CN101591322A - 细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物及其制法和用途 - Google Patents
细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物及其制法和用途 Download PDFInfo
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- CN101591322A CN101591322A CNA2009101402754A CN200910140275A CN101591322A CN 101591322 A CN101591322 A CN 101591322A CN A2009101402754 A CNA2009101402754 A CN A2009101402754A CN 200910140275 A CN200910140275 A CN 200910140275A CN 101591322 A CN101591322 A CN 101591322A
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- methylene radical
- piperazine
- organic amine
- scutellarin
- wogonin
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Abstract
一种细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物及其制备方法和用途。以中药黄芩提取物黄芩黄酮为先导化合物,与甲醛溶液和有机胺类化合物按1∶1-1.2∶1-1.2摩尔比混合,加入黄芩黄酮重量倍数的甲醇,在50-70℃下反应,将析出沉淀滤出,经干燥得含量大于97%的产品。该衍生物对细胞周期素依赖蛋白激酶抑制强度与Flavopiridol和P276-00类似,比黄芩苷提高约50多倍,能选择性诱导增殖期肿瘤细胞凋亡,而对正常组织几乎无影响,属于细胞周期抑制剂类抗肿瘤药物。本品原料来源丰富,工艺简捷,纯度高,成本低,代谢机理明确,高效低毒,可制成口服或注射剂型,有望成为高效低毒的抗癌和抗艾滋病药物。
Description
技术领域
本发明涉及黄芩黄酮含氮衍生物及其合成方法的技术领域,同时也涉及对肿瘤治疗的医疗的潜在用途。
背景技术
细胞周期调控是一个非常复杂和精细的调节过程,它与细胞的分化、生长、增殖和死亡有着紧密的关系。在过去的十几年里,调控细胞周期进程的信号传导途径的发现是一个重要的里程碑。人恶性肿瘤的分子特征是细胞周期调节的失控,引起细胞分化的缺乏和细胞生长的失控,导致细胞无限增殖。其中癌症,糖尿病,病毒感染等许多疾病都与一种细胞信号传导物质-蛋白激酶的混乱有关。人类基因编码的600多种蛋白激酶已被发现,其中细胞周期素依赖蛋白激酶(CyclinDependent Kinases,Cdks)是控制细胞循环与增殖过程的重要调节者。Cdks是一种丝氨酸/苏氨酸的蛋白磷酸激酶,与所对应的周期蛋白(Cyclin)形成的蛋白复合物通过控制细胞循环的关键部分来实现细胞周期高效有序的运转。Cdks可以激发三磷酸腺苷(ATP)磷酸化宿主细胞蛋白的丝氨酸或苏氨酸残基而发挥作用,而磷酸化蛋白具有调节各种细胞蛋白的活性。有丝分裂是由Cdk1/Cyclin B激活驱动的理论已被广泛认可。已发现90%的肿瘤形成是由于Cdks被高度激活导致肿瘤抑制蛋白Rb被磷酸化,使Rb程路径失活。Cdks抑制剂可有效地诱导癌细胞凋亡,提高肿瘤和艾滋病化疗药物的敏感性,对Cdks的抑制成为抗肿瘤和抗艾滋病药物研究的新靶点。[Science,2004,303,1800;The AAPS Journal,2006,8,E204;Cancer Biology Therapy,2003,4,S84]
天然黄酮类化合物广泛存在于天然植物中,具有多种生物活性,是天然的Cdks抑制剂。但是,由于天然黄酮类化合物的水溶性差,生物利用度低,生物活性相对较弱。通过对天然黄酮结构修饰,增强其生物活性,具有重要的实用价值。1994年美国国家卫生研究院癌症研究所(NCI)在全球大规模天然抗癌药物筛选中,从Dysoxylumbinectariferum的茎和树皮中分离得到一种含氮的黄酮Rohitukine,显示具有一定的抗癌活性。以此为先导化合物,Aventis公司研制合成了第一个作为高效低毒的Cdks抑制剂Flavopiridol[US-A-5849733]。Flavopiridol是一种黄酮胺基衍生物。最早被认为是酪氨酸蛋白激酶抑制剂,但后来发现其抑制Cdks活性更强,而对其它激酶作用较弱,它也是mRNA转录抑制剂。因此,Flavopiridol成为美国第一个针对细胞周期进入临床试验的可口服抗癌药物,已经进入II期临床试验。美国Iowa州立大学的研究人员同时还发现Flavopiridol可阻碍艾滋病病毒HIV—1在细胞内的增殖,能显著提高化疗药物的敏感性,显示了良好的抗癌和艾滋病应用前景。由于Flavopiridol对P-TEFb酶具有高度的抑制力,很小剂量即能对HIV-1病毒产生极强的杀伤力。[Cancer Biology Therapy,2003,4,S84,77,146;Curr.Pharm.Des.,2006,12,1949]一个有趣的发现是细胞凋亡抑制剂survivin被Cdk1/CyclinB磷酸化,可取消其抗凋亡活性,而survivin只在恶性肿瘤中表达,不在成熟的组织中表达。