CN104817568B - 5,6‑双脱氢去甲斑蝥醇衍生物及其抗肿瘤应用 - Google Patents
5,6‑双脱氢去甲斑蝥醇衍生物及其抗肿瘤应用 Download PDFInfo
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明提供了一种5,6‑双脱氢去甲斑蝥醇衍生物及其应用,其结构式如式I所示,;其中,R选自‑H或‑CH2COOH。活性测试证明,本发明设计并合成得到的5,6‑双脱氢去甲斑蝥醇衍生物I具有很好的抗肝癌效果,可望应用于临床作为斑蝥素类抗肿瘤药物。此外,本发明设计的新化合物的合成方法,原料易得,成本低廉,合成路线简单,收率也高,便于操作实施。
Description
技术领域
本发明属于新药设计与合成领域,具体涉及一类新型5,6-双脱氢去甲斑蝥醇衍生物及其抗肿瘤应用。
背景技术
斑蝥是一种昆虫,又称“放屁虫”,是我国传统中药材中的一种。我国是最早运用斑蝥作为药材的国家,在《本草纲目》、《神龙本草经》等医药名著里就曾有过关于斑蝥素入药的记载。
斑蝥素(cantharidin,C10H12O4)是一种从昆虫体内提取的比较有效果的抗癌物质,是民间治疗恶性肿瘤的有效成分,它与其他的抗肿瘤药物相比,有许多优点。比如:它和它的类似物不会抑制人体的免疫功能,另外,可提升人体白细胞等。它对肝癌,卵巢癌,食道癌等有良好的疗效,它是通过改变蛋白质的活性,抗肿瘤侵袭转移,引起细胞周期阻滞,抑制肿瘤生长,从而使得其死亡。其抗肿瘤的机制为通过减少癌细胞对氨基酸的摄取,抑制蛋白质的合成,刺激淋巴细胞、巨噬细胞、多形核细胞产生白细胞介素,从而提高机体免疫力,同时杀伤肿瘤细胞而达到治疗目的。
但斑蝥素对泌尿系统和肠胃系统有较大的毒副作用,斑蝥素既是抗肿瘤的活性成分,同时也是毒性的主要成分。对其进行恰当的结构修饰,会在保留其抗肿瘤活性的基础上,大大减低对机体的毒副作用,以去甲斑蝥素衍生物的合成为例。去甲斑蝥素不但保留了其较强的抗肿瘤活性和升高白细胞的作用,还消除了其对泌尿系统的副作用,后来,以去甲斑蝥素为先导化合物进行结构改造成为了研究的热点。这种优势在抗肿瘤药物中还是少见的,所以引起了广泛的关注,陆续合成了许多减少其毒副作用但同时又保留其活性的同类药物,开发更新高效低毒的衍生物是一个很好的研究方向。
对斑蝥素进行结构修饰后用于治疗癌症的衍生物近年来陆续的出现,并开始运用于临床治疗。如去甲斑蝥素,它比斑蝥素少了两个甲基,其毒性明显减低,而治疗作用却优于斑蟊素。
目前,斑蝥素和去甲斑蝥素都已经应用在临床中,这两个药物都各具有临床特点,但不足之处是:这两个药物的水溶性都较差,生物利用度不高。从化学结构中看出,斑蝥素和去甲斑蝥素的结构中均包含了分子内酸酐结构。而斑蝥酸即斑蝥素化合物的酸酐水解后得到的二元羧酸化合物;斑蝥酸还未被开发成为药物,仅仅是报道了其结构式。
此外,临床上还研究了斑蝥素钠,去甲斑蝥素钠,甲基斑蝥胺等,这些结构改造均将斑蝥素及去甲斑蝥素的内酸酐环打开,以开环方式存在,从化学结构上看;对应的开环化合物其相应的溶解度较大,其体内生物利用度也高。对斑蝥素的结构进行修饰,寻找高效低毒的斑蝥素抗肿瘤药物,具有重要的工业应用价值和广泛的市场前景。申请号为ZL201410163619.4、ZL201410163711.0、ZL201410163705.5的中国专利公开了制备去甲基斑蝥素酸盐的方法,迄今,尚未有报道设计并合成开环的5,6-双脱氢去甲斑蝥醇衍生物结构及合成方法。
发明内容
为解决现有技术的不足,本发明的目的在于提供一种新型5,6-双脱氢去甲斑蝥醇衍生物、其合成方法及其抗肿瘤应用。
为了实现上述目标,本发明采用如下的技术方案:
一方面,本发明提供了一种新型的5,6-双脱氢去甲斑蝥醇衍生物,其结构式如式I所示,
;
其中,R选自-H或-CH2COOH。
