CN105153142B - 香豆素母核的呋咱衍生物及抗肿瘤活性 - Google Patents
香豆素母核的呋咱衍生物及抗肿瘤活性 Download PDFInfo
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- CN105153142B CN105153142B CN201410242359.XA CN201410242359A CN105153142B CN 105153142 B CN105153142 B CN 105153142B CN 201410242359 A CN201410242359 A CN 201410242359A CN 105153142 B CN105153142 B CN 105153142B
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Abstract
本发明属化学制药领域,涉及香豆素母核及其异构体通过不同长度和结构链接与呋咱氧化物结合的呋咱衍生物,经实验证实其具有优良抑制敏感人肿瘤细胞、耐药瘤株以及测定新生血管抑制作用的HUVEC正常细胞生长抑制活性;以及对耐顺铂的A2780和耐吉西他滨的HM231细胞株的细胞增殖具有抑制活性。初步药理显示其通过释放高浓度一氧化氮,诱导癌细胞的凋亡功能;抑制MEK活性和明显抑制MAPK/ERK通路中MEK的磷酸化作用,产生显著地抑制肿瘤生长作用。本发明的化合物为获得对敏感和耐药肿瘤均具有抑制活性的候选药物以及阐明其药理作用机理奠定了良好基础。
Description
技术领域
本发明属化学制药领域,具体涉及香豆素母核呋咱衍生物和其抗肿瘤活性。
背景技术
据报道,肿瘤已是严重威胁人类健康和生命的常见病和多发病,也已成为导致全球人类死亡的主要疾病之一;癌症已经超越心血管和脑血管疾病成为危害人类健康的“头号杀手”和全球最大的公共卫生问题之一。统计显示,我国癌症病及死亡率呈上升趋势;在城镇居民中,癌症已成为死亡率居首的疾病。目前,临床肿瘤治疗手段主要包括外科手术治疗、放射治疗(放疗)、化学药物治疗(化疗)及近年来蓬勃兴起的生物治疗(包括免疫治疗和基因治疗)和介入治疗、热疗等,其中化学药物治疗仍为主要的治疗手段。过去的几十年来,人类已发现100多种有效的抗肿瘤药物,但临床实践显示,常用的抗肿瘤药物因长期或大量使用而降低了选择性,产生了较大毒副作用和出现耐药性等缺点。因此,寻找低毒、高效及靶向性强抗肿瘤药物仍然是目前药物学家们的重要课题之一和临床迫切需求。
研究显示,丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPKs)是细胞内一类具高度保守性的丝氨酸/苏氨酸蛋白激酶。MAPKs信号转导通路将细胞外刺激信号转导至细胞及其核内,并在细胞的增殖、分化、转化及凋亡等过程中发挥至关重要的作用。MAPKs包括四个亚家族:细胞外信号调节蛋白激酶(ERKs,extracellular-signalregulated protein kinase);c-Jun氨基末端蛋白激酶(JNK),p38丝裂原活化蛋白激酶(p38MAPK)以及ERK5通路;研究显示ERK是MAPKs中的一个重要的家族,由Raf、MEK和ERK三个核心蛋白激酶组成,它的信号传导遵循MAPKs的三级酶促级联反应,即上游激活蛋白→MAPK激酶的激酶(MAPKKK)→MAPK激酶(MAP-KK)→MAPK,在ERKs通路中Ras作为上游激活蛋白,Raf作为MAPKKK,MAPK/ERK激酶(MEK)作为MAPKK,ERK即MAPK,即Ras/Raf/MEK/ERK途径;Ras/Raf/MEK/ERK信号转导通路与肿瘤的发生密切相关,而ERK的过度活化与肿瘤的增殖、存活、分化和凋亡同样有着重要的联系,如在肺癌、结肠癌、肾癌、胰腺癌以及乳腺癌中均发现了由病理性Ras或突变的b-Raf引起的下游蛋白激酶的逐级激活,最终会导致ERK的过度活化(Oncogene,1999,18,813-822.);
