CN108938612A - 氨基亚甲基环己烷1,3-二酮化合物的用途 - Google Patents

氨基亚甲基环己烷1,3-二酮化合物的用途 Download PDF

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CN108938612A
CN108938612A CN201710364909.9A CN201710364909A CN108938612A CN 108938612 A CN108938612 A CN 108938612A CN 201710364909 A CN201710364909 A CN 201710364909A CN 108938612 A CN108938612 A CN 108938612A
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disease
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罗成
乐立艳
万伟
张元元
蒋华良
陈凯先
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Suzhou Even Lead Biological Medicine Co Ltd
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Suzhou Even Lead Biological Medicine Co Ltd
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Priority to CN201710364909.9A priority Critical patent/CN108938612A/zh
Priority to PCT/CN2018/087452 priority patent/WO2018214814A1/zh
Priority to US16/614,521 priority patent/US11529321B2/en
Priority to CN201880033796.7A priority patent/CN111108083B/zh
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Abstract

本发明涉及氨基亚甲基环己烷1,3‑二酮化合物的用途，具体涉及下式(I)所示化合物或其药学上可接受的盐单独或者与其他药物联合在制备调节细胞自噬及治疗细胞自噬，特别是哺乳动物ATG8同源蛋白，相关的疾病的药物中的用途。

Description

氨基亚甲基环己烷1,3-二酮化合物的用途
技术领域
本发明涉及生物医药领域，具体涉及一类氨基亚甲基环己烷1,3-二酮化合物或其盐在制备治疗与细胞自噬，特别是哺乳动物ATG8同源蛋白，相关的疾病的药物的用途。
背景技术
细胞自噬是一种细胞内降解的通路，是将细胞内受损或失去功能的蛋白质以及细胞器运输至溶酶体，并进行消化和降解的过程。在生物进化中，细胞自噬是一种保守的过程，从酵母到植物细胞再到哺乳动物，都存在这样的过程。
现有的研究表明，细胞自噬在维持生理功能如饥饿时提供营养、清除细胞内容物、抗原呈递等方面起着重要的作用，并在癌症、心血管疾病、自身免疫性疾病、神经退行性疾病、高血压、骨组织细胞及骨类疾病、克罗恩氏病、急性肾损伤、脑缺血、视网膜疾病、支气管哮喘、Vici综合征以及各类感染性疾病等扮演着重要的角色。
细胞自噬在肿瘤的发生发展中起到双刃剑的作用：在肿瘤发生早期，自噬缺陷会增加基因组的不稳定性，促进癌变过程；肿瘤快速生长和转移阶段，自噬可以抵抗应激条件抑制失巢凋亡，维持肿瘤细胞生存。虽然自噬与肿瘤之间的关系在肿瘤发生发展的不同阶段不同，针对进展晚期以及化疗耐药的癌症，细胞自噬调节剂的开发将有重大的价值。