另一方面,本发明提供了如上所述的5,6-双脱氢去甲斑蝥醇衍生物I的合成方法,包括以下步骤:1)、以呋喃为原料,与顺丁烯二酸酐在有机溶剂中反应得到5,6-双脱氢去甲斑蝥素1,2)、5,6-双脱氢去甲斑蝥素在有机溶剂中经还原剂还原得到5,6-双脱氢去甲斑蝥素二醇2,3)、5,6-双脱氢去甲斑蝥素二醇2与溴乙酸乙酯反应在碱催化剂存在下反应得到5,6-双脱氢去甲斑蝥素氧代乙酸乙酯II,4)、步骤3)得到的酯在碱存在下水解生成相应的去甲斑蝥素蝥醇衍生物I;合成路线见以下:
其中,合成路线中,所述化合物II的取代基R’选自H或CH2COOH;所述化合物I的取代基R选自-H或-CH2COOH。
在上述合成路线中,有机溶剂可以依据反应对温度、溶剂极性的需求,从N,N-二甲基甲酰胺(缩写:DMF)、二甲基亚砜(缩写:DMSO)、二氯甲烷、氯仿、乙腈、四氢呋喃或乙醚中选择。
例如,在一种实施方式中,所述步骤1)采用的有机溶剂为醚类溶剂或卤代烃,例如:乙醚、丙醚、四氢呋喃、二氯甲烷、氯仿等。
在一种实施方式中,所述步骤2)采用的有机溶剂为醚类溶剂,例如:乙醚、丙醚、四氢呋喃等;所述还原剂选自硼氢化钠、硼氢化钾、硼氢化锂、四氢铝锂。
在一种实施方式中,所述步骤3)采用的有机溶剂为醚类溶剂等,例如:乙醚、丙醚、四氢呋喃、甲苯、乙腈等;所述碱催化剂选自如氢氧化钠、氢氧化钾等的碱金属氢氧化物或如钠氢的碱金属氢化物。
在一种实施方式中,所述步骤4)采用的有机溶剂为低级醇类溶剂、水或其混合溶剂等,例如:甲醇、乙醇、丙醇、水或其混合溶剂等;所述碱催化剂选自如氢氧化钠、氢氧化钾等的碱金属氢氧化物或者如三乙胺或吡啶的有机碱。
活性测试证明,本发明设计并合成得到的5,6-双脱氢去甲斑蝥醇衍生物I具有很好的抗肝癌效果。
因此,第三方面,本发明提供了5,6-双脱氢去甲斑蝥醇衍生物I用于制备抗肿瘤药物的用途;优选地,用于制备抗肝癌药物的用途。
本发明的有益之处在于:本发明提供的一类新型的5,6-双脱氢去甲斑蝥醇衍生物I,即5,6-双脱氢去甲斑蝥素氧代单乙酸Ia及双乙酸Ib,经活性测试证明该类衍生物具有良好的抗肝癌效果,可望应用于临床作为斑蝥素类抗肿瘤药物。此外,本发明设计的新化合物的合成方法,原料易得,成本低廉,合成路线简单,收率也高,便于操作实施。
具体实施方式
以下将通过具体实施例进一步阐述本发明,但并不用于限制本发明的保护范围。在不脱离本发明构思的前提下,本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进,这些改进也应视为本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
本发明中使用的呋喃,顺丁烯二酸酐,四氢铝锂(LiAlH4),NaH(60%),溴乙酸乙酯均来自上海国药集团。所用溶剂来自遵义双巨化工有限公司。除特别说明外,所用试剂均为化学纯。
前述的本发明的去甲斑蝥素蝥醇衍生物I的合成方法,具体包括以下步骤:
(1)取顺丁烯二酸酐,研细,加入有机溶剂溶解,待完全溶解后滴加呋喃,于35℃~45℃反应24h,抽滤,得白色固体产物5,6-双脱氢去甲斑蝥素,干燥备用;
(2)室温下,取步骤(1)中的白色固体产物,加入有机溶剂后溶解,冷却至0oC,再缓慢分批加入LiAlH4,搅拌反应过夜,反应结束后抽滤,用四氢呋喃和水洗涤充分,得澄清液体5,6-双脱氢去甲斑蝥素二醇,干燥备用;
(3)将5,6-双脱氢去甲斑蝥素二醇溶于有机溶剂中,冰水冷却至0oC下,先加入60%NaH,然后加入溴乙酸乙酯,再在搅拌下继续反应过夜后抽滤,旋干,剩余物经快速柱层析即得5,6-双脱氢去甲斑蝥素氧代乙酸乙酯II(备注:此步骤反应可以得到包括5,6-双脱氢去甲斑蝥素氧代单乙酸乙酯IIa及5,6-双脱氢去甲斑蝥素氧代双乙酸乙酯IIb在内的产物)。
(4)取5,6-双脱氢去甲斑蝥素氧代单乙酸乙酯及双乙酸乙酯分别悬浮于水中,在碱性条件下水解生成相应的5,6-双脱氢去甲斑蝥素氧代单乙酸Ia及5,6-双脱氢去甲斑蝥素氧代双乙酸Ib。