MEK是Ras/Raf/ERK/MAPK通路的关键节点:ERKs是MEK的唯一底物,而ERKs也只能由MEK激活;这预示着MEK抑制剂阻断ERK活化的作用是高度特异性,这也使得MEK抑制剂成为很有前景的抗肿瘤靶标(Oncogene,2007,26,3291-3310);已报道的MEK抑制剂主要有ATP竞争性和ATP非竞争性抑制剂两种,前者由于受到ATP浓度的影响,选择性和特异性低,毒性大;后者既不与ATP结合位点竞争性结合,也不与ERK竞争MEK的结合位点,且同其他激酶没有同源序列,因此具有很好的特异性和选择性;
目前研究最多的是二芳基胺类,已经有多个小分子MEK抑制剂进入了临床或临床前研究,例如,辉瑞公司的PD325901和阿斯利康公司的司美替尼(Selumetinib,如下式所示)均已通过I期临床,进入了II期临床;而葛兰素史克(GSK)公司的小分子MEK抑制剂曲美替尼(Trametinib,如下式所示)已于2013年5月被美国FDA批准上市,用于黑色素瘤的治疗;此外,亦有文献(Bioorg.Med.Chem.Lett.2005,15,5467–5473;Bioorg.Med.Chem.Lett.2013,23,6223-6227)报道了香豆素骨架的MEK抑制剂,例如G8935,其同MEK(PDB code:1S9J)中的共结晶小分子二芳基胺类MEK抑制剂PD318088(如下式所示)具有良好的重叠性;此外,有研究者以二芳基胺类MEK抑制剂为基础提出了MEK抑制剂的三个药效团模型,分子模拟显示G8935拥有其中的两个,如与MEK激酶活性中心SER212残基可形成关键的氢键作用;此外,香豆素母核3-位苄基还占据一个新的结合口袋,这个新的作用对于该类香豆素骨架MEK抑制剂的活性具有至关重要的作用。
(Ⅰ)部分临床二期及已上市的MEK抑制剂
天然香豆素及其衍生物普遍存在植物、动物以及微生物代谢物中,它们不但在农业和医药领域发挥着重要作用(John Wiley&Sons Ltd,New York,1982,21.),其中的衍生物还具有抗菌、抗病毒、抗骨质疏松及抗肿瘤等多种生物活性(J.Enz.Inhib.Med.Chem.2004,19,373-379;PCT Int.Appl.Wo9747634,1997;Chem.Abstr.1999,128,75634;Anticancer Res.2001,21,917-923;Med.Res.Rev.2003,23,322-345)。有研究显示,在合成的一系列香豆素及其吡喃酮位置异构体的衍生物中,发现4-甲基-7-芳杂环硫基或取代苄基硫基香豆素在体外对KB(鼻咽癌细胞)及其耐药瘤株KB-vin(耐长春碱亚型鼻咽癌细胞),A549(肺癌细胞)和DU145(***癌细胞)四种人肿瘤细胞具有良好的细胞毒活性,尤其是化合物7-(6-氯代吡啶-2-硫基)-4-甲基-2H-色烯-2-酮(CY-1-140A)对上述四种瘤株分别显示IC50值为0.92,0.92,2.11和1.15μM的抑制活性。初步药理研究表明该类化合物对A549肺癌细胞凋亡活性呈明显浓度依赖关系,并且作用在细胞***周期的G2/M期(Eur.J.Med.Chem.2012,49,74-85.)。基于上述文献(Bioorg.Med.Chem.Lett.2005,15,5467–5473;Bioorg.Med.Chem.Lett.2013,23,6223-6227)报道了香豆素衍生物G8935抑制MEK活性,推测这些化合物可能具有MEK抑制作用。
