CN101139335B - 7－羟基－3－[(4-羟基）－3－((e)-3，7-二甲基－辛基－2，6－二烯基）苯基]-4h-1-苯并吡喃－4－酮的用途 - Google Patents
7－羟基－3－[(4-羟基）－3－((e)-3，7-二甲基－辛基－2，6－二烯基）苯基]-4h-1-苯并吡喃－4－酮的用途 Download PDFInfo
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Abstract
本发明涉及“7-羟基-3-[(4-羟基)-3-((E)-3，7-二甲基-辛基-2，6-二烯基)苯基]-4H-1-苯并吡喃-4-酮的用途”，属医药领域。该化合物在低浓度条件下，不改变ERα66，ERα46和ERα36的表达，而高浓度下能同时抑制三者的表达；同时该化合物能杀死表达ERα66，ERα46和ERα36的乳腺癌细胞MCF7细胞；因此该化合物也可作为雌激素受体ERα36的调节剂，用于治疗因雌激素受体ERα36的异常表达而引起的疾病，如肿瘤，骨质疏松，哮喘，心脏疾病或老年痴呆等病症。
Description
技术领域
本发明属医药领域，涉及天然化合物在制备抗肿瘤药，骨质疏松，老年痴呆药物方面的应用。
背景技术
雌激素是一种由内分泌系统产生的类固醇类激素，它在生殖系统、骨组织、心血管、免疫系统及中枢神经系统中都发挥着重要的作用[J Cell Sci，2003；116(4)：585-586]。雌激素信号传递系统在调节细胞生长、分化和凋亡过程中都起到很大的作用。雌激素依赖型肿瘤，如乳腺癌、卵巢癌和子宫内膜癌等的发生和发展都与雌激素有着密切的关系[J Steroid Biochem.Mol.Biol.，2002，81(1)：1-24，J Mammary Gland Biol.Neoplasia，1998，3(1)：49-61，Curr.DrugTargets Immune Endocr.Metabol.Disord；2001，1(1)：1-12，Cancer Res.，1998，58(23)：5367-5373，J Psychiatry Neurosci，2002；27(1)：1-27]，因此对雌激素受体的研究具有指导抗雌激素和雌激素受体拮抗剂等药物的开发和应用和指导对雌激素依赖型肿瘤等疾病的治疗的重要意义[Nat.Rev.Drug Discov.，2004，3(11)：950-964]。
目前已知的雌激素受体分为α、β两种亚型。雌激素受体α在1958年被Toft和Gorski等人[Proc.Natl.Acad.Sci.USA，1966，55(6)：1574-1581]率先从老鼠子宫细胞中分离得到，1986年Green[Nature，1986，320(6058)：134-139]和Greene[Science，1986，231(4742)：1150-1154]等人克隆得到第一个分子量为66kDa的人雌激素受体ERα；1996年，Kuiper等[Proc.Natl.Acad.Sci.USA，1996，93(12)：5925-5930]从大鼠前列腺中克隆得到另一种雌激素受体ERβ。此后，Mosselman等人[FEBS Lett.1996，392(1)：49-53]从人睾丸组织中克隆得到不完整的人ERβ；Ogawa[Biochem.Biophys.Res.Commun.1998，243(1)：122-126]和Moore等人[Biochem.Biophys.Res.Commun.，1998，247(1)：75-78]相继克隆得到完整的人ERβ。雌激素受体ERα与ERβ亚型具有类似的序列组成[FEBS Lett.2003，546：17-24，Biochem.Soc.Trans.2003，31：56-59]；它们都由三个独立但又相互作用的功能区组成：位于N端的A/B区，中间的C区，以及C端的D/E/F区。N端的A/B区是一个不依赖于配体的转录活化区(AF-1)，负责与共活化因子的结合以及转录激活相关的靶基因(图1)。C区是DNA结合区，含有两个锌指结构，对于分子的二聚化以及和特定DNA序列的结合至关重要。C端的D/E/F区是一个配体结合区，由它介导配体的结合，受体的二聚化，核定位，以及配体依赖的转录活化功能(AF-2)。
