CN114874108B - 一种百里醌衍生物及其在制备ampk激活剂和治疗乳腺癌的药物中的用途 - Google Patents
一种百里醌衍生物及其在制备ampk激活剂和治疗乳腺癌的药物中的用途 Download PDFInfo
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Abstract
本发明属于生物医药技术领域,具体涉及一种百里醌衍生物及其在制备AMPK激活剂和治疗乳腺癌的药物中的用途。本发明提供的百里醌衍生物如式Ⅰ所示。本发明还提供了式Ⅰ化合物的合成方法。本发明提供的化合物(例如TQFL12)能够显著抑制乳腺癌细胞的生长、迁移和侵袭,且对于三阴性乳腺癌(TNBC)细胞具有特异性的细胞毒性。且TQFL12对乳腺癌细胞的抑制作用显著强于百里醌(TQ)。因此,TQFL12具有作为治疗乳腺癌的药物的潜力。此外,TQFL12在蛋白水平通过稳定AMPKα而激活AMPK/ACC信号通路表达。因此,TQFL12也能够作为AMPK激活剂。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种百里醌衍生物及其在制备AMPK激活剂和治疗乳腺癌的药物中的用途。
背景技术
恶性肿瘤是肿瘤患者的主要死因,对肿瘤转移机制的研究也是近年来研究的热点。乳腺癌是严重威胁妇女身心健康的恶性肿瘤。三阴性乳腺癌(TNBC)和转移性乳腺癌(mBC)是一种高侵袭性、高度异质性的乳腺癌亚型,预后差,是女性癌症死亡的主要原因。三阴性乳腺癌即雌激素受体(ER)、孕激素受体(PR)和原癌基因Her-2均为阴性的乳腺癌。近年来尽管死亡率有所降低,但晚期TNBC的5年生存率仍然很低。科学家们正试图应对这一挑战。许多研究和实验正在为这些乳腺癌患者研究治疗方案。在各种肿瘤临床治疗方法中,包括小分子化合物在内的靶向治疗是目前最有效的策略。
从天然产物中提取的生物活性剂引起了研究人员和临床医生的极大关注,并将其作为中药用于抗癌、抗炎、神经保护等方面。青蒿素就是其中最成功的天然药物之一,它被科学家屠呦呦视为中药的礼物。然而,这类药物并没有被完全接受,主要是由于其作用有限,分子机制不明确和费用昂贵。
此外,恶性肿瘤对传统化疗药物容易产生耐药性和副作用,因此寻找低毒、高效、天然的新型抗乳腺癌药物已成为亟待解决的问题之一。百里醌(thymoloquinone,TQ)是从黑籽油中分离出来的主要活性成分,已被报道用于多种疾病的治疗,具有潜在的抗癌作用。TQ还具有抑制肿瘤转移的作用,如可抑制前列腺癌、乳腺癌、膀胱癌、肺癌和其他恶性肿瘤的转移。因此,TQ可能具有临床治疗的潜力。
但是TQ的有效药物浓度在某些乳腺癌细胞中仍然较高,其IC50高于165μM。这限制了其在相关药物中的应用。
发明内容
针对现有技术中存在的问题,本发明提供一种百里醌衍生物及其在制备AMPK激活剂和治疗乳腺癌的药物中的用途,其目的在于设计合成并筛选出更有效、低毒的TQ抗癌衍生物。从而为临床治疗乳腺癌等癌症提供更多的临床用药选择。
式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其晶型:
其中,n=0-5;
R独立选自取代或未取代的C1~C10烷基、取代或未取代的C6~C20芳基、取代或未取代的C1~C10烷氧基、取代或未取代的C1~C10酯基、氰基、羟基、羧基、卤素或硝基;其中,所述取代基是C1~C10烷基、C6~C20芳基、C1~C10烷氧基、C1~C10酯基、氰基、羟基、羧基、卤素或硝基。
优选的,式Ⅰ所述化合物为:
本发明还提供上述化合物的制备方法,包括如下步骤:
(a)化合物TQ经氨基化反应,得到化合物NTQ;
(b)化合物NTQ与化合物反应,即得式Ⅰ化合物。
优选的,步骤(a)中,将化合物TQ与NaN3进行反应,优选的所述化合物TQ与NaN3的用量摩尔比为1:1.2-1.5;和/或,所述反应以乙醇或四氢呋喃作为溶剂;和/或,所述反应在乙酸作用下进行,优选的所述化合物TQ与乙酸的用量比为1mmol:6-10ml,优选为1mmol:10ml;和/或,所述反应的温度为75~85℃,优选为80℃;和/或,所述反应的时间为6-8h,优选为6h。