众所周知,一氧化氮(NO,Nitric oxide)是人体内一类重要的信号和效应分子,参与众多的病理和生理过程(Nat.Rev.Cancer 2006,6,521-534.)。尤其是其经多靶点作用抗肿瘤活性得到广泛的关注,对此NO表现出两面性,也即,低浓度NO促进肿瘤的发生与发展,而高浓度的NO(>500nM)则抑制(Carcinogenesis 2013,34,503–512)肿瘤生长;有研究显示,经过修饰的一氧化氮供体释放出高浓度一氧化氮,不仅可以诱导凋亡和抑制癌细胞的转移,还可以通过抑制缺氧诱导因子(hypoxia-inducible factor-1α,HIF-1α)、核因子-κB(nuclear factor-κB,NF-κB)、DNA的损伤修复、以及药物转运体而对化疗、放疗以及免疫治疗产生增敏的作用(Nitric Oxide 2008,19,152-157;Cancer Res.2005,65,516-525;Curr.Pharm.Des.2008,14,1113-1123)而达到抑制肿瘤作用。其中,苯磺酰呋咱氮氧化物作为一类重要的一氧化氮供体,可以在体内释放高浓度一氧化氮而产生抗肿瘤活性(Pharmazie 2006,61,54-59.)。张奕华和田季德课题组(Bioorg.Med.Chem.Letts.2010,20,6416–6420;J.Med.Chem.2011,54,3251–3259;J.Med.Chem.2013,56,4738-4748)曾报道了活性化合物如FTs、WZ4002以及GA等与呋咱型一氧化氮供体的拼合产物,表现出很好的抗肿瘤活性(如式(Ⅱ)所示)。还有报道MEK抑制剂和一氧化氮供体联合使用可以产生协同的抗肿瘤活性(Int.J.Oncol.2012,40,807-815)。
基于前期研究所得构效关系显示的香豆素母核7-位杂环取代基引入有利于抗肿瘤活性,本申请的发明人拟在进一步结构修饰中,将呋咱一氧化氮供体杂环引入到香豆素母核,观察其抗肿瘤活性并探索相应的MEK抑制作用机理,提供新的具有抗肿瘤活性的香豆素母核的呋咱衍生物。
(Ⅱ)部分活性化合物同呋咱型一氧化氮供体的拼合物
发明内容
本发明的目的是提供活性明确,同时对耐药株有作用的抗肿瘤新型药效化合物。具体涉及化合物4-(2-(4-甲基-2-氧代-2H-色酮-7-羟基)-乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(8b)及其衍生物和抑制肿瘤生长活性的应用。
本发明以原有活性化合物CY-1-140A(1)为基础,利用骨架跃迁及拼合原理设计合成得到如图1所示的具有抗肿瘤活性的香豆素母核的呋咱衍生物,本发明所述的化合物是香豆素母核及其异构体通过不同长度和结构链接与呋咱氧化物结合的呋咱衍生物,
本发明中,优选的香豆素呋咱衍生物具有式18和19的结构,所述的香豆素呋咱衍生物为香豆素母核及其吡喃酮骨架异构体与呋咱型一氧化氮供体的拼合产物,中间为不同长度链状或环状连接基团(英文为linker),(如图6所示),
其中:X为氧、硫和氮原子以及烷基取代的氮原子
R1为烷基或氢原子
R2为烷基、烷氧基、卤代烷基、酯基
R3为不同长度的连接基团,包括不同长度的链状或环状碳链、酯基链、杂环链。
本发明中,更优选的式18和19结构的香豆素呋咱衍生物中:X=O,S,N或N-甲基;R1为烷基,氢原子;R2为烷基、烷氧基、卤代烷基、酯基;R3为不同长度的链状或环状脂肪碳链、酯基碳链以及杂环链(包含哌嗪环)。
本发明提供了所述的香豆素母核的呋咱衍生物的制备方法,其包括:
(1).按参考文献(J.Heterocycl.Chem.1977,14,1415-1416.)合成关键中间体(4);以苯硫酚与氯乙酸为起始原料同碳酸钠和氢氧化钠在乙醇和水的混合溶液中反应得到化合物2;然后以冰醋酸为溶剂,用过氧化氢氧化得到3;化合物3与发烟硝酸缩合得到关键中间体苯磺酰呋咱氮氧化物(4);其化学反应如下述通式一:
通式一:
(2).市售无甲基、4-甲基或4,8-二甲基取代的7-羟基香豆素衍生物(5a-e)和参考文献(Eur.J.Med.Chem.2011,46,4924-4936)自制香豆素母核的吡喃酮骨架异构体14,在二甲基甲酰胺(DMF)或丙酮中,碳酸钾碱性条件下与相应卤代醇经回流反应,得到7-位带有不同长度碳链的化合物7a-g和16a-b;而边链含N的中间体7g与碘甲烷进一步得到N-甲基化产物9a,化合物5a-b与氯乙酸、碳酸钾在DMF中回流反应得到7-羧基边链中间体11a-b,进一步与乙二醇用1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC,)和4-(二甲氨基)吡啶(DMAP)缩合催化,得到含酯键边链中间体12a-b,最后,具有7-位不同长度链接链的中间体5a-c,7a-g,9a,12a-b,14和16a-b与呋咱氮氧化合物4,在含碱1,8-二氮杂二环十一碳-7-烯(DBU)的二氯甲烷中,室温反应合成目标衍生物6a-c,8a-g,10a,13a-b,15和17a-b。化学反应如下通式二:
通式二:
本发明所述的香豆素母核及其异构体通过不同长度和结构链接与呋咱氧化物结合的呋咱衍生物,进行了体外抗肿瘤活性筛选试验,在体外药理实验中,以原活性化合物CY-1-140A(1)、呋咱片段4和顺铂为阳性对照,检测对A549、Hela、A2780、HUVEC、SKOV3、231HM以及耐药的A2780/CDDP、SKOV3/CDDP和231HM/Gem多种敏感和耐药的人肿瘤细胞生长抑制活性,结果显示,所述的化合物具有优良抑制A2780(敏感和耐药人类卵巢癌细胞)、SKOV3(敏感和耐药人类卵巢癌细胞)、HM231(敏感和耐药乳腺癌肺转细胞)、Hela(子宫癌细胞)、A549(肺癌细胞)和HUVEC(人脐静脉内皮细胞)五种敏感人肿瘤细胞、三种耐药瘤株以及一种测定新生血管抑制作用的HUVEC正常细胞生长抑制活性;其中部分化合物还对耐顺铂的A2780和耐吉西他滨的HM231细胞株的细胞增殖同样具有纳摩尔水平的抑制活性;尤其,化合物8b对耐顺铂的A278和SKOV3细胞及耐吉西他滨的HM231细胞IC50值分别为0.062、0.14和0.14μM,显示了明显的抑制活性;
本发明中,初步药理研究显示所述的化合物的多重机理,通过释放高浓度一氧化氮,诱导癌细胞的凋亡功能;抑制MEK活性和明显抑制MAPK/ERK通路中MEK的磷酸化作用,最终产生显著地抑制肿瘤生长作用;
本发明进一步进行了体内荷瘤裸鼠模型试验,经体内药理实验结果显示,所述的化合物具明显的肿瘤生长抑制作用,尤其化合物8b在荷瘤裸鼠模型中显示出了良好的抑制肿瘤生长活性(15和30mg/Kg给药)。
本发明中通过下述方法检测所述的化合物抑制肿瘤活性的作用。
1、采用MTT法检测本发明化合物抑制肿瘤细胞增殖的活性,将对数生长期的癌细胞接种于96孔板中,分为空白对照组、顺铂对照组和不同浓度的本发明化合物处理组,37℃培养48h后进行MTT检测,计算细胞增殖抑制率及IC50;
2、应用Western blot(免疫印迹法)分析,检测本发明化合物抑制MEK磷酸化和促凋亡作用,A2780细胞用DMSO和不同浓度本发明化合物处理24h后,收集细胞用冷PBS洗涤1次,用RIPA蛋白裂解液冰上裂解细胞30分钟,4℃离心15分钟,总蛋白用BCA法蛋白定量,每道30μg的上样量,经SDS-PAGE电泳转印到聚偏二乙烯的氟化物PVDF膜上,封闭于10%脱脂奶中,依次进行一抗、二抗反应,曝光显色;
3、采用经典的Griess试剂检测本发明化合物的NO释放水平,肿瘤细胞A2780(1×106个于6cm盘)用100μM浓度本发明化合物孵化150分钟后,收集细胞用RIPA蛋白裂解液冰上裂解细胞30分钟,然后与Griess试剂混合30分钟,在540nm下检测吸光度,用稀释液处理后细胞中亚硝酸盐作为本底对照,不同浓度下硝酸钠检测制备标准曲线;
4、体内抑瘤实验,于裸鼠皮下移植瘤接种后第10天,将已经建成的荷瘤小鼠随机分组,每组6只。实验组腹腔注射受试样品(根据溶解度不用选择合适溶剂),每个样品设2个浓度,并设阴性对照组(给予空白溶剂),每周给药2次,并测量、记录瘤生长大小,停药后第2天处死裸鼠,剥离瘤组织,称取瘤质量。
本发明中,初步药理研究显示所述的化合物的多重机理,通过释放高浓度一氧化氮,诱导癌细胞的凋亡功能;抑制MEK活性和明显抑制MAPK/ERK通路中MEK的磷酸化作用,最终产生显著地抑制肿瘤生长作用;
本发明所述的香豆素母核呋咱衍生物结构新颖,具有明显的体外抑制肿瘤细胞的活性和体内显著地抑制肿瘤生长的作用,为深入研究获得对敏感和耐药肿瘤均具有抑制活性的候选药物以及阐明其药理作用机理奠定了良好基础。
附图说明
图1为香豆素及其母核异构体呋咱衍生物拼合示意图.