目前共有30余项关于调节自噬的药物临床试验，例如单独使用羟氯喹、氯喹或与其他抗肿瘤药物联用评价细胞自噬的抑制对难治性、复发性为主的实体瘤的治疗效果，相关结果可在clinicaltrial.gov官网查询。不过，由于缺乏明确的分子靶标，抗溶酶体抑制剂的副作用以及化学空间改造的方向不明会严重限制该类细胞自噬抑制剂的进一步发展。
目前靶向细胞自噬的小分子调节剂主要限于mTOR和溶酶体调节剂，针对细胞自噬相关蛋白，如ATG4和ULK1的小分子调控剂的研究依然处于开发的早期。而最重要的细胞自噬相关蛋白，ATG8及其哺乳动物同源家族蛋白LC3,GABARAP和GATE-16子家族的调控剂均未有任何报道。在人体内，LC3家族有LC3A,LC3B,LC3C,GABARAP家族有GABARAPL和GABARAPL1,GATE-16家族有GABARAPL2。在ATG8的哺乳动物同源蛋白中，LC3B无疑是研究得最为深入的一个，它被认为是细胞自噬的标志物。目前尚未有任何针对LC3B的调控剂的报道，开发LC3B的调控剂对于治疗相关疾病的来说十分迫切。
同时，将调控细胞自噬的化合物与已上市药物的组合物应用于各种癌症、心血管疾病、自身免疫性疾病、神经退行性疾病、高血压、骨组织细胞及骨类疾病、克罗恩氏病、急性肾损伤、脑缺血、视网膜疾病、支气管哮喘、Vici综合征以及各类感染性疾病将有广阔的前景。
发明内容
本发明通过设计FITC标记肽、表达LC3B的GST融合蛋白建立了基于荧光偏振的高通量筛选平台，对已知化合物库进行高通量筛选，发现了一类氨基亚甲基环己烷1,3-二酮化合物或其盐可以作为靶向哺乳动物ATG8同源蛋白(尤其是LC3B)的调控剂。此外，通过LC3-I/LC3-II蛋白的免疫印迹、免疫荧光染色和荧光显微镜拍照验证了上述化合物或其盐具有调控细胞自噬的能力，从而可以用于调节细胞自噬及治疗相关疾病。
本发明的第一方面提供了下式(I)所示化合物或其药学上可接受的盐单独或者与其他药物联合在制备调节细胞自噬及治疗与细胞自噬相关的疾病的药物中的用途：
其中：
R1和R2各自独立选自：氢，羟基，氨基，氰基，甲酰基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C(＝O)Ra，SO2Ra，取代或未取代的-(CH2)m-C5-10芳基或5-10元杂芳基，取代或未取代的-(CH2)m-C3-7环烷基或3-7元杂环基；所述Ra选自氢，羟基，C1-6烷基，C1-6卤代烷基，取代或未取代的C1-6羟基烷基，取代或未取代的氨基，取代或未取代苯基，取代或未取代的五至六元杂芳基；
R3、R4、R5和R6各自独立选自：氢，羟基，氨基，卤素，氰基，硝基，羧基，甲酰基，酰胺基，酯基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，取代或未取代的C6-10芳基，取代或未取代的5-10元杂芳基，C3-7环烷基，和3-7元杂环基；
所述卤素选自F，Cl，Br，I；优选自F，Cl，Br；
所述取代表示所述基团被一个或多个取代基取代，所述取代基选自：羟基，氨基(-NH2)，氰基，卤素，硝基，三氟甲基，羧基，酯基，甲酰基，C1-6烷基，C1-6卤代烷基，C1-6羟基烷基，C1-6烷氧基，3-10元杂环基，C6-10芳基，和5-10元杂芳基；
m选自0、1、2和3，优选为1或2。
本发明使用的术语具有其在本技术领域的一般含义，在有抵触的情况下，适用本申请中的定义。化学名称、通用名称和化学结构可以互换使用以描述相同的结构。无论术语是单独使用还是与其他术语组合使用，这些定义都适用。因此，“C1-6烷基”的定义适用于“C1-6烷基”以及“C1-6羟基烷基”、“C1-6卤代烷基”、“C1-6烷氧基”等的“C1-6烷基”部分。
“C1-6烷基”是指含有1至6个碳原子的直链或支链烷基，优选为1至4个碳原子的直链或支链烷基。支链是指一个或多个碳原子的烷基如甲基、乙基或丙基等与直链烷基连接。优选的C1-6烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基等。
“C1-6卤代烷基”是指如上定义的C1-6烷基中含有一个或多个卤素原子取代基。优选的C1-6卤代烷基包括但不限于三氟甲基。