优选的,步骤(b)中,所述化合物NTQ与化合物的摩尔比为1:1;和/或,所述反应以乙醇或四氢呋喃作为溶剂;和/或,所述反应在HCl作用下进行,优选的,所述化合物NTQ与浓度36-38%的HCl的用量比例为1mmol:0.5ml;和/或,所述反应的温度为75~85℃,优选为80℃;和/或,所述反应的时间为8-12h,优选为8h。
本发明还提供上述化合物、或其立体异构体、或其药学上可接受的盐、或其晶型在制备用于抑制乳腺癌的生长和/或侵袭和/或迁移的药物中的用途。
优选的,所述乳腺癌为三阴性乳腺癌,优选的,所述三阴性乳腺癌为雌激素受体、孕激素受体和原癌基因Her-2均为阴性的乳腺癌。
本发明还提供一种用于抑制乳腺癌的生长和/或侵袭和/或迁移的药物,它是以权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其晶型为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成。
本发明还提供上述化合物、或其立体异构体、或其药学上可接受的盐、或其晶型在制备AMPK激活剂中的用途。
优选的,所述AMPK激活剂用于治疗高血压、高血脂、高血糖、雄性激素过高、痤疮、多毛症、前列腺增生、抑郁症、乳腺癌、口腔癌、口咽癌、鼻咽癌、呼吸系统癌、泌尿生殖系统癌、胃肠癌、中枢神经系统或周围神经系统组织癌、内分泌或神经内分泌癌或造血系统癌、胶质瘤、肉瘤、肿瘤、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、肾癌、胆道癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni肿瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺肿瘤、成骨肉瘤、I型多发性神经内分泌和II型肿瘤、肺癌、头颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌或皮肤癌中的一种或多种。
本发明还提供一种AMPK激活剂,它是以权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其晶型为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca-Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1-C4烷基”是指包含1-4个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。例如,C1-C6烷基是指具有1至6个成员原子,例如1至4个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分,所述其他基团为例如C1-C6烷氧基。
“环烷基”是指具有3至14个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系,当连接点位于非芳族碳原子时,适用术语“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“环烷基”包括环烯基基团,诸如环己烯基。环烷基基团的实例包括例如,金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。
“烯基”是指具有2至10个碳原子和在一些实施方案中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C=C<)的直链或支链烃基基团。例如,(Ca-Cb)烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
“卤素”为氟、氯、溴或碘。
“立体异构体”包括对映异构体和非对映异构体。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常
在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明设计合成了一类新的百里醌衍生物。实验表明,该衍生物相比于百里醌,对乳腺癌细胞的生长、侵袭和迁移具有更好的抑制作用。该抑制作用产生的机理是由于其激活了AMPK/ACC通路。本发明提供的百里醌衍生物为治疗乳腺癌等疾病提供了一种新的临床用药选择。