图2显示了:(A)促细胞凋亡和(B)抑制MEK磷酸化作用。
图3 A、B和C显示了体内抑瘤活性。
图4显示了NO释放水平。
图5显示了化合物8b与MEK1蛋白对接图。
图6显示了优选的香豆素呋咱衍生物具有式18和19的结构,所述的香豆素呋咱衍生物为香豆素母核及其吡喃酮骨架异构体与呋咱型一氧化氮供体的拼合产物,中间为不同长度链状或环状连接基团(英文为linker)。
具体实施方式
通过以下实施方法将有助于理解本发明,但并不限制于本发明的内容。
实施例1
通式二中化合物6a-c中一个化合物4-(4-甲基-2H-色烯-2-二酮-7-氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(6b)的合成
7-羟基-4-甲基-香豆素(5b,300mg,1.2mmol)与苯磺酰呋咱N-氧化物(4,256mg,1.0mmol)以及DBU(2.0mmol)在二氯甲烷(6mL)溶剂中,室温反应3小时;然后用3×5ml水洗去DBU,减压蒸除溶剂,得到油状液体。加入少量甲醇,析出白色固体,过滤后用乙酸乙酯重结晶,得到产品6b(320mg),收率90%,熔点为201-203℃.ESI-MS m/z 401.0[M+H]+;1H NMR(400MHz,CDCl3)δ2.46(s,CH3C=),6.32(s,1H,-CH3C=CHCOO),7.31(m,2H,ArH),7.68(m,3H,ArH),7.81(t,1H,ArH,J=6.4Hz),8.10(d,2H,ArH,J=7.48Hz)。
实施例2
通式二中化合物4-(2-乙基-4H-色稀-4-酮-7-氧基)-3-(苯磺酰)-1,2,5-噁二唑2-氧化物(15)的合成
7-羟基-2-乙基-香豆素(14,300mg,1.2mmol)与苯磺酰呋咱N-氧化物(4,256mg,1.0mmol)以及DBU(2.0mmol)在二氯甲烷(6mL)溶剂中,室温反应3小时;然后用3×5ml水洗去DBU,减压蒸除溶剂,得到油状液体。加入少量甲醇,析出白色固体,过滤后用乙酸乙酯重结晶,得到产品15(280mg)。产率89%,熔点为159-161℃。ESI-MS m/z415.0[M+H]+;1H NMR(400MHz,CDCl3)δ1.32(t,3H,CH2CH3,J=7.56Hz),2.47(q,2H,CH2CH3,J=7.56Hz),6.21(s,1H,OC=CH),7.32(dd,1H,ArH,J=8.80,2.36Hz),7.46(d,1H,ArH,J=2.32Hz),7.66(t,2H,ArH,J=8.28Hz),7.81(t,1H,ArH,J=7.56Hz),8.08(dd,2H,ArH,J=1.28,8.48Hz),8.27(d,1H,ArH,J=8.80Hz)。
实施例3
通式二中化合物类型7a-g中一个化合物4-甲基-7-羟乙氨基-香豆素(7g)的合成
原料4-甲基-7-氨基-香豆素(5e,300mg,1.56mmol),2-溴乙醇(975mg,7.80mmol)、碳酸钾(372mg,4.68mmol)以及碘化钾(51mg,0.31mmol)溶于丙酮(10mL),回流反应10小时,过滤后,减压蒸除溶剂,层析柱分离纯化,得到淡黄色固体产物7g(212mg),收率40%。ESI-MS m/z 220.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.40(d,1H,ArH,J=8.7Hz),6.61(dd,1H,ArH,J=8.7,1.7Hz),6.41(d,1H,ArH,J=1.7Hz),5.89(s,1H,-CH=),3.54(t,2H,-OCH2CH2O-,J=5.8Hz),3.19–3.10(m,2H,-OCH2CH2O-),2.28(s,3H,-CH3)。
实施例4
通式二中化合物类型8a-g中一个化合物4-(2-(4-甲基-2-氧代-2H-色烯-7-氧基)乙氧基)-3-(苯磺酰)-1,2,5-噁二唑-2-氧化物(8b)的合成
原料7-羟乙氧基-4-甲基-香豆素(7b,100mg,0.45mmol)与苯磺酰呋咱N-氧化物(4,140mg,0.38mmol),在DBU(205mg,1.35mmol)存在下,于二氯甲烷(5mL)溶剂中室温反应3小时;然后用3×5ml水洗去DBU,有机相用无水硫酸钠干燥,过滤后滤液减压蒸除溶剂,残留物用乙酸乙酯重结晶得白色固体8b(140mg),收率70%,熔点为162-165℃.ESI-MS m/z445.0[M+H]+;1H NMR(400MHz,CDCl3)δ2.43(s,3H,=CCH3),4.45(t,2H,-CH2O-,J=4.12Hz),4.81(t,2H,-OCH2-,J=4.20Hz),6.18(s,1H,-CH3C=CH-COO-),6.85(d,1H,ArH,J=2.32Hz),6.92(dd,1H,ArH,J=8.80,2.36Hz),7.57(m,3H,ArH),7.73(t,1H,ArH,J=7.57Hz),8.03(d,2H,ArH,J=7.72Hz)。
实施例5
通式二中化合物N-甲基-N-羟乙氨基-4-甲基-香豆素(9a)的合成