Flavopiridol通过抑制Cdk1/Cyclin B而降低survivin在细胞中的浓度。NCI的Louis Staudt等用DNA芯片技术揭示了Flavopiridol诱导癌细胞凋亡及其抑制HIV增殖机理为能够关闭大多数基因转录mRNA,然而它并没有杀死各种类型的细胞,只是有选择性的针对癌细胞。这是由于使癌细胞无节制生长的RNA分子是非常短命的,完全依赖mRNA的持续合成,一旦Flavopiridol进入细胞,mRNA持续时间短的基因产生mRNA的速度没有降解的快,这种mRNA迅速被降解,而正常细胞mRNA分子寿命长的却仍旧存在。Flavopiridol为ATP选择性Cdks抑制剂与细胞毒类抗癌药物不同,并不是直接杀伤细胞,而是通过强效抑制细胞周期素依赖蛋白激酶活性来诱导癌细胞凋亡,这就意味着虽然作用的对象是一种所有人体细胞中普遍存在的生物过程,但由于其所需的药用剂量很小,因此对人体正常细胞几乎没有伤害。[Genome Biology,2001,2(10),0041.1]Flavopiridol与细胞毒类治疗药物交替使用,能有效提高化疗药物的敏感性,具有明显的减毒增效协同以及抑制“多药耐药性”作用,也可用于癌症晚期治疗,能明显改善患者生存质量,延缓生命。但是Flavopiridol具有手性结构,合成工艺复杂,产率较低,成本较高,价格昂贵,脂水分配系数较大,血药浓度较低,同时还存在着严重腹泻等不良反应。尽管如此,作为ATP选择性Cdks抑制剂Flavopiridol的发现还是给癌症和艾滋病的治疗带来了新的理念与希望。
2008年Kalpan S.Joshi等在全合成了一种新的黄酮有机胺类Cdks抑制剂P276-00[CN16686131A(W02004/004632)],对12种人肿瘤细胞具有明显的抑制活性,而对2株正常组织细胞人胚胎肺纤维细胞几乎无影响,无严重腹泻等不良反应,毒性较Flavopiridol低,已完成II期临床,但是似乎也存在脂水分配系数较大,血药浓度较低等问题。[Molecular Cancer Therapeutics,2007,6,918]。
黄芩为唇形科植物Scutellaria baicalensis Geoygi,是中国人工种植量最大的药材品种。黄芩的主要有效成分为黄芩黄酮,含量高达10-20%。具有抗癌,抑菌,抗炎,抗变态反应,抗氧化,降血脂,抗血栓等作用。作为天然的CDKs抑制剂,黄芩黄酮苷的水解产物黄芩黄酮苷元黄芩素和汉黄芩素等活性更强,能诱导细胞凋亡,抑制细胞增殖,抑制HIV复制与逆转录酶,在抗肿瘤和抗艾滋病等方面显示出有独特的作用,受到了广泛关注。[Cancer Treatment Reviews,2009,35,57]但是黄芩黄酮不溶于水,容易被氧化,血药浓度较低,活性强度达不到临床需要。因此,本发明希望通过对黄芩黄酮进行结构修饰来寻找新型高效低毒的ATP选择性Cdks抑制剂。
有关黄酮衍生物US-A-5849733公开了Flavopiridol的硫代和氧代衍生物作为Cdks抑制剂用于治疗增生疾病CN16686131A(W02004/004632)公开了作为Cdks抑制剂的黄酮衍生物。US-A-5116954公开了具有抗肿瘤和免疫调节活性的黄酮类化合物。CN1990481公开了一种黄芩素衍生物及其制法与用途。CN1427003A公开了具有抑制蛋白激酶C活性的黄芩素8-位取代的甲胺类衍生物及其制备方法。上述专利并未提到本发明所涉及的黄芩黄酮有机胺衍生物,以及作为Cdks抑制剂的用途。
发明内容
本发明希望通过对黄芩黄酮结构修饰来寻找新型高效低毒的选择性Cdks抑制剂。本发明的目的是:提供用黄芩黄酮为先导化合物黄芩素和黄芩素与甲醛和有机仲胺类化合物缩合成黄芩黄酮有机胺衍生物的制备方法;黄芩黄酮有机胺衍生物与酸成盐,并与药学上可以接受的辅料配合制成口服或注射等有利应用的剂型;使其成为抑制Cdks活性,抑制肿瘤生长并诱导肿瘤细胞凋亡,以及在预防和治疗癌症和艾滋病方面等有效药物。
本发明的目标化合物黄芩黄酮有机胺衍生物为:
其中:R6为OH时,R8为哌嗪亚甲基,甲基哌嗪亚甲基,哌嗪乙醇亚甲基,哌嗪乙硫醇亚甲基,哌啶醇亚甲基,哌啶酮亚甲基,羟甲基吡咯烷亚甲基,吡咯烷醇亚甲基或二乙醇胺亚甲基;R8为OCH3时,R6为哌嗪亚甲基,甲基哌嗪亚甲基,哌嗪乙醇亚甲基,哌嗪乙硫醇亚甲基,哌啶醇亚甲基,哌啶酮亚甲基,羟甲基吡咯烷亚甲基,吡咯烷醇亚甲基,二乙醇胺亚甲基,二甲胺亚甲基,吡咯烷亚甲基,哌啶亚甲基,吗啉亚甲基或硫吗啉亚甲基。
以上所述黄芩黄酮有机胺衍生物中,以如下结构的化合物效果较好:以R6为OH时,R8为哌啶醇亚甲基,哌嗪乙醇亚甲基,哌嗪乙硫醇亚甲基,甲基哌嗪亚甲基,吡咯烷醇亚甲基、二乙醇胺亚甲基中的一种;或/和R8为OCH3时,R6为哌嗪乙醇亚甲基,哌啶醇亚甲基,甲基哌嗪亚甲基,吡咯烷醇亚甲基,二乙醇胺亚甲基中的一种。特别是在R6为OH时,R8为哌啶醇亚甲基,吡咯醇亚甲基或哌嗪乙醇亚甲基;R8为OCH3时,R6为哌嗪乙醇亚甲基,哌啶醇亚甲基,吡咯烷醇亚甲基或二乙醇胺亚甲基时效果更好。
本发明解决其技术问题所采用的技术方案是:黄芩黄酮有机胺衍生物的制备原理:中药黄芩中主要含有黄芩苷和汉黄芩苷,以及黄芩素和汉黄芩素等黄芩黄酮,经酶水解后,分离提纯可得到黄芩素和汉黄芩素。利用黄芩素在C8或汉黄芩素C6位与甲醛和有机胺发生Mannich反应,可合成出高纯度黄芩黄酮有机胺系列衍生物:
