1蛋白的抑制作用较强。
图2为不同浓度倍半萜对LSD1蛋白的抑制率曲线。
上述实验结果表明，atractylenolide V、8β-methoxyatractylenolide、8β-ethoxyasterolid为有效的LDS1抑制剂。本领域技术人员知道，组蛋白去甲基化酶在多种肿瘤中扮演着致癌蛋白的角色，而LSD1作为第1个被确认的酶在包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤等多种肿瘤中高表达并对其生长、转移和侵袭起着重要作用，因此LSD1是一个比较理想的抗肿瘤药物作用靶点。LSD1抑制剂atractylenolide V、8β-methoxyatractylenolide、8β-ethoxyasterolid具有开发成抑制肿瘤生长、转移和侵袭药物的前景。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。
Claims (8)
1.一种如下化学结构的倍半萜类化合物：
2.权利要求1所述的化合物用于制备LSD1抑制剂药物的医药用途。
3.权利要求1所述的化合物用于制备抑制肿瘤生长的药物的医药用途。
4.根据权利要求3所述的医药用途，所述肿瘤包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤。
5.权利要求1所述的化合物用于制备抑制肿瘤转移的药物的医药用途。
6.根据权利要求5所述的医药用途，所述肿瘤包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤。
7.权利要求1所述的化合物用于制备抑制肿瘤侵袭的药物的医药用途。
8.根据权利要求7所述的医药用途，所述肿瘤包括前列腺癌、乳腺癌、神经母细胞瘤、胃癌、结肠癌、膀胱癌、食管癌、急性粒细胞白血病和成视网膜细胞瘤。
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