本领域公知的,AMPK激活剂可以治疗高血压、高血脂、高血糖、雄性激素过高、痤疮、多毛症、前列腺增生、抑郁症、乳腺癌、口腔癌、口咽癌、鼻咽癌、呼吸系统癌、泌尿生殖系统癌、胃肠癌、中枢神经系统或周围神经系统组织癌、内分泌或神经内分泌癌或造血系统癌、胶质瘤、肉瘤、肿瘤、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、肾癌、胆道癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni肿瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺肿瘤、成骨肉瘤、I型多发性神经内分泌和II型肿瘤、肺癌、头颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌以及皮肤癌。
因此,本发明药物作为AMPK激活剂,还可以治疗高血压、高血脂、高血糖、雄性激素过高、痤疮、多毛症、前列腺增生、抑郁症、乳腺癌、口腔癌、口咽癌、鼻咽癌、呼吸系统癌、泌尿生殖系统癌、胃肠癌、中枢神经系统或周围神经系统组织癌、内分泌或神经内分泌癌或造血系统癌、胶质瘤、肉瘤、肿瘤、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、肾癌、胆道癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni肿瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺肿瘤、成骨肉瘤、I型多发性神经内分泌和II型肿瘤、肺癌、头颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌以及皮肤癌。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为TQFL12和TQ对不同的三阴性乳腺癌细胞系活力的生物学影响。A和B:CCK8测定显示了TQFL12和TQ作用16h(A)和24h(B)对4T1细胞系中的影响;C和D:TQFL12和TQ作用16h(C)和48h(D)对MDA-MB-231细胞系的影响;E&F:TQFL12和TQ作用16h(E)和48h(F)对BT549细胞系的影响;G&H:TQFL12和TQ对正常乳腺上皮细胞系MCF-10A在24h(G)和48h(H)的作用。结果表示为平均值±果表(n=3,*p<0.05,0.05<**p<0.001,***p<0.001)。
图2为TQFL12对乳腺癌细胞生长,迁移,侵袭,细胞周期和凋亡中的作用。A~C:在指定的TQFL12浓度下,TQFL12抑制乳腺癌细胞的生长(A),迁移(B)和侵袭(C);D:在指定的TQFL12浓度下对4T1细胞周期的影响;E:TQFL12在指定的浓度下对4T1细胞凋亡的影响;F.在指定的TQFL12浓度下对MDA-MB-231(MDA231)细胞凋亡的影响。
图3为在动物模型中,TQFL12对乳腺癌生长的抑制作用。A:TQ治疗组小鼠的存活曲线;B:TQ和TQFL12对小鼠的体重的影响;C:TQ和TQFL12通过剂量依赖性的方式抑制肿瘤的体积;D和E:TQ(D)和TQFL12(E)通过剂量依赖性方式以抑制肿瘤的大小;F:TQ和TQFL12通过剂量依赖性的方式抑制肿瘤的重量。
图4为TQFL12治疗抑制乳腺癌向肺转移的效果。A:TQFL12治疗组的肺转移菌落大小小于TQ治疗组;B:TQFL12治疗组的肺转移结节数少于TQ治疗组;C:未经TQFL12治疗的肺部转移性肿瘤的代表性图像;D:用TQFL12治疗的肺转移性肿瘤的代表性图像;E:未经(左图)和经(右图)TQFL12治疗的原位肿瘤代表图像。
图5为TQFL12在乳腺癌细胞中影响AMPK细信号传导。A:浓度依赖性的AMPK性的总蛋白和磷酸化蛋白水平;B:时间依赖性的AMPKα总蛋白和磷酸化蛋白水平;C.环己酰亚胺(CHX)和TQFL12的治疗。D:AMPK1的mRNA的半定量RT-PCR结果。