“C1-6羟基烷基”是指如上定义的C1-6烷基中含有一个或多个羟基。优选的C1-6羟基烷基包括但不限于羟甲基和2-羟乙基。
“C1-6烷氧基”是指C1-6烷基-O-基团，通过氧与母体部分键接，其中C1-6烷基如上所述。优选的C1-6烷氧基包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基和正丁氧基。
“C6-10芳基”是指含有6至10个碳原子的芳族单环或多环系统。优选的C6-10芳基包括但不限于苯基和萘基。
“C3-7环烷基”是指环上含有3至7个碳原子，优选3至6个碳原子的非芳族饱和单环或多环基团。优选的单环C3-7环烷基包括但不限于环丙基、环戊基、环己基、环庚基等。
“5-10元杂芳基”是指含有5至10个环原子的芳族单环或多环基团，所述5-10元杂芳基包含选自N、O和S中的1至4个杂原子。优选的5-10元杂芳基含有5至6个环原子。5-10元杂芳基的氮原子可以任选地被氧化成相应的N-氧化物。优选的C5-10杂芳基包括但不限于吡啶基、吡嗪基、呋喃基、噻吩基、嘧啶基、吡啶酮、噁唑基、异噻唑基、噁唑基、噁二唑基、噻唑基、噻二唑基、吡唑基、呋咕基(furazanyl)、吡咯基、三唑基、1,2,4-噻二唑基、哒嗪基、喹喔啉基、酞嗪基、羟吲哚基、咪唑并[1,2-a]吡啶基、咪唑并[2,1-b]噻唑基、苯并呋咕基(benzofurazanyl)、吲哚基、氮杂吲哚基、苯并咪唑基、苯并噻吩基、喹啉基、咪唑基、噻吩并吡啶基、喹唑啉基、噻吩并嘧啶基、吡咯并吡啶基、咪唑并吡啶、异喹啉基、苯并吖嗪基、1,2,4-三嗪基、苯并噻唑基其氧化物等。术语“5-10元杂芳基”也指部分饱和的5-10元杂芳基，例如四氢异喹啉基，四氢喹啉基等。
“3-7元杂环基”是指含有3至7个环原子，优选3至6个环原子，优选5至6个环原子的非芳族单环或多环基团，其中，所述3-10元杂环基包含选自N、O和S中的1至4个杂原子。所述3-10元杂环基的氮或硫原子可以任选地氧化成相应的N-氧化物、S-氧化物或S-二氧化物。因此本发明中术语“氧化物”是指相应的N-氧化物、S-氧化物或S-二氧化物。“3-7元杂环基”还包括环上相同碳原子上的两个可用氢原子同时被单一的基团＝O取代(即形成羰基)，这样的＝O基团在本发明中可以称为“氧代”。优选的单环3-7元杂环烷基包括但不限于哌啶基、氧杂环丁烷基、吡咯基、哌嗪基、吗啉基、硫代吗啉基、噻唑烷基、1,4-二噁烷基、四氢呋喃基、四氢噻吩基、内酰胺基(如吡咯烷酮基)、具有3至7个环原子的内酯基及其氧化物。
“酯基”是指由具有1-20个碳原子的脂肪族或芳香族羧酸与具有1－20个碳原子的伯、仲或叔醇经酯化反应形成的酯中除去一个氢原子而获得的基团。优选的酯基包括但不限于甲酯基，乙酯基，异丙酯基，叔丁酯基，苯酯基。
“酰胺基”是指由具有1-20个碳原子的脂肪族或芳香族羧酸与具有1－20个碳原子的伯或仲胺经酰胺化反应组成的酰胺中除去一个氢原子而获得的基团。
在一个优选的实施方式中，所述C5-10芳基或5-10元杂芳基优选选自由下列环失去一个氢原子形成的基团：
所述C3-7环烷基或3-7元杂环基优选选自由下列环失去一个氢原子形成的基团：
在一个优选的实施方式中，所述通式(I)的化合物选自下述化合物：
在一个具体实施方式中，所述调节细胞自噬的药物是哺乳动物ATG8同源蛋白(尤其是LC3B)的调节剂。
在一个具体实施方式中，所述调节细胞自噬的药物是治疗与细胞自噬，特别是哺乳动物ATG8同源蛋白(尤其是LC3B)相关的疾病的药物。
本发明的第二方面，提供了一种调控哺乳动物ATG8同源蛋白(尤其是LC3B)活性的方法，其中，用上述化合物或其盐单独或者与其他药物联合调控LC3B及哺乳动物ATG8同源蛋白与体内其他蛋白的相互作用。所述方法可以在体内或体外进行。
本发明的第三方面，提供了调节细胞自噬的方法，所述方法包括单独或者与其他药物联合施用上述化合物或其盐的步骤。
本发明的第四方面，提供了治疗与细胞自噬，特别是哺乳动物ATG8同源蛋白(尤其是LC3B)，相关的疾病的方法，所述方法包括像需要该治疗的患者单独或者与其他药物联合施用上述化合物或其盐的步骤。