黄芩黄酮有机胺衍生物的制备方法,以黄芩黄酮先导化合物黄芩素或汉黄芩素与甲醛溶液和有机胺类化合物反应而成;其原料摩尔配比为:黄芩素或汉黄芩素∶甲醛溶液∶有机胺类化合物=1∶1-1.2∶1-1.2;
工艺步骤为:将黄芩素或汉黄芩素,与甲醛溶液和有机胺类化合物按比例在反应容器中混合均匀,加入为黄芩素或汉黄芩素质量10-40倍的甲醇,在50-70℃下搅拌缩合1-6h;过滤,用黄芩素或汉黄芩素质量1-20倍的甲醇洗涤沉淀,甲醇洗涤沉淀,干燥,得含量不少于98%(重量)的黄芩黄酮有机胺衍生物。
当黄芩黄酮先导化合物选自黄芩素时,所述有机胺类化合物选自哌嗪,甲基哌嗪,哌嗪乙醇,哌嗪乙硫醇,哌啶醇,哌啶酮,羟甲基吡咯烷,吡咯烷醇,二乙醇胺;当黄芩黄酮导化合物选自汉黄芩素时,所述有机胺类化合物选自哌嗪,甲基哌嗪,哌嗪乙醇,哌嗪乙硫醇,哌啶酮,羟甲基吡咯烷,吡咯烷醇,二乙醇胺,二甲胺,吡咯烷,哌啶,吗啉,硫吗啉。
黄芩素衍生物对Cdk1/Cyclin B抑制作用筛选:该筛选生化分析技术是基于酶对磷酸化和非磷酸化底物水解的灵敏性不同的一种荧光共振能量转移技术(Fluorescence resonance energy transfer FRET)。测定采用一种合成的缩氨酸底物,这种底物是由带有荧光供体香豆素和受体荧光素共同组成的FRET。在初级反应中,蛋白激酶将ATP的γ磷酸基转移到一个丝氨酸或者苏氨酸残余羟基上,然而当蛋白激酶抑制剂存在时,磷酸化受阻。在接下来的反应中,加入一种定点切断酶,淬灭了蛋白激酶反应,这种定点切断酶能定点识别和切断未被磷酸化的底物。没有磷酸化的底物FRET系统被断开,而磷酸化底物依然维持FRET。断开的和没有断开的底物在400nm波长激发,分别在445nm和520nm波长有发射波长,计算发射比,如果底物被磷酸化后发射比会比较低表明很少或者没有蛋白激酶的抑制作用,发射比高则表明底物没有被磷酸化从而具有蛋白激酶的抑制作用。
将待测黄芩黄酮有机胺衍生物用二甲基亚砜溶解,制成每1ml含1mg的溶液,再依次用4%二甲基亚砜和蛋白激酶缓冲液稀释成8个不同浓度,Cdk1/Cyclin B抑制活性按Invitrogen公司蛋白激酶分析试剂盒操作方法测定。黄芩黄酮有机胺衍生物最终反应液浓度控制在0.01-25μM之间,ATP为10μM,Cdk1/Cyclin B酶活力控制在空白磷酸化率20-50%之间,对Cdk1/Cyclin B抑制作用筛选结果见表1。结果显示:黄芩苷对Cdk1/Cyclin B活性显示有轻度抑制作用。当被水解为黄芩素时,活性比黄芩苷提高约9倍。黄芩素C8单胺亚甲基衍生物活性比黄芩素提高约2倍。含有2个以上杂原子新结构类型化合物黄酮有机胺衍生物活性比黄芩素提高了约5-7倍,比黄芩苷提高了约50多倍,作用机理和作用强度与Flavopiridol相近(IC50为0.30μM),为选择性ATP结合位点Cdks抑制剂,而有别于非选择性Cdks毒剂星孢菌素。其中,8-N-甲基哌嗪亚甲基黄芩素对Cdk1/Cyclin B活性抑制作用测定结果曲线见图1。研究果显示部分黄芩黄酮有机胺衍生物具有较强的抑制Cdk1/Cyclin B活性作用,在预防和治疗癌症和艾滋病方面具有良好应用前景。
构效关系推论:
(1)C8位含氮取代基的存在与位置对Cdk1/Cyclin B的抑制活性起到了至关重要的作用,且随着杂原子数目增多以及脂水分配系数降低,活性增强。这是由于N原子占据了Cdk1/Cyclin B的ATP结合口袋中氨基位的原因。
(2)C4=O,C5=-OH,C7=-OH是必需基团,酚羟基的缺失以及甲基化都会影响到抑制活性,增加C6=-OH,活性增强,这是由于该组酸性基团占据了Cdk1/Cyclin B的ATP结合口袋中磷酸位的缘故。
(3)C2位为疏水取代基团是必须的,再引入卤素等疏水性基团,活性增加,而羟基等亲水基团的引入,可使活性消失。这种脂溶性基团是ATP所不具有的,它可能与Cdk1/Cyclin B的疏水性口袋融合,导致其构型发生明显的改变。
黄芩黄酮有机胺衍生物成药性筛选:黄芩黄酮有机胺衍生物成药性主要包括脂水分配系数,PBS(pH7.4)溶解度,蛋白结合率,家兔体内消除相半衰期,平均稳态血浆浓度等。结果见表1,仅就目前检测结果而言黄芩素哌啶醇、黄芩素羟哌嗪和汉黄芩素羟哌嗪和表现出良好的成药性,其中平均稳态血浆浓度比先导化合物黄芩素提高了约1000-3000倍,比对照药Flavopiridol提高了约100-300倍。此外,黄芩素吡咯醇和汉黄芩素二乙醇胺也有一定的应用前景,其黄芩黄酮有机胺衍生物成药性的筛选正在进行之中。
表1.黄芩黄酮有机胺衍生物成药性筛选
黄芩黄酮及其有机碱衍生物 | CyclinB/Cdk1IC50(μM) | MCT-7GI50(μM) | MCF-7LC50(μM) | 蛋白结合率(%) | PBSpH7.4中溶解度(μM) | 稳态血浆浓度(μM) | 消除相半衰期(h) |
黄芩素苷 | 18.15 | ||||||
黄芩素 | 2.08 | 0.026 | 5.26 | ||||
黄芩素二甲胺 | 1.05 | 12.33 | 37.07 | ||||
黄芩素吡咯烷 | 1.22 | 10.33 | 34.53 | ||||
黄芩素哌啶 | 1.28 | 10.50 | 37.17 | ||||
黄芩素吗啉 | 0.30 | 10.13 | 48.90 | ||||
黄芩素硫吗啉 | 0.38 | 14.17 | 84.33 | ||||
黄芩素哌嗪 | 0.28 | 13.80 | 53.10 | 166 | |||