上述反应中,可以用色谱法、液质连用谱来监控反应进程。色谱法中,可适用薄层色谱TLC还可用气相色谱法或液相色谱法如HPLC代替等。
实施例1. 5,6-双脱氢去甲斑蝥素1的制备
从试剂瓶中取出一定量的顺丁烯二酸酐,置于干燥的研体中研细,再用电子天平称取研细的顺丁烯二酸酐12.021g,置于干燥的三口烧瓶中,塞上塞子,再加乙醚搅拌,在乙醚量为90 mL时顺丁烯二酸酐完全溶解。待顺丁烯二酸酐完全溶解后,用滴液漏斗缓慢加入13 mL呋喃,用时13分钟(分钟,也缩写为min)。控制温度在38℃开始反应。反应1小时(小时,也缩写为h)后溶液出现白色固体,且时间越长白色固体越多。反应至24h后抽滤,得白色固体的化合物1,即5,6-双脱氢去甲斑蝥素。干燥称重为17.459 g,收率85.75%。熔点:122~123℃,比移值Rf:0.52 (展开剂为石油醚∶乙酸乙酯=3∶1);1HNMR(CDCl3) :δ:3.18 (s,2H),5.47 (s,2H),6.58 (s,2H)。
上述实施例1中用于溶解顺丁烯二酸酐的有机溶剂除了乙醚外,还可用N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、乙腈、四氢呋喃中的任一种代替;所述反应温度可在35℃~45℃之间。
实施例2. 5,6-双脱氢去甲斑蝥素二醇2的制备:
称取已生成的化合物A 2.0g,于25ml洁净烧瓶中,加入25ml除水的THF,冰浴搅拌至溶液澄清。缓慢地分四批加入LiAlH4 (689mg),反应24h,点板。加乙酸乙酯,水淬灭反应,使反应稳定。抽滤,用乙酸乙酯,水反复滤洗三次,合并滤液并旋干,得5,6-双脱氢去甲斑蝥素二醇2的粗品2.05g。 收率>100% , Rf:0.21(展开剂为乙酸乙酯);1HNMR(CDCl3):δ: 6.38(s,2H),4.68 (s,2H),3.76-3.85 (m, 4H), 1.94 (t,2H)。
实施例3. 5,6-双脱氢去甲斑蝥素氧代单乙酸乙酯IIa及5,6-双脱氢去甲斑蝥素氧代双乙酸乙酯IIb的制备
将生成的化合物2粗品取1.3g置于50ml洁净的烧瓶中,加25ml除水的THF,冰浴搅拌,再加入60% NaH 513mg,最后加入BrCH2COOEt(1.4ml).反应24h,点板,抽滤,旋干,得粗品1.7g。将粗品利用柱色谱层析原理,用硅胶柱进行分离,得到化合物IIa和化合物IIb。其中,得到化合物IIa 0.45g,收率:45%,Rf: 0.67(展开剂为石油醚:乙酸乙酯 = 5:1);1HNMR(CDCl3)δ: 6.36-6.42(m, 2H), 4.76(t, 2H), 4.21-4.23(m, 2H), 4.12-4.19(m, 2H),3.76-3.85(m, 2H), 3.63-3.65(m, 2H), 1.93-2.08(m, 2H), 1.29(t,3H);
以及得化合物IIb 0.55g ,收率:40%,Rf:0.18(展开剂为乙酸乙酯);1HNMR(CDCl3)δ: 6.32(s, 2H), 4.89(s, 2H), 4.17(q, 4H), 4.04-4.06(m, 4H), 3.63-3.65(m, 2H),3.37(d, 2H), 1.92-1.96(m, 2H), 1.22(q, 6H)。
实施例4. 5,6-双脱氢去甲斑蝥素氧代单乙酸Ia及5,6-双脱氢去甲斑蝥素氧代双乙酸Ib的制备
取化合物IIa 0.45g ,于25ml洁净的烧瓶中,加入9 ml水,搅拌,再加入NaOH 148mg,反应 24h 。加10% HCl 调 PH 4-5,旋干。利用柱色谱层析原理,用硅胶柱分离得化合物Ia 0.31g, 收率:78%,Rf:0.25(展开剂为乙酸乙酯:乙醇=5:1);1HNMR(CDCl3)δ: 6.47 (s,2H), 4.76(s,2H),4.02-4.09 (m, 4H), 3.56-3.82(m, 6H), 1.88-2.01(m, 2H)。