图6为化合物TQFL12和AMPKα蛋白的分子对接结果。A:TQFL12与AMPK1的结合方式;B:TQFL12和AMPK1相互作用的二维模式;C:TQFL12结合在AMPK1上的疏水表面。
具体实施方式
以下实施例和实验例所用的试剂和细胞:
NaN3(DDN)来自西雅试剂(中国山东)。4-氯苯甲醛来自能源化工(中国上海)。盐酸(HCl,分析级)来自株洲石英玻璃有限公司(中国株洲),无水乙醇(EtOH)来自国药集团化学试剂有限公司(中国上海)。
TQ和基质胶是从美国Sigma公司购买。CCK8试剂购自上海同仁化学科技有限公司。胎牛血清(FBS)购自德国PAN-Biotech生物科技公司。DMEM和RPMI 1640培养基购自美国Gibco。MCF-10A细胞专用培养基购自上海赛哲生物科技有限公司。抗生素、胰蛋白酶和4%多聚甲醛从上海碧云天生物科技有限公司购买。细胞凋亡及周期试剂盒购自美国BD公司。一抗p-AMPKα(Thr172,2535)、AMPKα(2532)、p-ACC(S79,530298)、兔源二抗(7074)、鼠源二抗(7076)均购自CST公司,内参Actin抗体(A1978)购自Sigma。Schrodinger分子对接软件购自美国Schrodinger公司。环己酰亚胺购自美国Sigma公司。BALB/c小鼠购自北京腾信生物科技有限公司。
所有乳腺癌细胞系(BT549,MDA-MB-231,4T1)和正常乳腺上皮细胞系(MCF-10A)均来自美国ATCC细胞库,并于10% FBS的培养基中,在37℃、5% CO2培养箱中培养。
实施例1TQFL12的合成
本实施例通过如下方式合成TQFL12:
包括如下步骤:
(a)合成3-氨基-5-异丙基-2-甲基环己烷-2,5-二烯-1,4-二酮(NTQ):将TQ(1.640g,10mmol)溶液溶解于无水NaN3和无水EtOH(80mL)的混合物中,然后添加乙酸(30mL)。在80℃加热搅拌6h后,将反应混合物冷却至室温(RT),薄层色谱显示TQ已完全反应。在硅胶上电泳分离反应混合物以获得纯产物(NTQ)。NTQ显示红色固体,收率1.16g(65%);
1H NMR(500MHz,DMSO-d6):δH 1.37(6H,d),2.31(3H,s),3.23(1H,m),6.53(1H,d),6.73(1H,s),7.34(1H,d).13C NMR(125MHz,DMSO-d6):δC 10.5,22.9,29.2,103.0,108.9,110.4,110.9,117.8,128.5,133.6,140.0,140.1,148.2,151.0,153.0,162.3。
(b)合成(E)-3-((4-氯亚苄基)氨基)-5-异丙基-2-甲基环己烷-2,5-二烯-1,4-二酮(TQFL12):化合物NTQ(0.179g,1mmol)和4-氯苯甲醛(0.144g,1mmol)在乙醇(20ml)中与浓盐酸(0.5mL)混合,80℃搅拌8h,将所得混合物过滤以获得滤液。滤液在减压下浓缩得到粗产物,并从乙醇中再结晶得到纯化合物TQFL12。TQFL12呈淡黄色固体,产率255mg(85.1%);
化合物TQFL12:1H NMR(500MHz,DMSO-d6):δH 1.33(6H,d),2.33(3H,s),3.24(1H,m),6.77(1H,d),7.62(2H,m),8.14(2H,m),9.22(1H,s)13C NMR(125MHz,DMSO-d6):δC 10.6,22.9,29.3,111.3,112.1,126.3,128.7,129.1,136.5,142.1,152.8,161.0。(C17H16ClNO2+H)+302.0948的HRESIMS计算结果为302.0957。
实验例1 TQFL12对乳腺癌细胞的作用
1、实验方法
(1)CCK8分析
96孔板培养细胞,每孔3000-5000个细胞,用不同浓度的TQ或TQFL12处理16h、24h、48h,每孔加入10μL CCK8试剂,37℃,孵育1h,用酶标仪检测每孔450nm的吸光度。每个实验分别重复三次。
(2)细胞生长、迁移和侵袭试验