将4-甲基-7-羟乙氨基-香豆素(7g,100mg,0.46mmol)加入50ml三口烧瓶中,再加入碘甲烷(199mg,1.38mmol),反应7h,倾入水中,二氯甲烷(10ml)萃取三次,合并有机相,无水硫酸钠干燥,过滤,滤液减压除去溶剂后,用柱层析分离得淡黄色固体9a(45mg),产率45%。ESI-MS m/z 233.1.0[M+H]+。
实施例6
通式二中化合物4-(2-(4-甲基-2-氧代-2H-色烯-7-甲氨基)-乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑-2-氧化物(10a)的合成
将N-甲基-N-羟乙氨基-4-甲基-香豆素(9a,40mg,0.17mmol),苯磺酰呋咱N-氧化物(4,63mg,0.17mmol),及DBU(78mg,0.51mmol)加入到25ml圆底烧瓶,再加入二氯甲烷(5ml),室温反应3h后,然后用3×5ml水洗去DBU,有机相用无水硫酸钠干燥,过滤后滤液减压蒸除溶剂,柱层析分离的目标产物10a(35mg),熔点为181-185℃,产率45%。ESI-MS m/z458.0[M+H]+;1H NMR(400MHz,CDCl3)δ2.36(s,3H,=CCH3),3.19(s,3H,-NCH3),3.95(t,2H,-CH2NCH3-,J=5.32Hz),4.63(t,2H,OCH2-,J=5.28Hz)6.02(s,1H,-CH3C=CH-COO-),6.59(d,1H,ArH,J=2.52Hz),6.76(dd,1H,ArH,J=8.92,2.56Hz),7.46(d,1H,ArH,J=8.92Hz),7.57(t,2H,ArH,J=7.88Hz),7.74(t,1H,ArH,J=7.48Hz),7.95(d,2H,ArH,J=7.40Hz)。
实施例7
通式二中化合物类型16a-b中一个化合物7-(3-羟丙基)-2-乙基-4H-色烯-4-酮(16b)的合成
将2-乙基-4H-色烯-4-酮化合物(14,500mg,2.6mmol)和3-氯丙醇(491mg,5.2mmol)加入到50ml三口烧瓶中,再加入碳酸钾(1.07g,7.8mmol),四丁基溴化铵(TBAB,10%mol),碘化钠(10mol%)反应4h,停止反应,倾入水(40ml)中,10ml二氯甲烷萃取三次,合并有机相,以二氯甲烷和甲醇为洗脱剂进行柱层析分离纯化,得淡黄色固体16b(483mg),产率75%,熔点为71-73℃。ESI-MS m/z 249.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.86(d,1H,ArH,J=8.8Hz),7.07(s,1H,ArH),6.99(d,1H,ArH,J=8.9Hz),6.11(s,1H,COC=CH),4.59(t,1H,OH,J=4.7Hz),4.15(t,2H,OCH2-,J=6.0Hz),3.54(q,2H,-CH2-,J=5.4Hz),2.62(q,2H,-CH2O-,J=7.4Hz),2.05–1.67(m,2H),1.20(dd,3H,-CH2CH3,J=8.1,6.9Hz)。
实施例8
通式二中化合物类型17a-b中一个化合物4-(3-(2-乙基-4H-色烯-4-酮-7-氧基)-丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(17b)的合成
化合物7-(3-羟丙基)-2-乙基-4H-色烯-4-酮(16b,100mg,0.40mmol)与苯磺酰呋咱N-氧化物(4,123mg,0.33mmol),在DBU(180mg,1.2mmol)存在下,于二氯甲烷(5mL)溶剂中,室温反应3小时;然后加入3×5ml水洗去DBU,有机相无水硫酸钠干燥,过滤,减压蒸除溶剂,乙酸乙酯重结晶残留物,得到淡黄色晶体17b(130mg),产率69%,熔点为153-155℃。ESI-MS m/z 473.0[M+H]+;1H NMR(400MHz,CDCl3)δ1.28(t,3H,CH2CH3,J=7.52Hz),2.40(m,2H,CCH2C),2.62(q,2H,CH2CH3,J=7.60Hz),4.25(t,2H,CH2O,J=5.84Hz),4.64(t,2H,OCH2,J=6.00Hz),6.11(s,1H,C=CH),6.86(d,1H,ArH,J=2.32Hz),6.93(dd,1H,ArH,J=8.86,2.32Hz),7.51(t,2H,ArH,J=8.16Hz),7.69(t,1H,ArH,J=7.56Hz),7.96(d,2H,ArH,J=7.32Hz),8.09(d,1H,ArH,J=8.84Hz)。
实施例9
通式二中化合物类型11a-b中一个化合物2-(4-甲基-2-氧代-2H-色烯-7-氧基)乙酸(11b)的合成