所述哺乳动物ATG8同源蛋白包括LC3，GABARAP和GATE-16子家族蛋白。在人体内，LC3家族有LC3A,LC3B和LC3C，GABARAP家族有GABARAPL和GABARAPL1，GATE-16家族有GABARAPL2。
优选地，所述与细胞自噬相关的疾病包括：肿瘤，例如肝癌、肺癌、胰腺癌、乳腺癌、宫颈癌、子宫内膜癌、大肠癌、胃癌、肺癌、鼻咽癌、卵巢癌、前列腺癌、白血病、淋巴瘤、骨髓瘤等；心血管疾病；自身免疫性疾病；神经退行性疾病；高血压；骨组织细胞及骨类疾病；克罗恩氏病；急性肾损伤；脑缺血；视网膜疾病；支气管哮喘；Vici综合征；以及感染性疾病，例如艾滋病等。
所述其他药物可以是已上市药物，非限制性地包括：依鲁替尼，伊马替尼，吉西他滨，厄洛替尼，培美曲塞二钠，AZD3759和来那度胺等。
附图说明
图1显示了LC3B在细胞自噬中的作用。
图2显示了化合物38对细胞自噬的影响。
图3显示了化合物38与部分已上市药物联用对部分肿瘤细胞增殖的影响。
具体实施方式
如无特殊说明，所用试剂均为商业购买。
实施例1 化合物或其盐靶向LC3B的分子水平实验
通过构建原核表达系统来表达纯化LC3B蛋白，利用荧光偏振实验建立了初步的筛选验证平台，对购买及合成的小化合物库进行活性测定。
重组蛋白GST-LC3B(终浓度180nM,SEQ ID NO:1)和N末端FITC标记肽(SEQ ID NO:2，终浓度18nM)置于FP缓冲液(50mM HEPES pH7.5，0.1mg/mL BSA，1mM DTT)中，向其中加入使用FP缓冲液连续梯度稀释的化合物，然后将上述混合物于25℃下在避光孵育。监测荧光偏振值(PerkinElmer Envision，发射光波长480nm；吸收光波长535nm)，并用GraphPadPrism 6.0程序计算IC50值。
测试结果如表1所示，其中化合物的IC50值表示方法：100μM<IC50≤1mM被认为对LC3B的活性较低(+)；化合物15μM<IC50≤100μM被认为是对LC3B的活性中等(++)；3μM<IC50≤15μM被认为对LC3B活性较高(+++)；IC50≤3μM被认为对LC3B具有高活性(++++)。
表2 化合物对LC3B调节的活性数据
实施例2 化合物或其盐对细胞自噬的调节作用
LC3-I/LC3-II蛋白的免疫印迹检测
将Hela细胞接种至6孔板中，培养过夜，加入一定浓度化合物处理12h，之后换无血清的培养基饥饿处理24小时。吸除培养基，用PBS洗一遍，加入SDS-PAGE用2×上样缓冲液裂解细胞。样品在99℃煮沸10分钟，经SDS-PAGE分离后，使用LC3B抗体(Novus)进行LC3-I/LC3-II检测，检测结果如图2A所示。
由图2A可以看出，LC3-II随化合物处理时间延长而出现累积。
免疫荧光染色和荧光显微镜拍照
将Hela细胞接种至6孔板中的玻璃盖玻片上，培养至细胞状态良好，加入一定浓度化合物处理12小时，之后换无血清的培养基饥饿处理24小时。细胞先预冷10分钟后用0.2％的Triton X-100打孔处理，室温放置10分钟。然后用含2.5％BSA的PBS封闭处理后放置4度抗LC3B一抗孵育过夜，后用荧光二抗识别一抗并用DAPI对细胞核进行染色，置于显微镜下拍照。检测结果如图2B所示。
由图2B可以看出，相对对照组，化合物38处理后细胞自噬体出现累积，且浓度越高，累积越多。
实施例3 化合物或其盐与部分上市药物联合使用对不同类型肿瘤细胞增殖的抑制作用
肿瘤细胞株：大B淋巴瘤细胞(DB、Toledo、Pfeiffer、SU-DHL6、WSU-DLCL2、OCI-Ly19、SU-DHL2、SU-DHL8)，套细胞淋巴瘤细胞株(REC-1、Z-138、Jeko-1、Maver-1)，胰腺癌细胞株(AsPC-1、BxPC-3、MIAPaCa-2、Panc-3.014、CaPan-1、Panc-1)，结肠癌细胞株HCT116，非小细胞肺癌细胞株(PC9、HCC827、NCI-H1975)和多发性骨髓瘤细胞株(H929、KMS26、RPMI-8226)。
联合使用的上市药物：依鲁替尼，伊马替尼，吉西他滨，厄洛替尼，培美曲塞二钠，AZD3759和来那度胺。