将含有100μl(1001×104个细胞/ml)的细胞悬浮液接种于16孔板上,检测细胞生长。细胞迁移和侵袭指数分析采用CMI板,下腔孔加入含10%血清的培养基,上腔加入细胞悬液(1×104细胞/ml)。细胞侵袭试验:在细胞侵袭试验前,将1:40稀释于1×PBS的基质凝胶接种于CMI平板上。细胞生长8h后,加入2.5μM或5μM TQFL12或DMSO。用实时细胞分析仪(xCELLigence RTCADP,Roche,Germany)检测细胞迁移和侵袭过程,直至结束(详见《精编医学分子生物学实验指导》(中国医药科技出版社,2012年,主编:傅俊江)。每个实验分别重复三次。
(3)细胞凋亡和细胞周期检测
将4T1或MDA-MB-231细胞(1.5×105个/孔)接种于6孔板中,用不同浓度(0、2.5、5.0μM)TQFL12处理24小时,用Annexin-V FITC和PI染色,流式细胞仪检测凋亡细胞。细胞周期分析:细胞在300μl PI溶液中暗染,流式细胞仪分析细胞周期的各个阶段。
2、实验结果
(1)TQFL12和TQ对乳腺癌细胞的细胞毒性
为了确定TQFL12是否比TQ对乳腺癌细胞有更特异的细胞毒作用,用TQFL12和TQ对TNBC细胞系进行细胞毒性实验进行分析。采用不同浓度的TQFL12和TQ对人的正常乳腺细胞(MCF10A)、人乳腺癌细胞系(MDA-MB-231和BT549)和小鼠乳腺癌细胞系(4T1)进行不同时间的处理,并用CCK8法测定不同时期的细胞存活率,结果如图1所示。此外,TQFL12和TQ对各细胞系的IC50如表1和表2所示。
表1 TQFL12和TQ对4T1细胞系的IC50值
表2 TQFL12和TQ对人乳腺癌细胞系或正常乳腺细胞的IC50值
结果表明,TQFL12对这些细胞系的毒性作用是呈时间依赖性的。此外TQFL12对不同TNBC细胞的细胞毒性比TQ敏感。
TQFL12对TNBC细胞的IC50显著低于TQ对TNBC细胞的IC50。说明TQFL12对乳腺癌细胞具有更强的毒性。特别的,TQ12对TNBC细胞4T1的IC50低至20.24μM有,说明TQFL12对TNBC细胞的毒性作用比TQ敏感。
TQFL12对正常乳腺上皮细胞系(MCF10A)的IC50测量值明显高于所有TNBC细胞系(<100μM),说明TQFL12对MCF10A的作用没有突出的效果。
由此可见,TQFL12对肿瘤细胞有毒性而正常细胞无或者低毒性。证明TQFL12的毒性作用对癌症细胞具有特异性。
(2)TQFL12抑制乳腺癌细胞生长、迁移和侵袭,促进细胞凋亡
为了确定TQFL12的特异性作用,利用实时细胞分析仪系统评价TQFL12对癌细胞生长、迁移和侵袭的影响。图2为不同浓度(0,2.5,5.0μM)的TQFL12对4T1细胞的影响。细胞指数结果显示,TQFL12在2.5μM和5.0μM时对癌细胞生长(图2A)、迁移(图2B)和侵袭(图2C)有明显的抑制作用。
鉴于TQFL12治疗不仅能抑制癌细胞的迁移和侵袭,而且能促进细胞死亡,通过流式细胞术检测TQFL12对4T1和MDA-MB-231乳腺癌细胞系的促凋亡作用。结果表明,TQFL12对细胞周期有轻微影响(图2D),但对4T1细胞的细胞凋亡有显著影响(图2E);对MDA-MB-231细胞的细胞周期无影响(数据未显示),对细胞凋亡影响较小(图2F)。
这些结果表明TQFL12能显著抑制乳腺癌细胞的迁移和侵袭,但是对细胞周期影响较小。
实验例2 TQFL12在体内对乳腺癌细胞源性异种移植瘤的作用
1、实验方法
小鼠的动物实验符合机构动物伦理指南,并遵循大学委员会批准的方案。
建立乳腺癌动物模型,将小鼠三阴性乳腺癌(4T1)细胞注射到雌性BALB/c小鼠的乳腺脂肪垫中,每5天测量一次肿瘤大小。注射细胞后第4天,将小鼠随机分为7组,每组6只,分别给予0、3.75kg/mg、7.5mg/kg、15mg/kg的TQFL12和0、3.75kg/mg、7.5mg/kg、15mg/kg的TQ。通过测量肿瘤的大小连续监测肿瘤。在27天治疗结束时,处死小鼠,解剖肿瘤组织,测量肿瘤组织的重量。(详见《精编医学分子生物学实验指导》(中国医药科技出版社,2012年,主编:傅俊江)
2、实验结果
图3A显示了TQ组小鼠的周期,高浓度TQ(15mg/kg)毒性更大,实验进行一半时间后,小鼠全部死亡,而高浓度TQFL12实验全部小鼠无死亡。同时,图3B中数据显示TQFL12处理对小鼠的体重没有影响,而TQ在7.5mg/kg时使小鼠的体重降低。可见TQ比TQFL12的毒性作用更显著。