将7-羟基-4-甲基-香豆素(5b,1g,5.68mmol)、氯乙酸(1.07g,11.4mmmol)及碳酸钾(2.35g,17.04mmol)加入DMF(30ml)中,回流反应1h后,反应液凝固,停止反应,加入2NHCl调节PH至2,静止,大量白色固体析出,过滤后,乙醇重结晶得到针状晶体11b(1.3g),产率99%,熔点为210~214℃。ESI-MS m/z 235.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.67(d,1H,ArH,J=9.0Hz),7.01–6.91(m,2H,ArH),6.21(s,1H,-CH=),4.81(s,2H,-COCH2O-),2.38(s,3H,-CH3)。
实施例10
通式二中化合物类型12a-b中一个化合物2-羟乙基-2-(4-甲基-2-氧代-2H-色烯-7-氧基)乙酸酯(12b)的合成
取化合物11b(1g,4.27mmol)和EDC(930mg,4.87mmol)以及DMAP(20%mol)加入到含二氯甲烷(10ml)的50ml圆底烧瓶,0℃下反应20min,加入乙二醇(1.3g,21.35mmol)后,恢复至室温反应3h,3×5ml水洗,有机相浓缩后用二氯甲烷/甲醇(V/V=50:1)柱层析分离,得白色固体12b(500mg),产率42%。熔点为93~96℃。ESI-MS m/z 279.1[M+H]+;1H NMR(400MHz,CDCl3)δ7.52(d,1H,ArH,J=8.8Hz),6.92(dd,1H,ArH,J=8.8,2.6Hz),6.79(d,1H,ArH,J=2.5Hz),6.16(d,1H,-CH=,J=1.1Hz),4.75(s,2H,-COCH2O-),4.37(t,2H,-CH2O-,J=4.6Hz),3.89(t,2H,-CH2O-,J=4.6Hz),2.40(d,3H,-CH3,J=1.1Hz)。
实施例11
通式二中化合物类型13a-b中一个化合物4-(2-(2-(4-甲基-2-氧代-2H-色烯-7-氧基)乙酰基)-氧乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(13b)的合成
取化合物12b(100mg,0.36mmol),苯磺酰呋咱氮氧化物(4,145mg,0.40mmol)以及DBU(164mg,1.08mmol)加入到25ml圆底烧瓶,在二氯甲烷(5ml)中,室温反应3h后,同上后处理,残留液经柱层析分离得目标产物13b(90mg),产率50%,熔点为113-115℃。产率45%。ESI-MS m/z 502.9[M+H]+;1H NMR(400MHz,CDCl3)δ2.39(s,3H,=CCH3),4.67(s,4H,OCH2CH2O),4.80(s,2H,COCH2O),6.16(s,1H,-CH3C=CH-COO-),6.82(d,1H,ArH,J=2.32Hz),6.92(dd,1H,ArH,J=8.88,2.08Hz),7.53(d,1H,ArH,J=8.80Hz),7.62(t,3H,ArH,J=7.69Hz),7.76(t,1H,ArH,J=7.44Hz),8.06(d,2H,ArH,J=8.16Hz)。
实施例12 体外抗肿瘤活性筛选试验
1、采用MTT法检测本发明化合物抑制肿瘤细胞增殖的活性,将对数生长期的癌细胞接种于96孔板中,分为空白对照组、顺铂对照组和不同浓度的本发明化合物处理组,37℃培养48h后进行MTT检测,计算细胞增殖抑制率及IC50;
2、应用Western blot(免疫印迹法)分析,检测本发明化合物抑制MEK磷酸化和促凋亡作用,A2780细胞用DMSO和不同浓度本发明化合物处理24h后,收集细胞用冷PBS洗涤1次,用RIPA蛋白裂解液冰上裂解细胞30分钟,4℃离心15分钟,总蛋白用BCA法蛋白定量,每道30μg的上样量,经SDS-PAGE电泳转印到聚偏二乙烯的氟化物PVDF膜上,封闭于10%脱脂奶中,依次进行一抗、二抗反应,曝光显色;
结果显示,所述的化合物具有优良抑制肿瘤细胞活性的作用和抑制耐药瘤株活性作用(如表1,表2所示),其中化合物4-(2-(4-甲基-2-氧代-2H-色酮-7-羟基)-乙氧基)-3-(苯磺酰基)-1,2,5-噁二-2-氧化物(8b)不但对四种敏感的A549,Hela,A2780,SKOV3(卵巢癌细胞)瘤株细胞增殖抑制活性为24、53、14和83nM的IC50值,而且对231HM(乳腺癌肺转细胞)及其耐吉西他滨的231HM/Gem、耐顺铂的A2780/CDDP和SKOV3/CDDP(卵巢癌细胞)四种耐药肿瘤株具有很好的抑制活性,分别显示0.15、0.14、0.062和0.14μM的IC50值。
表1是本发明化合物的抗肿瘤细胞增殖活性结果。
表2是本发明的化合物8b抑制耐药瘤株活性结果。
此外,初步药理实验结果显示,化合物8b在免疫蛋白印迹法中观察到对Bax、CyclinB1和p53的表达及p53的磷酸化有促进作用,而对Bcl-2的表达显示抑制作用,同时观察到凋亡标志物Cleaved-PARP的增加,即显示了显著的诱导人类卵巢癌细胞A2780凋亡作用(如图2中的A所示);以及具有明显地抑制Ras/Raf/MEK/ERK通路中MEK的磷酸化作用(如图2中的B所示)。
表1
表2
实施例13 体内荷瘤裸鼠模型试验