根据传统理论，雌激素通过与细胞浆或核内的雌激素受体(ER)结合并通过调节基因转录而发挥生物功能。近十年来对雌激素信号通路又有了许多新的认识：雌激素信号转导途径包括细胞核途径(经典途径)和细胞膜途径(非经典途径)。因此雌激素的生物效应，并不完全依赖于配体-受体的细胞核激活途径，还可通过其他信号通路发挥作用。非经典雌激素信号通路在不同细胞产生的效应各异，例如：17β雌二醇(E2β)可通过膜信号通路及P38激酶和PI3K激酶调节心肌细胞调亡，从而对心血管系统具有保护作用[Curr.Treat.Options Cardiovasc.Med.2001，3(1)：67-79]；此外，细胞内几个重要的信号传导通路如G-蛋白信号通路、磷脂酶C，腺苷酸环化酶及MAPK等信号传导通路都和非经典的雌激素膜信号通路有相互作用[Trendsin Endocrinol.Metabol.，2002，13，349-354]。人们广泛认为血清中的高水平雌激素通过经典及非经典雌激素信号传导途径刺激腺管上皮细胞的持续增生，从而参与雌激素依赖型肿瘤，如乳腺肿瘤、子宫内膜癌及卵巢癌的发生和发展。然而非经典雌激素膜信号通路的作用目前尚不清楚。
Flouriot等[EMBO，2001，19：4688-4700]的研究发现除了全长的ER-α66外还有一个缺失了第一个外显子所编码的173个氨基酸的ER-α同源异构体。这个新发现的分子量为46kDa的ER-α同源异构体被称为ER-α46，而较早发现的分子量为66kDa的ER-α[Nature，1986，320(6058)：134-139；Science，1986，231(4742)：1150-1154]就被称为ER-α66。该异构体缺失了AF1功能区，但保持了其他功能区的完整性。进一步研究发现ER-α46能竞争性抑制ER-α66的AF1的功能，而对AF2的作用没有影响。
2005年另一个分子量为36kDa的全新的ER-α的同源异构体被发现并克隆了，并将其命名为ER-α36[Biochem.Biophy.Res.Commu.2005，336：1023-1027；Proc.Natl.Acad.Sci.USA，2006，103(24)：9063-9068]。该异构体从存在于ER-α66基因的第一个内含子中的启动子开始转录，经一小段外显子后，利用ER-α66的外显子2-6进行编码。因此，ER-α36缺失两个转录功能区AF1和AF2，但保留了DNA结合功能区和二聚化功能区。重要的是ER-α36激素配体结合区(ligand binding domain)缺失了8-12螺旋区(helix)，从而完全改变了其与激素配体结合的专一性和亲和力(图1)。因此，ER-α36具有和ER-α66及ER-β完全不同的激素配体结合能力，为筛选针对ER-α36的特异性配体提供了结构基础。
因ER-α36缺失AF1和AF2功能区，ER-α36本身缺失任何转录调节功能，但可以有效地抑制ER-α66介导的经典的雌激素核信号通路。ER-α36主要分布在细胞膜和细胞浆中，少量分布于细胞核中。ER-α36从而可通过非经典的雌激素膜信号传导通路并经过MAPK/ERK信号传递途径刺激细胞分裂[Proc.Natl.Acad.Sci.USA，2006，103(24)：9063-9068]。ER-α36在不同的雌激素依赖型肿瘤，如乳腺癌、卵巢癌和子宫内膜癌中皆有高表达。因此ER-α36介导的信号途径可能参与了多种雌激素依赖型肿瘤的形成和发展。
发明内容
本发明的目的是通过对天然有效成分的研究，提供新的可以调节ER-α和-β生物传导系统的化合物，可以用于抗肿瘤，心脏疾病，骨质疏松和老年痴呆的作用.
式(I)化合物或式(I)化合物的药学上可接受的盐或溶剂合物
在制备治疗因雌激素受体ER-α亚型(包括ER-α36，ER-α46以及ER-α66)和ER-β亚型引起的疾病的药物中的应用。
所述式(I)化合物或式(I)化合物的药学上可接受的盐或溶剂合物是作为雌激素受体ER-α和ER-β亚型的调节剂。
所述药物包括片剂，口嚼剂，胶囊剂，悬浮液剂，溶液剂。
所述疾病包括肿瘤，骨质疏松，哮喘，心脏疾病和老年痴呆。
所述肿瘤为乳腺癌，卵巢癌，子宫内膜癌，胃癌，结肠癌，前列腺癌，血癌或肺癌。
所述肿瘤为乳腺癌，前列腺癌.