图3C-E展示了TQ和TQFL12通过剂量依赖性的方式以抑制肿瘤的体积,图3F展示了TQ和TQFL12通过剂量依赖性方式抑制肿瘤的重量。从图中可以看出,TQFL12对肿瘤的大小和重量的抑制效果显著优于TQ,说明TQFL12对肿瘤的抑制效果更好。
实验例3 TQFL12在体内对乳腺癌细胞侵袭和迁移的抑制作用
1、实验方法
小鼠的动物实验符合机构动物伦理指南,并遵循大学委员会批准的方案。
建立乳腺癌动物模型,将小鼠三阴性乳腺癌(4T1)细胞注射到雌性BALB/c小鼠的乳腺脂肪垫中,每5天测量一次肿瘤大小。注射细胞后第4天,将小鼠随机分为7组,每组6只,分别给予0、3.75kg/mg、7.5mg/kg、15mg/kg的TQFL12和0、3.75kg/mg、7.5mg/kg、15mg/kg的TQ。通过测量肿瘤的大小连续监测肿瘤。在27天治疗结束时,处死小鼠,解剖肿瘤组织。为了评估TQFL12和TQ对肿瘤细胞迁移/侵袭的影响,在治疗结束时解剖动物的肺,并计算肺部转移的肿瘤数。(详见《精编医学分子生物学实验指导》(中国医药科技出版社,2012年,主编:傅俊江)
HE染色:肿瘤组织在4%多聚甲醛中固定24小时,包埋在石蜡中,每5μm切片一次。在二甲苯中脱蜡,不同浓度酒精脱水,并用苏木精和伊红染色。
2、实验结果
本实验例通过肺部转移形成的肿瘤菌落数来估算TQFL12在体内对乳腺癌细胞侵袭和迁移的抑制作用。根据图4A可见,非治疗组的肺中存在大量肿瘤菌落,而TQFL12治疗组中仅发现少量菌落。此外,图4B显示,当用TQ治疗小鼠时,代表癌细胞迁移和侵袭的每只小鼠的平均菌落数以剂量依赖性方式减少。同时,与TQFL12治疗组相比,相同浓度的TQ治疗组肺内菌落数量多、体积大(图4C&D)。此外,与对照组相比,TQFL12治疗的原位肿瘤图像显示出更多的气泡(图4E,从右到左)。这些体内数据清楚地表明TQFL12能够更好地抑制乳腺癌的生长、迁移和侵袭。
实验例4 TQFL12影响乳腺癌细胞AMPK信号转导和自我稳定
1、实验方法
(1)蛋白质免疫印迹和半定量PCR:
将4T1和BT549细胞接种于6孔板中培养24h,然后用不同浓度(0、2.5、5.0μM)TQFL12处理,加入裂解缓冲液使细胞裂解。上样40μg蛋白进行8%、10%和12%的SDS-PAGE分离,转移到硝酸纤维素膜上。分别孵育一抗及二抗。用LI-COR Odesy成像扫描仪检测每一条带的强度。每个实验分别重复三次。
将BT549细胞接种于6孔板中培养24h,加入不同浓度(0、2.5、5μM)TQFL12处理,提取RNA并反转录为cDNA,设计PRKAA1和GAPDH引物,进行半定量PCR。每个实验分别重复三次。
(2)环己酰亚胺和TQFL12处理方法的测定:
4T1或BT549细胞加入TQFL12(5μM)进行处理,且设置不加药组进行对照。并在添加0.1mg/ml放线菌酮(CHX)之前培养24小时。收集细胞,提取蛋白进行Western blot。用密度计半定量分析条带强度,并用成像扫描仪进行分析。
2、实验结果
为研究受TQFL12影响的潜在信号通路,在不同的乳腺癌细胞系中作用TQFL12并进行western blotting,结果如图5所示。
与TQ相似,TQFL12对4T1细胞(图5A,左图)和BT-549(图5B,右)的AMPKα总蛋白水平和磷酸化蛋白水平都有剂量依赖性的增加。相应地,AMPKα下游p-ACC(磷酸化乙酰辅酶A羧化酶)也相应的增加(图5A)。
进行不同时间的TQFL12处理,发现与0小时(不进行TQFL12处理)相比,AMPKα比总蛋白水平和磷酸化AMPKα从1小时开始逐渐增加,4小时达到最高水平(图5B)。这些结果表明TQFL12可能直接影响AMPK蛋白的稳定性。
然后,进行环己酰亚胺(CHX)和TQFL12共同处理,以检测TQFL12是否稳定AMPKα,结果如图5C所示,TQFL12处理显著增加AMPKα蛋白水平(图5C,左,western blots;右,定量曲线)。AMPKα(PRKAA1)的mRNA水平没有变化(图5D),表明TQFL12蛋白水平的增加不是由于其mRNA转录的增加。
本实验例证实TQFL12是通过直接稳定AMPK来影响AMPK信号通路。
实验例5 TQFL12与AMPKα疏水表面相互作用