黄芩素甲哌嗪 | 0.29 | 10.90 | 37.23 | 98 | 6.02 | ||
黄芩素哌啶醇 | 0.30 | 10.21 | 40.05 | 91 | 377 | 28.7 | 4.23 |
黄芩素羟哌嗪 | 0.28 | 13.1 | 42.10 | 96 | 607 | 31.6 | 3.75 |
黄芩素吡咯醇 | 0.29 | ||||||
6-甲氧基黄芩素甲哌嗪 | 0.88 | 26.10 | >100 | ||||
汉黄芩素 | 3.50 | ||||||
汉黄芩素二甲胺 | 7.63 | ||||||
汉黄芩素吡咯烷 | 17.21 | ||||||
汉黄芩素哌啶 | 10.50 |
汉黄芩素吗啉 | >25 | ||||||
汉黄芩素硫吗啉 | 3.17 | ||||||
汉黄芩素哌嗪 | 6.62 | ||||||
汉黄芩素甲哌嗪 | >25 | ||||||
汉黄芩素哌啶醇 | 6.91 | ||||||
汉黄芩素羟哌嗪 | 0.32 | 11.1 | 43.10 | 9390 | 94.0 | 4.00 | |
汉黄芩素二乙醇胺 | 0.31 | ||||||
Flavopiridol | 0.30 | 0.048 | 35.90 | 0.271 | 3.60 | ||
P276-00 | 0.79 |
(注:空格为尚未检测)
黄芩素甲哌嗪抑制人癌细胞生长并诱导凋亡作用:黄芩素甲哌嗪对人宫颈癌Hela、人乳腺癌MCF-7、人胃癌BGC823细胞株在24、48、72h MTT法测定半数抑制浓度IC50,以及在IC50浓度下,作用于癌细胞48h后,用AnnexinV-PI双染检测流式细胞仪分析早期凋亡细胞的比例,晚期凋亡细胞和坏死细胞比例,测定结果见表2。结果表明:黄芩素甲哌嗪具有较强的抑制癌细胞生长和诱导凋亡作用,其中诱导早期癌细胞凋亡比例远大于晚期,其中Cdks抑制是诱导凋亡的关键机制,在医疗上可用于制备抗癌药物。
表2.黄芩素甲哌嗪对人癌细胞生长抑制与诱导凋亡
IC50(μM) | HeLa | MCF-7 | BGC823 |
24h | 12.8±0.20 | 13.7±0.21 | 9.6±0.21 |
48h | 8.2±0.15 | 10.6±0.17 | 7.2±0.23 |
72h | 6.7±0.24 | 7.4±0.25 | 6.5±0.19 |
早期凋亡细胞(%) | 67.3 | 72.3 | 69.2 |
晚期凋亡和坏死细胞(%) | 27.1 | 23.1 | 22.2 |
黄芩黄酮有机胺衍生物体外抗癌活性筛选:黄芩素甲哌嗪、黄芩素羟哌嗪、黄芩素哌啶醇、以及黄芩素甲哌嗪的代谢物6-甲氧基黄芩素甲哌嗪对人前列腺PC3、人乳腺癌MCF-7、人胃癌BGC823细胞株在48h体外抗癌活性测定结果见表3。与NCI合作研究结果:10μM黄芩素甲哌嗪、黄芩素羟哌嗪和黄芩素哌啶醇对人58种人肿瘤细胞体外48h生长抑制率分别为50.0%,46.2%,40.6%;但是(100μM)对2种正常人胚胎肺纤维细胞WI-38以及HLF体外48h生长率与空白对照组基本一致,无明显差异。结果表明:黄芩素甲哌嗪、黄芩素羟哌嗪和黄芩素哌啶醇具有明显的抗癌活性,对正常组织细胞几乎无影响,黄芩素甲哌嗪的代谢物6-甲氧基黄芩素甲哌嗪活性减弱。
表3.黄芩黄酮有机胺衍生物体外抗癌活性
Cancer μM | 黄芩素甲哌嗪 | 黄芩素羟哌嗪 | 黄芩素哌啶醇 | 6-甲氧基黄芩素甲哌嗪 |
PC-3 IC50GI50TGILC50 | 21.18.219.838.8 | 11.66.215.436.6 | 18.16.016.441.0 | 87.611.276.1 |
BGC-823 IC50GI50TGILC50 | 23.16.419.862.7 | 19.36.115.451.0 | 18.65.716.453.1 | 114.726.2 |
MCF-7 IC50GI50TGILC50 | 19.36.416.431.3 | 20.46.015.432.6 | 20.16.016.431.0 |
黄芩黄酮有机胺衍生物对T淋巴祖细胞分化的影响:10μM汉黄芩素羟哌嗪和黄芩素哌啶醇对CD3单克隆抗体捕获的淋巴T祖细胞体外在生长因子IL-3和IL-5等诱导下分化为T细胞48h生长抑制率测定结果分别为55.0%和46.2%。结果表明:汉黄芩素羟哌嗪和黄芩素哌啶醇可诱导CD3阳性T淋巴细胞凋亡,预测也可诱导HIV病毒感染的CD3阳性T淋巴细胞凋亡,其中Cdks抑制是这种诱导凋亡的关键机制,显示出对艾滋病的良好应用前景,在医疗上可用于制备抗艾滋病药物。
黄芩素甲哌嗪家兔体内主要代谢过程:高效液相-质谱-紫外光谱(LC-MSn)检测结果表明:黄芩素甲哌嗪进入家兔体内后,迅速分布到各组织,蛋白结合率为98%,呈现浓度非依赖性。主要代谢途:(1)首先6位羟基被葡萄糖醛酸化为8-N-甲基哌嗪亚甲基异黄芩苷;(2)进入组织的药物6位羟基被甲基化为6-甲氧基-8-N-甲基哌嗪亚甲基黄芩素,然后进入肝脏后7羟基再被葡萄糖醛酸化为6-甲氧基-8-N-甲基哌嗪亚甲基黄芩苷;(3)进入组织的药物经历了水解,重排为4`,5,6,7-四羟基-8-氨甲基查耳酮,在分子内schiff化重排为代谢物m/z=179。代谢产物主要由尿液排除体外。代谢物6-甲氧基-8-N-甲基哌嗪亚甲基黄芩素(即6-甲氧黄芩素甲哌嗪)抑制Cdk1/Cyclin B活性和抗肿瘤活性均降低(结果见表1)。