实验方法：采用含10％FBS的完全培养基，细胞计数后，以每孔～10000个/100μL接种于96孔板中，同时给予上市药物和化合物38处理，药物按1:3的浓度梯度稀释，化合物38的浓度点设置为100μM,50μM,30μM三组。通过Cell Titer-Glo法检测给药72小时后细胞增殖的变化。以细胞存活率为纵坐标，药物浓度为橫坐标做图。结果见图3。
细胞存活率(％)计算方法为：存活率(％)＝(给药孔OD-空白孔OD)/(对照孔OD-空白孔OD)×100。
检测结果如表2所示，其中：“++++“表示30μM联用效果很明显；“+++”表示50μM联用效果明显；“++”表示100μM联用效果明显；“+”表示100μM联用效果不明显。
表2 化合物38与已上市药物联用对各种肿瘤细胞增殖的影响
SEQUENCE LISTING
<110> 中国科学院上海药物研究所
<120> 氨基亚甲基环己烷1,3-二酮化合物的用途
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Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
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Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
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Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
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Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
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Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
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Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
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Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Glu Val Leu
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Phe Gln Gly Pro Leu Gly Ser Met Pro Ser Glu Lys Thr Phe Lys Gln
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Arg Arg Thr Phe Glu Gln Arg Val Glu Asp Val Arg Leu Ile Arg Glu
245 250 255
Gln His Pro Thr Lys Ile Pro Val Ile Ile Glu Arg Tyr Lys Gly Glu
260 265 270
Lys Gln Leu Pro Val Leu Asp Lys Thr Lys Phe Leu Val Pro Asp His
275 280 285
Val Asn Met Ser Glu Leu Ile Lys Ile Ile Arg Arg Arg Leu Gln Leu
290 295 300
Asn Ala Asn Gln Ala Phe Phe Leu Leu Val Asn Gly His Ser Met Val
305 310 315 320
Ser Val Ser Thr Pro Ile Ser Glu Val Tyr Glu Ser Glu Lys Asp Glu