本实验例为了确定TQFL12是否与AMPKα相互作用,进行了分子对接分析,发现TQFL12和AMPK1的分子对接分数为-5.08kcal/mol。TQFL12可以与AMPKα的侧链羟基残基Val24形成一个距离为的强氢键(图6A)。此外,TQFL12的苯环可与残基Leu22形成显著的疏水相互作用(图6B)。进一步二维模式(2D)显示TQFL12和AMPKα之间的相互作用在AMPKα上的疏水表面(图6C)。
综上所述,本发明提供的化合物TQFL12能够显著抑制乳腺癌细胞的生长、迁移和侵袭,且对于三阴性乳腺癌(TNBC)细胞具有特异性的细胞毒性。且TQFL12对乳腺癌细胞的抑制作用显著强于TQ。因此,TQFL12具有作为治疗乳腺癌的药物的潜力。此外,TQFL12在蛋白水平通过稳定AMPKα而激活AMPK/ACC信号通路表达。因此,TQFL12也能够作为AMPK激活剂。
Claims (6)
1.式Ⅰ所示的化合物或其药学上可接受的盐,其特征在于:式Ⅰ所述化合物为:
。
2.权利要求1所述化合物的制备方法,其特征在于,包括如下步骤:
步骤a,合成3-氨基-5-异丙基-2-甲基环己烷-2,5-二烯-1,4-二酮NTQ:将10mmol的TQ溶解于无水NaN3和80mL无水EtOH的混合物中,然后添加30mL乙酸,在80°C加热搅拌6h后,将反应混合物冷却至室温RT,薄层色谱显示TQ已完全反应,在硅胶上电泳分离反应混合物以获得纯产物NTQ;
步骤b,合成(E)-3-((4-氯亚苄基)氨基)-5-异丙基-2-甲基环己烷-2,5-二烯-1,4-二酮TQFL12:1mmol的化合物NTQ和1mmol的4-氯苯甲醛在20 ml乙醇中与0.5mL浓盐酸混合,80°C搅拌8h,将所得混合物过滤以获得滤液,滤液在减压下浓缩得到粗产物,并从乙醇中再结晶得到纯化合物TQFL12。
3.权利要求1所述的化合物或其药学上可接受的盐在制备用于抑制乳腺癌的生长、侵袭和/或迁移的药物中的用途。
4.按照权利要求3所述的用途,其特征在于:所述乳腺癌为三阴性乳腺癌。
5.一种用于抑制乳腺癌的生长、侵袭和/或迁移的药物,其特征在于:它是以权利要求1所述的化合物、或其药学上可接受的盐为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成。
6.权利要求1所述的化合物或其药学上可接受的盐在制备AMPK激活剂中的用途。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102285934A (zh) * | 2009-01-08 | 2011-12-21 | 四川大学 | 螺环二烯酮衍生物及其制备方法和用途 |
WO2017159877A1 (en) * | 2016-03-18 | 2017-09-21 | Eisai R&D Management Co., Ltd. | Use of eribulin and 3-quinuclidinone derivatives in the treatment of cancer |
CN110123809A (zh) * | 2018-12-31 | 2019-08-16 | 中国科学院昆明植物研究所 | 5-甲基-二氢苯并呋喃-咪唑盐类化合物在制药中的应用 |
CN110396071A (zh) * | 2019-09-10 | 2019-11-01 | 陈昱西 | 一种百里醌衍生物及其制备方法和用途 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10875859B2 (en) * | 2018-04-13 | 2020-12-29 | Ankh Life Sciences Limited | Thymoquinone/harmaline and related reaction products |
-
2021
- 2021-02-05 CN CN202110159842.1A patent/CN114874108B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102285934A (zh) * | 2009-01-08 | 2011-12-21 | 四川大学 | 螺环二烯酮衍生物及其制备方法和用途 |