所述肿瘤为乳腺癌.
式(I)化合物可从豆科植物补骨脂果实中提取分离得到(J.Sep.Sci.2007，30(6)，813-818；Bioorg.Med.Chem.2004，12(16)，4387-4392；J.Chromatogr.A 2005，1089；Chem.Pharm.Bull.2007，55，106-110.)。其药效未见报导。
实验表明：正常乳腺上皮细胞表达少量ER-α36，而在700例乳腺癌的检查中发现大约39.9％乳腺癌样品高表达ER-α36，且40％雌激素受体阴性的乳腺癌样品虽不表达ER-α66，但可表达ER-α36。ER-α36也表达在100％ER-，PR-and HER-2+乳腺癌样品.上述结果表明：ER-α36不仅参与ER阳性的乳腺癌的形成和发展，而且可能参与过去被认为是ER阴性的乳腺癌的形成和发展。进一步研究表明，表达ER-α36的乳腺肿瘤预后极差，并对抗雌激素药物，如他莫昔芬的治疗反应不强。
雌激素受体阴性的乳腺癌细胞系MDA-MB-231不表达ER-α66，但高表达ER-α36，而且雌激素可促进MDA-MB-231细胞快速增殖。因此ER-α36启动的促细胞生长信号转导可导致细胞增殖。同时表达ER-α66和ER-α36的ER-阳性MCF7细胞，对雌激素刺激可产生更强增殖反应，并对抗雌激素药物如他莫昔酚有抵抗作用。
此外，研究表明，心脏疾病，骨质疏松和老年痴呆等疾病同ER-α36的生物功能有着直接的关系.因此以ER-α36为靶点筛选药物将提供一种新的筛选抗肿瘤，心脏疾病，骨质疏松和老年痴呆药物的途径。
通过实验证明，式(I)化合物，在低浓度条件下，不改变ERα66，ERα46和ERα36的表达。然而高浓度的化合物(I)能同时抑制三者的表达；同时化合物(I)能杀死表达ERα66，ERα46和ERα36的乳腺癌细胞MCF7细胞。因此式(I)化合物可作为雌激素受体ERα36的调节剂，用于治疗因雌激素受体ERα36的异常表达而引起的疾病，如肿瘤，骨质疏松，哮喘，心脏疾病或老年痴呆等病症。
附图说明
图1雌激素受体的结构分区
图2ERα66，ERα46和ERα36在6个不同患者的乳腺癌组织中的表达。
1、正常乳腺组织2、浸润性导管癌组织，3、浸润性导管癌组织，4、浸润性导管癌组织，5、浸润性小叶癌，6、浸润性小叶癌，7、非浸润性导管癌
图3在乳腺癌细胞MDA-MB-231中，抗ERα36特异性抗体显色情况
αER-α36，阳性结果显示为绿色，DAPI，阳性结果显示为蓝色，联合显色者标注为“Merge”。
图4 MCF7细胞经化合物(I)处理后，Western blot检测ERα66，ERα46和ERα36表达的情况。
图5 MCF7细胞经化合物(I)处理后，存活细胞数量变化情况。
图6式(I)化合物对仅表达ERα-36或ERα-66的HEK293细胞的ERK的活化情况。
具体实施方式
下面结合实施例对本发明作进一步的详细说明。
式(I)化合物：7-羟基-3-[(4-羟基)-3-((E)-3，7-二甲基-辛基-2，6-二烯基)苯基]-4H-1-苯并吡喃-4-酮从上海友思生物技术有限公司购买。
实施例1 式(I)化合物的体外生物试验
试验1-1：
试验方法：含有不同患者乳腺癌组织蛋白的pre-blot滤膜片购至ProSci公司(Poway，CA)。使用ERα36特异性的抗ERα36抗体[ER-α36特异抗体(针对ER-α36 C-端的20个氨基酸)是由Alpha Diagnostic International(San Antonio，TX)制备，可参阅Proc.Natl.Acad.Sci.USA，2006，103(24)：9063-9068]，HRP标记的二抗以及增强化学发光试剂(ECL，AmerShamPharmacia Biotech)检测滤膜片并显色。该膜洗脱后，使用能同时检测ER三种亚型(ERα66，ERα46和ERα36)的抗ERα抗体H222(Novocastra Laboratories Ltd，UK)检测膜片。(见图2)