对荷瘤(A2780)裸鼠模型体内抑瘤活性实验,将已经建成的荷瘤小鼠随机分组,每组6只。实验组腹腔注射受试样品(根据溶解度不用选择合适溶剂),每个样品设2个浓度,并设阴性对照组(给予空白溶剂),每周给药2次,并测量、记录瘤生长大小,停药后第2天处死裸鼠,剥离瘤组织,称取瘤质量,结果显示化合物8b腹腔注射分别给予15和30mg/kg剂量,可见到明显抑制肿瘤生长(如图3中的A和B所示),与空白对照比较,体重没有显著降低(如图3中的C所示)。
实施例14
采用经典的Griess试剂检测本发明化合物的NO释放水平,肿瘤细胞A2780(1×106个于6cm盘)用100μM浓度本发明化合物孵化150分钟后,收集细胞用RIPA蛋白裂解液冰上裂解细胞30分钟,然后与Griess试剂混合30分钟,在540nm下检测吸光度,用稀释液处理后细胞中亚硝酸盐作为本底对照,不同浓度下硝酸钠检测制备标准曲线;结果如图4所示,不含呋咱结构的母体化合物CY-1-140A(1)没有NO的释放,呋咱片段即化合物4释放浓度为30.48μM/100μM,而通过链接将呋咱引入香豆素环后,NO释放能力明显提高,尤其抑瘤活性最强的化合物8b释放NO能力也最强,达到99.6μM/100μM;结果表明,香豆素和呋咱环的结合后,通过抑制Ras/Raf/MEK/ERK通路中MEK的磷酸化作用和NO释放后促凋亡作用等多途径协同产生抗肿瘤作用。
进一步,本实施例中,利用薛定谔软件对8b与MEK1蛋白(PDB code:1S9J)进行对接,结果显示8b与G8935高度重叠(如图5所示),具有同MEK相似的作用模式,8b和GC8935与MEK的SER212残基形成了关键的氢键作用,并且8b的苯磺酰基与G8935的三位苄基显示良好重叠。
Claims (4)
1.香豆素呋咱衍生物,其特征在于,所述衍生物具有如下式所示的结构:
其中:X为氧原子;
R1为氢原子;
R2为甲基;
n=1。
2.权利要求1的衍生物在制备抑制敏感和耐药人类肿瘤细胞的药物制剂中的用途;所述的敏感肿瘤细胞是敏感人类卵巢癌细胞A2780、SKOV3,敏感乳腺癌肺转细胞HM231,子宫癌细胞Hela,人脐静脉内皮细胞HUVEC和肺癌细胞A549;
所述的耐药肿瘤细胞是耐药人类卵巢癌细胞A2780、SKOV3,耐药乳腺癌肺转细胞HM231。
3.按权利要求2的用途,其特征在于,所述的衍生物释放高浓度的一氧化氮,诱导癌细胞的凋亡;同时,抑制MAPK/ERK通路中MEK的磷酸化作用,其中,NO释放量、MEK活性抑制强度与肿瘤细胞增殖抑制作用成正相关系。
4.权利要求1的衍生物在制备抑制HUVEC正常细胞增殖活性的药物制剂中的用途,所述的HUVEC用于测定新生血管抑制作用。
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Non-Patent Citations (4)
Title |
---|
Identification of coumarin derivatives as a novel class of allosteric MEK1 inhibitors;Shulin Han,et al.;《 Bioorganic & Medicinal Chemistry Letters》;20050930;第15卷;第5467-5473页 * |
Novel Hybrids of (Phenylsulfonyl)furoxan and Anilinopyrimidine as Potent and Selective Epidermal Growth Factor Receptor Inhibitors for Intervention of Non-Small-Cell Lung Cancer;Chun Han, et al.;《 Journal of Medicinal Chemistry》;20130513;第56卷;第4738-4748页 * |
Novel Nitric Oxide-Releasing Derivatives of Farnesylthiosalicylic Acid: Synthesis and Evaluation of Antihepatocellular Carcinoma Activity;Yong Ling, et al.;《Journal of Medicinal Chemistry》;20110419;第54卷;第3251-3259页 * |
Synthesis and biological evaluation of furoxan-based nitric oxide-releasing derivatives of glycyrrhetinic acid as anti-hepatocellular carcinoma agents;Yisheng Lai,et al.;《Bioorganic & Medicinal Chemistry Letters》;20100917;第20卷;第6416-6420页 * |
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