高纯度黄芩黄酮有机胺系列衍生物,黄芩黄酮有机胺系列衍生物可与药学上可接受的有机酸或无机酸成盐,制成注射用黄芩黄酮有机胺酸盐,制成口服制剂或注射剂用于癌症和艾滋病的治疗,如注射用黄芩黄酮有机胺甲磺酸盐或注射用黄芩黄酮有机胺磷酸盐等。
与现有技术相比,本发明突出的优点在于:本发明提供了一种细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物及其制法,该衍生物是从中药黄芩中提取分离得到的黄芩黄酮为先导化合物与甲醛和有机仲胺类化合物缩合制得的。成药性初步研究表明本发明的黄芩黄酮有机胺衍生物对细胞周期素依赖蛋白激酶抑制强度与Flavopiridol和P276-00类似,比黄芩苷提高约50多倍,能选择性诱导增殖期肿瘤细胞凋亡,诱导CD3阳性T淋巴细胞凋亡,而对正常组织几乎无影响,属于新型细胞周期抑制剂类抗肿瘤药物。本发明原料来源丰富,工艺简捷,纯度高,成本低,代谢机理明确,高效低毒,与酸成盐可制成口服制剂或注射剂,有望成为新型高效低毒的周期素依赖蛋白激酶抑制剂类抗癌和艾滋病药物。
附图说明
图1:黄芩素甲哌嗪(8-N-甲基哌嗪亚甲基黄芩素)对Cdk1/CyclinB活性抑制测定曲线,横坐标为8-N-甲基哌嗪亚甲基黄芩素浓度(nM),纵坐标为对Cdk1/Cyclin B活性抑制率(%)。
下面结合实施例对本发明作进一步的说明。
具体实施方式
实施例1
黄芩素甲哌嗪[8-N-甲基哌嗪亚甲基黄芩素;5,6,7-三羟基-8-N-甲基哌嗪亚甲基-黄酮;5,6,7-trihydroxy-8-((4-methylpiperazin-1-yl)methyl)-2-phenyl-4H-chromen-4-one]的制备:
取黄芩素100g,加入甲醇2L,甲基哌嗪45g,37%甲醛溶液36.5ml,在55℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,干燥,得到浅黄色固体113g,含量为99.9%。m.p.:280~282℃;UV:λmax(乙醇)278,330nm;MS:(API-ES)m/z 383.1[M+H]+,405.1[M+Na]+;IR:3400,3050,2925,2861,1637,1570,1509cm-1;1H NMR(DMSO-d6/CF3COOD,400MHz):δ2.14(s,3H,CH3),2.62(s,8H,N-CH2),3.96(s,2H,8-CH2),6.87(s,1H,3-H),7.46-7.54(m,3H,Ar-H),8.01-8.02(m,2H,Ar-H),8.11(s,6-OH),12.64(s,1H,5-OH)。
实施例2
黄芩素羟哌嗪[8-N-羟乙哌嗪亚甲基黄芩素;5,6,7-三羟基-8-N-羟乙基哌嗪亚甲基-黄酮;5,6,7-trihydroxy-8-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-2-phenyl-4H-chromen-4-one]的制备:
称取黄芩素27g,加入甲醇350ml,羟乙基哌嗪13.1g,37%的甲醛溶液8.04ml,51℃加热搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,抽干,55℃减压干燥,得黄色粉末40.3g,含量为98.5%,m.p.:192℃。MS:(API-ES)m/z 413.3[M+H]+,825.5[2M+H]+,847.5[2M+Na]+;1H NMR(DMSO-d 6/CF3COOD,400MHz):δ8.18-8.19(m,2H,Ar-2′,6′-H),7.61-7.67(m,3H,Ar-3′,4′,5′-H),7.09(s,1H,3-H),4.73(s,2H,CH2),3.76(t,2H,-CH2-OH),3.59-3.69(m,8H,CH2),3.33(t,2H,N-CH2)。
实施例3
黄芩素哌啶醇[8-羟基哌啶亚甲基黄芩素;5,6,7-三羟基-8-(4-羟基哌啶)亚甲基-黄酮;5,6,7-trihydroxy-8-((4-hydroxypiperidin-1-yl)methyl)-2-phenyl-4H-chromen-4-one]及其甲磺酸盐的制备:
称取黄芩素27g,加入甲醇350ml,哌啶醇(4)10.2g,37%的甲醛溶液8.04ml,51℃加热搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,抽干,55℃减压干燥,得黄色粉末37.02g,含量为99.2%,m.p.:221℃。MS:(API-ES)m/z 384.2[M+H]+,767.5[2M+H]+,789.5[2M+Na]+;1H NMR(DMSO-d 6,400MHz):δ8.05-8.07(m,2H,Ar-2′,6′-H),7.58-7.59(m,3H,Ar-3′,4′,5′-H),6.87(s,1H,3-H),4.17(s,2H,CH2),3.67(m,1H,CH),2.68,3.03(m,2H,CH2),2.71,3.05(m,2H,CH2),1.52,1.82(m,2H,CH2),1.53,1.84(m,2H,CH2)。
称取黄芩素哌啶醇11.00g,加入无水乙醇100ml,室温搅拌均匀,加入甲磺酸3.07g,搅拌,将析出的沉淀滤出,用少量无水乙醇洗涤,65℃减压干燥,即得黄芩素哌啶醇甲磺酸盐浅黄色粉末13.40g,m.p.:243℃。
实施例4
黄芩素吡咯醇[8-羟基吡咯烷亚甲基黄芩素;5,6,7-三羟基-8-(3-羟基吡咯烷)亚甲基-黄酮;5,6,7-trihydroxy-8-((3-hydroxypyrrolidin-1-yl)methyl)-2-phenyl-4H-chromen-4-on]的制备:
黄芩素27g,加入甲醇350ml,3-吡咯烷醇8.8g,37%的甲醛溶液8.04ml,在50℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到浅黄色固体36.0g,含量为99.0%。MS:(API-ES)m/z 370.1[M+H]+,739.2[2M+H]+,761.2[2M+Na]+;1H NMR(DMSO-d 6,400MHz):δ8.05-8.07(m,2H,Ar-2′,6′-H),7.58-7.59(m,3H,Ar-3′,4′,5′-H),6.87(s,1H,3-H),4.17(s,2H,CH2),3.32(m,1H,CH),2.28,2.53(m,2H,CH2),2.20,2.30(m,2H,CH2),1.81,1.62(m,2H,CH2)。
实施例5
汉黄芩素甲哌嗪[6-N-甲基哌嗪亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-N-甲基哌嗪亚甲基-黄酮;6-((4-methylpiperazin-1-yl)methyl)-5,7-dihydroxy-8-methoxy--2-phenyl-4H-chromen-4-one]的制备:
取汉黄芩素28.4g,加入甲醇350ml,甲基哌嗪10.1g,37%甲醛溶液8.04ml,在51℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,干燥,得到橙红色固体38.6g,含量为99.7%,m.p.:179℃。MS:(API-ES)m/z 397.5[M+H]+,419.5[M+Na]+;1H NMR(DMSO-d 6/CF3COOD,400MHz):δ8.12-8.14(m,2H,Ar-2′,6′-H),7.64-7.66(m,3H,Ar-3′,4′,5′-H),7.15(s,1H,3-H),4.44(s,2H,CH2),3.96(s,3H,8-OCH3),3.43-3.74(m,8H,CH2),2.93(s,3H,N-CH3)。
实施例6
汉黄芩素羟哌嗪[6-N-羟乙基哌嗪亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-N-羟乙基哌嗪亚甲基-黄酮;6-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-5,7-dihydroxy-8-methoxy-2-phenyl-4H-chromen-4-one]的制备:
汉黄芩素28.4g,加入甲醇350ml,羟乙基哌嗪13.1g,37%甲醛溶液100ml,在50℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到浅黄色固体41.7g,含量为99.5%。MS:(API-ES)m/z 427.5[M+H]+,449.5[M+Na]+;1H NMR(DMSO-d 6/CF3COOD,400MHz):δ8.11-8.13(m,2H,Ar-2′,6′-H),7.62-7.67(m,3H,Ar-3′,4′,5′-H),7.11(s,1H,3-H),4.45(s,2H,CH2),3.98(s,3H,8-OCH3),3.78(t,2H,-CH2-OH),3.49-3.69(m,8H,CH2),3.36(t,2H,N-CH2)。
实施例7
汉黄芩素哌啶醇[6-羟基哌啶亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-(4-羟基哌啶)亚甲基-黄酮;5,7-dihydroxy-6-((4-hydroxypiperidin-1-yl)methyl)-8-methoxy-2-phenyl-4H-chromen-4-one]的制备:
取汉黄芩素28.4g,加入甲醇350ml,哌啶醇(4)10.2g,37%的甲醛溶液8.04ml,在50℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到橙红色固体38.5g,含量为99.4%。MS:(API-ES)m/z 398.5[M+H]+,420.5[M+Na]+;1H NMR(DMSO-d 6,400MHz):δ8.05-8.06(m,2H,Ar-2′,6′-H),7.60-7.61(m,3H,Ar-3′,4′,5′-H),6.90(s,1H,3-H),3.94(s,2H,CH2),3.83(s,3H,8-OCH3),3.65-3.67(m,1H,CH),2.62,2.98(m,4H,CH2),1.51,1.83(m,4H,CH2)。
实施例8
汉黄芩素二乙醇胺[6-二乙醇胺亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-二乙醇胺亚甲基-黄酮;6-((bis(2-hydroxyethyl)amino)methyl)-5,7-dihydroxy-8-methoxy-2-phenyl-4H-chromen-4-one]的制备:
汉黄芩素28.4g,加入甲醇350ml,二乙醇胺10.5g,37%的甲醛溶液8.04ml,在55℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到浅黄色固体39.3g,含量为99.2%。MS:(API-ES)m/z 402.4[M+H]+,424.4[M+Na]+;1H NMR(DMSO-d 6,400MHz):δ8.05-8.06(m,2H,Ar-2′,6′-H),7.60-7.61(m,3H,Ar-3′,4′,5′-H),6.90(s,1H,3-H),3.94(s,2H,CH2),3.83(s,3H,8-OCH3),3.63(m,4H,O-CH2),2.55(m,4H,N-CH2)。
实施例9
汉黄芩素二甲胺[6-二甲胺亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-二甲胺亚甲基-黄酮;6-((dimethylamino)methyl)-5,7-dihydroxy-8-methoxy-2-phenyl-4H-chromen-4-one]的制备:
取汉黄芩素28.4g,加入甲醇350mL,33%的二甲胺溶液13.6g,37%的甲醛溶液8.1g,在55℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到浅黄色固体32.7g,含量为99.3%。MS:API-ES)m/z 342.5[M+H]+;1H NMR(DMSO-d6,400MHz)δ:8.03-8.04(m,2H,Ar-2′,6′-H),7.59-7.60(m,3H,Ar-3′,4′,5′-H),6.81(s,1H,3-H),3.97(s,2H,CH2),3.82(s,3H,8-OCH3),2.56(s,6H,CH3)。
实施例10
汉黄芩素吡咯烷[6-吡咯烷亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-吡咯烷亚甲基-黄酮;5,7-dihydroxy-8-methoxy-2-phenyl-6-(pyrrolidin-1-ylmethyl)-4H-chromen-4-one]的制备:
取汉黄芩素28.4g,加入甲醇350mL,吡咯烷7.1g,37%的甲醛溶液8.1g,在55℃下搅拌4.5h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到橙红色固体35.4g,含量为99.1%。MS:(API-ES)m/z 368.5[M+H]+,390.5[M+Na]+;1H NMR(DMSO-d6,400MHz)δ:8.03-8.04(m,2H,Ar-2′,6′-H),7.59-7.60(m,3H,Ar-3′,4′,5′-H),6.79(s,1H,3-H),4.09(s,2H,CH2),3.81(s,3H,8-OCH3),3.03(s,4H,CH2),1.90(s,4H,CH2).
实施例11
汉黄芩素哌嗪[6-哌嗪亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-哌嗪亚甲基-黄酮;5,7-dihydroxy-8-methoxy-2-phenyl-6-(piperazin-1-ylmethyl)-4H-chromen-4-one]的制备:
取汉黄芩素28.4g,加入甲醇350mL,哌嗪8.6g,37%的甲醛溶液8.1g,在55℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到浅黄色固体36.1g,含量为99.1%。MS:(API-ES)m/z383.5[M+H]+;1H NMR(DMSO-d6,400MHz)δ:8.13-8.14(m,2H,Ar-2′,6′-H),7.64-7.66(m,3H,Ar-3′,4′,5′-H),7.14(s,1H,3-H),4.43(s,2H,CH2),3.98(s,3H,8-OCH3),3.36(s,4H,CH2),3.56(s,4H,CH2),1.25(s,1H,NH)。
实施例12
汉黄芩素吗啉[6-吗啉亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-吗啉亚甲基黄酮;5,7-dihydroxy-8-methoxy-6-(morpholinomethyl)-2-phenyl-4H-chromen-4-one]的制备:
取汉黄芩素28.4g,加入甲醇350mL,吗啉8.7g,37%的甲醛溶液8.1g,在55℃下搅拌4h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到浅黄色固体36.3g,含量为99.1%。MS:API-ES)m/z384.5[M+H]+,406.5[M+Na]+;1H NMR(DMSO-d6,400MHz)δ:8.07-8.08(m,2H,Ar-2′,6′-H),7.61-7.63(m,3H,Ar-3′,4′,5′-H),7.00(s,1H,3-H),3.87(s,3H,8-OCH3),3.82(s,2H,CH2),3.65(s,4H,CH2),2.60(s,4H,CH2)。
实施例13
汉黄芩素硫吗啉[6-硫吗啉亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-硫代吗啉亚甲基-黄酮;5,7-dihydroxy-8-methoxy-2-phenyl-6-(thiomorpholinomethyl)-4H-chromen-4-one]的制备:
取汉黄芩素28.4g,加入甲醇350mL,硫吗啉10.3g,37%的甲醛溶液8.1g,在55℃下搅拌4.5h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到浅黄色固体37.6g,含量为99.2%。MS:(API-ES)m/z 400.5[M+H]+,422.5[M+Na]+;1H NMR(DMSO-d6,400MHz)δ:8.06-8.08(m,2H,Ar-2′,6′-H),7.61-7.63(m,3H,Ar-3′,4′,5′-H),6.99(s,1H,3-H),3.87(s,3H,8-OCH3),3.84(s,2H,CH2),2.86(s,4H,CH2),2.71(s,4H,CH2)。
实例14
汉黄芩素哌啶[6-哌啶亚甲基汉黄芩素;5,7-二羟基-8-甲氧基-6-哌啶亚甲基-黄酮;5,7-dihydroxy-8-methoxy -2-phenyl-6-(piperidin-1-ylmethyl)-4H-chromen-4-one]的制备:
取汉黄芩素28.4g,加入甲醇350mL,哌啶8.5g,37%的甲醛溶液8.1g,在55℃下搅拌4.5h,将析出的沉淀滤出,用少量甲醇洗涤,65℃减压干燥,得到浅黄色固体35.3g,含量为99.2%。MS:API-ES)m/z382.5[M+H]+,404.5[M+Na]+;1H NMR(DMSO-d6,400MHz)δ:8.05-8.06(m,2H,Ar-2′,6′-H),7.60-7.61(m,3H,Ar-3′,4′,5′-H),6.89(s,1H,3-H),3.95(s,2H,CH2),3.83(s,3H,8-OCH3),2.79(s,4H,CH2),1.64(m,4H,CH2),1.50(m,2H,CH2)。
Claims (7)
2、根据权利要求1所述细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物,其特征在于在R6为OH时,R8为哌啶醇亚甲基,哌嗪乙醇亚甲基,哌嗪乙硫醇亚甲基,甲基哌嗪亚甲基,吡咯烷醇亚甲基,二乙醇胺亚甲基中的一种。
3、根据权利要求1所述细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物,其特征在于R8为OCH3时,R6为哌嗪乙醇亚甲基,哌啶醇亚甲基,甲基哌嗪亚甲基,吡咯烷醇亚甲基,二乙醇胺亚甲基中的一种。
4、根据权利要求1、2或3所述细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物,其特征在于在R6为OH时,R8为哌啶醇亚甲基,吡咯烷醇亚甲基,哌嗪乙醇亚甲基中的一种;R8为OCH3时,R6为哌嗪乙醇亚甲基,哌啶醇亚甲基,吡咯烷醇亚甲基,二乙醇胺亚甲基中的一种。
5、如权利要求1所述细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物的制备方法,其特征在于以黄芩黄酮先导化合物黄芩素或汉黄芩素,甲醛溶液和有机胺类化合物反应而成;其原料摩尔配比为:黄芩素或汉黄芩素∶甲醛溶液∶有机胺类化合物=1∶1-1.2∶1-1.2;工艺步骤为:将黄芩素或汉黄芩素,甲醛溶液和有机胺类化合物按比例在反应容器中混合均匀,加入为黄芩素或汉黄芩素质量10-40倍的甲醇,在50-70℃下搅拌缩合1-6h;过滤,用黄芩素或汉黄芩素质量1-20倍的甲醇洗涤沉淀,干燥,得含量不少于97%(重量)的黄芩黄酮有机胺衍生物。
6.根据权利要求5所述细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物的制备方法,其特征在于当黄芩黄酮先导化合物选自黄芩素时,所述有机胺类化合物选自哌嗪,甲基哌嗪,哌嗪乙醇,哌嗪乙硫醇,哌啶醇,哌啶酮,羟甲基吡咯烷,吡咯烷醇,二乙醇胺中的一种;当黄芩黄酮导化合物选自汉黄芩素时,所述有机胺类化合物选自哌嗪,甲基哌嗪,哌嗪乙醇,哌嗪乙硫醇,哌啶酮,羟甲基吡咯烷,吡咯烷醇,二乙醇胺,二甲胺,吡咯烷,哌啶,吗啉,硫吗啉中的一种。
7、如权利要求1细胞周期素依赖蛋白激酶抑制剂黄芩黄酮有机胺衍生物,在预防和治疗癌症和艾滋病的应用。
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CN110540566B (zh) * | 2019-08-08 | 2023-03-24 | 云南农业大学 | 紫云英苷衍生物及其应用 |
EP3909593A1 (en) | 2020-05-15 | 2021-11-17 | Rigshospitalet | Stem cells for treating skin lesions |
CN113549044B (zh) * | 2021-07-23 | 2024-01-23 | 中国药科大学 | 8-氮杂环取代色酮类衍生物及其制备方法与制药用途 |
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CN106117189B (zh) * | 2016-06-15 | 2019-02-01 | 张帆 | 乙酰基白杨素Mannich碱衍生物及其用途 |
CN114920755A (zh) * | 2022-02-07 | 2022-08-19 | 天津中医药大学 | 具有黄酮母核的化合物及其在制备cdk1抑制剂中的用途 |
CN114920755B (zh) * | 2022-02-07 | 2023-11-17 | 天津中医药大学 | 具有黄酮母核的化合物及其在制备cdk1抑制剂中的用途 |
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