试验结果：ERα66，ERα46和ERα36在浸润性导管癌(泳道2)、浸润性小叶癌(泳道5)和非浸润性导管癌(泳道7)中表达。此外，ERα36在浸润性导管癌(泳道4)和浸润性小叶癌(泳道6)中表达。泳道2和泳道3是来源于两位不同患者的浸润性导管癌。泳道5和泳道6是来源于两位不同患者的浸润性小叶癌。该结果显示ERα36可以在ERα66和ERα46表达阴性的乳腺癌中表达，而在正常乳腺组织中无表达(泳道1)。
试验1-2：
试验方法：MDA-MB-231细胞系是公认的缺乏ERα66和ERα46表达的乳腺癌细胞系[Relevanceof breast cancer cell lines as models for breast tumors：an update.Breast CancerResearch and Treatment 2004，83：249-289]MDA-MB-231细胞(购至ATCC细胞库)传代置于8孔BIOCOAT玻片(BD Science Discovery Labware)，培养于含10％胎牛血清的DMEM培养基，并在37℃，5％CO2的条件下培养12小时。使用无菌PBS冲洗两遍，4％多聚甲醛(PBS配制，PH7.4)在室温固定30分钟；然后用PBS洗，和0.5％(v/v)Triton X-100破膜10分钟；PBS洗，3％血清在室温封闭1小时；抗ERα36特异性抗体在室温孵育1小时，含0.5％Triton X-100的PBS(PBST)洗三次；异硫氰酸荧光素(FITC)标记的荧光二抗孵育1小时；PBST洗三次，PBS洗一次；防淬灭封片剂(Molecular Probes，Eugene，OR)封片。于Nikon E600显微镜下观察，使用MRC-1024激光共聚焦显微镜(Bio-Rad)拍摄图像。(见图3)试验结果：在ERα66和ERα46表达阴性的的乳腺癌细胞MDA-MB-231中，抗ERα36特异性抗体显色阳性(标注为αER-α36，阳性结果显示为绿色)，并可以被用作免疫的多肽所阻断。细胞核使用4，6-联咪-2-苯基-1H-吲哚染色(标注为DAPI，阳性结果显示为蓝色)。联合显色者标注为“Merge”。(图中的+Peptide表明在实验中加免疫源多肽来阻断抗体)
试验1-3：
MCF7细胞经浓度为0μm至25μm的化合物(I)处理后，免疫印迹法(Western blot)检测ERα66，ERα46和ERα36表达的情况。(见图4)。
试验结果：如图所示，随着化合物(I)浓度的上升，ERα66和ERα46的表达下降。然而高浓度的化合物(I)能抑制三者的表达。
试验1-4：
试验方法：MCF7细胞系是高表达ERα66，ERα46和ERα36的乳腺癌细胞系(Relevance ofbreast cancer cell lines as models for breast tumors：an update.Marc Lacroix，GuyLeclercq，Breast Cancer Research and Treatmen 2004，83；249-289。)MCF7细胞(购至ATCC细胞库)培养于含10％胎牛血清的DMEM/F12培养基(Invitrogen)，在37℃和5％CO2的条件中培养12小时。化合物(I)(购至上海有思生物技术公司)，通过DMSO溶解稀释。MCF7细胞按1×105的密度接种于100mm直径的培养皿中，由浓度为0μm至25μm的化合物(I)处理两周后，使用血球计数器在显微镜下对存活的细胞进行计数。按照浓度进行分组，5个培养皿为一组。(见图5)图示的是MCF7细胞经浓度分别为0μm，5μm，10μm，15μm，20μm和25μm的化合物(I)处理两周后，细胞数目变化的表现。细胞计数的单位为1×104个。
试验结果：如图所示，MCF7细胞经浓度为5μm的化合物(I)处理后活细胞数量明显下降。试验1-5：式(I)化合物对仅表达ERα-36或ERα-66的HEK293细胞的ERK的活化(见图6)