同上操作:取化合物IIb 0.55g,于50ml 洁净的烧瓶中,加入19ml 水,搅拌,再加入NaOH 268 mg,反应 24h 。加10% HCl 调 pH 4-5,旋干。利用柱色谱层析原理,用硅胶柱分离得化合物Ib 0.28g, 收率:61%, Rf:0.13(展开剂为乙酸乙酯:乙醇=5:1);1HNMR(CDCl3)δ: 6.36-6.40(m, 2H), 4.77( s, 2H), 4.07-4.19(m, 2H), 3.66-3.86(m, 6H),1.94-2.07(m, 2H)。
实验例5. 去甲斑蝥素单酸甲酯的抗肝癌活性测试
采用磺酰罗丹明(sulforhodamine B,SRB)染色法
接种细胞时,每种细胞平行接种两块96孔板,一块为对照板(T0),另一块为实验板。CO2培养箱中培养20 h后,将对照板(T0)取出,用50%三氯乙酸(TCA)固定,待测。实验板中加入待测化合物(终浓度分别为5、2.5、1.25、0.625、0.313μg·mL-1),并设阴性对照组(C),实验组(T),溶剂对照组。每组设5个复孔,继续培养48h后取出培养板,以预冷50% TCA固定(终浓度为10%),于4 ℃冰箱放置1 h后,以去离子水冲洗,自然晾干,用100μL 0.4%的SRB染色,10min后用0.1%乙酸冲洗、晾干,最后用200 μL10mmol·L-1的缓冲Tris碱液(pH10.5)溶解,在酶标仪上选择530 nm处测吸光度值(OD值),按照下列公式计算生长抑制率(Inhibition ratio,IR)。
本试验按照SRB方法,以斑蟊素、斑蝥素钠为阳性对照,进行了5,6-双脱氢去甲斑蝥醇衍生物I对人肝癌细胞Hep G2 的抑制活性测试,结果如表1所示:
表1、5,6-双脱氢去甲斑蝥醇衍生物I的抗癌活性测试
由表1可知,5,6-双脱氢去甲斑蝥醇衍生物I对人肝癌细胞Hep G2具有一定的抑制效果,可将其用于制备抗肝癌的候选药物。
Claims (8)
1.一种5,6-双脱氢去甲斑蝥醇衍生物,其结构式如式I所示,
其中,R选自-H。
2.权利要求1所述的5,6-双脱氢去甲斑蝥醇衍生物I的合成方法,包括以下步骤:1)、以呋喃为原料,与顺丁烯二酸酐在有机溶剂中反应得到5,6-双脱氢去甲斑蝥素1,2)、5,6-双脱氢去甲斑蝥素在有机溶剂中经还原剂还原得到5,6-双脱氢去甲斑蝥素二醇2,3)、5,6-双脱氢去甲斑蝥素二醇2与溴乙酸乙酯反应在碱催化剂存在下反应得到5,6-双脱氢去甲斑蝥素氧代乙酸乙酯II,4)、步骤3)得到的酯在碱存在下水解生成相应的去甲斑蝥醇衍生物I;合成路线见以下:
其中,所述合成路线中,化合物II的取代基R’选自H;化合物I的取代基R选自-H。
3.根据权利要求2所述的合成方法,其中,所述步骤1)采用的有机溶剂选自乙醚、丙醚、四氢呋喃、二氯甲烷、氯仿。
4.根据权利要求2所述的合成方法,其中,所述步骤2)采用的有机溶剂选自乙醚、丙醚、四氢呋喃;所述还原剂选自硼氢化钠、硼氢化钾、硼氢化锂、四氢铝锂。
5.根据权利要求2所述的合成方法,其中,所述步骤3)采用的有机溶剂选自乙醚、丙醚、四氢呋喃、甲苯、乙腈;所述碱催化剂选自氢氧化钠、氢氧化钾或钠氢。
6.根据权利要求2所述的合成方法,其中,所述步骤4)采用的有机溶剂选自甲醇、乙醇、丙醇、水或其混合溶剂;所述碱催化剂选自氢氧化钠、氢氧化钾、三乙胺或吡啶。
7.式I所示的5,6-双脱氢去甲斑蝥醇衍生物用于制备抗肿瘤药物的用途,其中,式I中的R选自-H或-CH2COOH;
8.根据权利要求7所述的用途,其中,所述抗肿瘤药物为抗肝癌药物。
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