WO2017159877A1 (en) * | 2016-03-18 | 2017-09-21 | Eisai R&D Management Co., Ltd. | Use of eribulin and 3-quinuclidinone derivatives in the treatment of cancer |
CN110123809A (zh) * | 2018-12-31 | 2019-08-16 | 中国科学院昆明植物研究所 | 5-甲基-二氢苯并呋喃-咪唑盐类化合物在制药中的应用 |
CN110396071A (zh) * | 2019-09-10 | 2019-11-01 | 陈昱西 | 一种百里醌衍生物及其制备方法和用途 |
Non-Patent Citations (11)
Title |
---|
AMPK在肿瘤发生发展中的研究现状;董莹,等;中国生物化学与分子生物学报;第16卷(第10期);第167-171页 * |
AMPK的功能调控及其与肿瘤之间的关系;许梦川,等;生理科学进展(第01期);第63-66页 * |
Combating breast cancer using combination therapy with 3 phytochemicals: Piperine, sulforaphane, and thymoquinone;Aumeeruddy MZ,et al;《Cancer》;第125卷(第10期);第1600-1611页 * |
Mujahid Yusufi,et al.Synthesis, characterization and anti-tumor activity of novel thymoquinone analogs against pancreatic cancer.《Bioorganic & Medicinal Chemistry Letters》.2013,第23卷(第10期),第3101 页摘要,第3102 页图1;第3102 页左栏第1 段第6-11 行、图1;第3101 页左栏第2 段. * |
NADPH quinone oxidoreductase 1 mediates breast cancer cell resistance to thymoquinone-induced apoptosis;Kimberly M. Sutton,et al;《Biochemical and Biophysical Research Communications》;第426卷(第03期);第421 页摘要 * |
Synthesis, characterization and anti-tumor activity of novel thymoquinone analogs against pancreatic cancer;Mujahid Yusufi,et al;《Bioorganic & Medicinal Chemistry Letters》;第23卷(第10期);第3101 页摘要,第3102 页图1;第3102 页左栏第1 段第6-11 行、图1;第3101 页左栏第2 段 * |
Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancer;Nashwa Kabil,et al;《Breast Cancer Research and Treatment》;第171卷(第03期);第 593-605 页 * |
百里醌对体内外乳腺癌细胞生长和凋亡的作用;封伟亮,等;《医学研究杂志》;第42卷(第06期);第178-188页 * |
百里醌抑制乳腺癌细胞的迁移和侵袭的分子机制;沈诗怡,等;《2019 年中国肿瘤标志物学术 大会暨第十三届肿瘤标志物 青年科学家论坛论文集》(第01期);第122页 * |
百里醌抑制人胰腺癌BxPC-3细胞体外运动和侵袭的研究;慕刚刚,等;胃肠病学;第19卷(第11期);第650-655页 * |
百里醌调控M2型巨噬细胞表型极化的机制研究;徐元,等;中成药;第38卷(第02期);第13-18页 * |
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