试验方法：HEK293，HEK 293/ERα-36(HEK293细胞用ER-α36表达质粒转染并高表达ER-α36的细胞株)；HEK 293/ERα-66 cells(HEK293细胞用ER-α66表达质粒转染并高表达ER-α66的细胞株)在10％胚胎牛血清(FBS)和无酚红的DMEM中，和5％CO2，37℃培养箱中培养。细胞在含5％活性碳处理的FBS的DMEM中培养24小时后，以2X106/培养皿的密度接种在Φ100mm培养皿中。细胞在经过24小时后，加到无血清的DMEM介质中培养18小时。细胞然后DMSO和化合物(I)在10-15，10-10和10-6M(图6中标为：0，-15，-10，-6)处理10分钟。细胞用PBS洗两次，收获和裂解细胞，用针对磷酸化或非磷酸化ERK的抗体做Westernblotting分析。
试验结果：式(I)化合物可活化表达ER-a36的293细胞中的MAPK/ERK磷酸化，但不活化表达ER-a66的293细胞中的ERK磷酸化。这一结果表明式(I)化合物可和ER-a36特异性结合并活化下游ERK信号通道。
实施例2：式(I)化合物的体内抑瘤药效学试验
2-1对人乳腺癌BCAP-37的作用
实验方法：采用BALB/c-nu裸鼠，25只，平均体重19-21g。实验给药前，裸鼠右前肢腋下移植人乳腺癌BCAP-37瘤株。参照抗肿瘤药物“他莫昔芬(Tamoxifen)临床人有效口服剂量10-20mg，口服，2次/日计算，将化合物(I)设单一剂量组，既：33mg/kg(0.66mg/天/只)，另设阳性药他莫昔芬对照组(16.5mg/kg，0.33 mg/天/只)和阴性荷瘤裸鼠对照组，给药组每组设9只裸鼠，阴性荷瘤裸鼠对照组设7只裸鼠，雌性。采用经口灌胃给药，每天一次。裸鼠移植人乳腺癌BCAP-37瘤株后经口灌胃“乙烯雌酚”，连续给药6天，第7天分组后开始口服化合物(I)，连续给药18天，荷瘤裸鼠给药期间每4天测量动物体重和移植肿瘤生长体积，并计算各剂量组动物肿瘤体积(VT)、相对体积(RVT)、肿瘤增殖率T/C(％)。停药后24小时后处死各组裸鼠，完整剥离瘤组织，用1/10000分析天平称重，计算平均肿瘤重量和肿瘤生长抑制率
实验结果：
1.给药期间各组荷瘤人乳腺癌BCAP-37瘤株裸鼠均无死亡，各给药组动物给药期间体重变化与阴性对照组动物比较均未见显著差异。各药物组荷瘤裸鼠给药期间各组体重变化(见表2)
表2.各实验组荷瘤裸鼠给药期间体重(g)变化比较
| 组别 | 给药1天 | 给药4天 | 给药8天 | 给药11天 | 给药14天 | 给药18天 |
| 阴性对照组他莫昔芬组化合物(I)组 | 20.19±1.0620.29±0.6320.06±1.41 | 21.19±1.1020.39±0.9820.27±1.03 | 21.96±0.5720.49±0.7020.98±1.16 | 21.83±1.1620.83±1.0322.23±1.05 | 22.97±0.9721.52±0.9122.78±1.54 | 24.50±1.0523.31±1.9123.63±1.04 |
注：各组间均无显著差异
2.化合物(I)组荷瘤裸鼠给药18天期间其肿瘤体积(VT)、相对体积(RVT)除给药组给药第1天、第4天的肿瘤体积(VT)相对体积(RVT)与同期阴性对照组统计学分析，p值大于0.05外、给药组其他给药时段的肿瘤体积(VT)和相对体积(RVT)均值与同期阴性对照组相比均有显著性差异(p＜0.01)。
荷瘤裸鼠给药期间各组裸鼠肿瘤体积变化(见表3)
表3.各实验组荷瘤裸鼠给药期间肿瘤体积(mm3)变化比较
| 组别 | 给药1天 | 给药4天 | 给药7天 | 给药11天 | 给药14天 | 给药18天 |