325 330 335
Asp Gly Phe Leu Tyr Met Val Tyr Ala Ser Gln Glu Thr Phe Gly Met
340 345 350
Lys Leu Ser Val
355
<210> 2
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> N末端FITC标记肽
<400> 2
Gly Gly Asp Asp Asp Trp Thr His Leu Ser Ser Lys Glu Val Asp
1 5 10 15

Claims (10)

1.下式(I)所示化合物或其药学上可接受的盐单独或者与其他药物联合在制备调节细胞自噬及治疗细胞自噬相关疾病的药物中的用途：
其中：
R1和R2各自独立选自：氢，羟基，氨基，氰基，甲酰基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C(＝O)Ra，SO2Ra，取代或未取代的-(CH2)m-C6-10芳基或5-10元杂芳基，取代或未取代的-(CH2)m-C3-7环烷基或3-7元杂环基；所述Ra选自氢，羟基，C1-6烷基，C1-6卤代烷基，取代或未取代的C1-6羟基烷基，取代或未取代的氨基，取代或未取代的苯基，取代或未取代的五至六元杂芳基；
R3、R4、R5和R6各自独立选自：氢，羟基，氨基，卤素，氰基，硝基，羧基，甲酰基，酰胺基，酯基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，取代或未取代的C6-10芳基，取代或未取代的5-10元杂芳基，C3-7环烷基，和3-7元杂环基，
或者R3和R5和/或R4和R6连接形成C6-10芳基或5-10元杂芳基；
所述卤素选自F，Cl，Br，I；优选选自F，Cl，Br；
所述取代表示所述基团被一个或多个取代基取代，所述取代基选自：羟基，氨基，氰基，卤素，硝基，三氟甲基，羧基，酯基，甲酰基，C1-6烷基，C1-6卤代烷基、C1-6羟基烷基、C1-6烷氧基，3-10元杂环基，C6-10芳基和5-10元杂芳基；
m选自0、1、2和3，优选为1或2。
2.根据权利要求1所述的用途，其中，所述C6-10芳基或5-10元杂芳基选自由下列环失去一个氢原子形成的基团：
所述C3-7环烷基或3-7元杂环基选自由下列环失去一个氢原子形成的基团：
3.根据权利要求1或2所述的用途，其中，所述通式(I)的化合物选自下述化合物：
4.根据权利要求1-3中任一项所述的用途，其中，所述调节细胞自噬的药物是哺乳动物ATG8同源蛋白(尤其是LC3B)的调节剂。
5.根据权利要求1-4中任一项所述的用途，其中，所述调节细胞自噬的药物是治疗与细胞自噬，特别是哺乳动物ATG8同源蛋白(尤其是LC3B)相关的疾病的药物。
6.根据权利要求5所述的用途，其中，所述与细胞自噬，特别是哺乳动物ATG8同源蛋白(尤其是LC3B)相关的疾病包括：肿瘤，心血管疾病，自身免疫性疾病，神经退行性疾病，高血压，骨组织细胞及骨类疾病，克罗恩氏病，急性肾损伤，脑缺血，视网膜疾病，支气管哮喘，Vici综合征，以及感染性疾病。
7.根据权利要求6所述的用途，其中，所述肿瘤选自肝癌、肺癌、胰腺癌、乳腺癌、宫颈癌、子宫内膜癌、大肠癌、胃癌、肺癌、鼻咽癌、卵巢癌、前列腺癌、白血病、淋巴瘤、骨髓瘤。
8.根据权利要求1-7中任一项所述的用途，其中，所述其他药物是已上市药物，选自：依鲁替尼，伊马替尼，吉西他滨，厄洛替尼，培美曲塞二钠，AZD3759和来那度胺。
9.根据权利要求4-6中任一项所述的用途，其中，所述哺乳动物ATG8同源蛋白包括LC3，GABARAP和GATE-16子家族蛋白。
10.根据权利要求9所述的用途，其中，
LC3家族蛋白包括LC3A,LC3B和LC3C蛋白；
GABARAP家族蛋白包括GABARAPL和GABARAPL1蛋白；
GATE-16家族蛋白包括GABARAPL2蛋白。
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