| 阴性对照组他莫昔芬组化合物(I)组 | 33.00±21.3141.34±12.7332.54±14.16 | 181.23±106.77164.23±68.46101.06±31.41<sup>b</sup> | 624.49±154.16249.74±32.96<sup>a</sup>219.77±58.56<sup>a</sup> | 803.15±330.57323.55±63.23<sup>a</sup>356.87±125.23<sup>a</sup> | 1325.05±484.24536.20±143.17<sup>a</sup>460.87±177.99<sup>a</sup> | 2317.38±768.691089.98±175.23<sup>a</sup>1252.01±560.14<sup>a</sup> |
注：分别与各批次阴性对照组比较a：p＜0.01；b：p＜0.05；
药物组荷瘤裸鼠相对肿瘤体积(RTV)比较(见表4)
表4.各实验组荷瘤裸鼠给药期间相对肿瘤体积(RTV)变化比较
| 组别 | 例数 | 给药4天 | 给药7天 | 给药11天 | 给药14天 | 给药18天 |
| 阴性对照组他莫昔芬组化合物(I)组 | 799 | 6.57±3.184.24±1.883.51±1.44 | 25.53±15.866.57±2.33<sup>a</sup>8.26±5.14<sup>a</sup> | 30.09±12.978.69±3.22<sup>a</sup>14.37±7.01<sup>a</sup> | 49.32±28.0613.81±5.59<sup>a</sup>15.71±7.29<sup>a</sup> | 92.35±23.48<sup>a</sup>28.27±8.80<sup>a</sup>45.37±24.53<sup>b</sup> |
注：分别与各批次阴性对照组比较a：p＜0.01；b：p＜0.05。
3.给药第18天，化合物(I)组肿瘤增殖率(T/C)为49.1％。阳性药他莫昔芬组为52.8％。
各药物组荷瘤裸鼠相对肿瘤增殖率(T/C)比较(见表5)
表5.各给药组荷瘤裸鼠给药期间相相对肿瘤增殖率(T/C)变化比较(％)
| 组别 | 给药4天 | 给药7天 | 给药12天 | 给药14天 | 给药18天 |
| 他莫昔芬组化合物(I)组 | 0.6450.534 | 0.2570.324 | 0.2890.478 | 0.2800.318 | 0.5280.491 |
4.给药组实测平均肿瘤重量分别为受试药物化合物(I)组：1.096±0.26g，给药组肿瘤重量分别与空白对照组(2.201±0.805g)比较，p值小于0.05。
5.给药组肿瘤生长抑制率为：受试药物化合物(I)组：50％，阳性药他莫昔芬组为54％。
各药物组荷瘤裸鼠肿瘤重量和肿瘤生长抑制率比较(见表6)
表6.各实验组荷瘤裸鼠肿瘤重量(g)和肿瘤生长抑制率(％)变化比较
| 组别 | 例数 | 肿瘤重量(g) | p值 | 肿瘤生长抑制率(％) |
| 阴性对照组他莫昔芬组比合物(I)组 | 799 | 2.201±0.8050.992±0.1421.096±0.261 | -0.000530.0016 | -0.540.50 |
注：p值＜0.001：各给药组与阴性对照组相比。
6.受试药物化合物(I)平均肿瘤重量与阳性药对照药组(他莫昔芬)比较，瘤重量无显著性差异(p＞0.05)。
Claims (3)
1.式(Ⅰ)化合物或式(Ⅰ)化合物的药学上可接受的盐
在制备治疗与雌激素受体ER-α亚型相关疾病的药物中的应用，所述ER-α亚型为ER-α36，ER-α46以及ER-α66，所述疾病为乳腺癌。
2.根据权利要求1所述的应用，所述式(Ⅰ)化合物或式(Ⅰ)化合物的药学上可接受的盐是作为雌激素受体ER-α的调节剂。
3.根据权利要求1所述的应用，所述药物包括片剂，口嚼剂，胶囊剂，悬浮液剂，溶液剂。
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