CN104744548B - 化合物3-o-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成及其作为抗肿瘤药物的应用 - Google Patents
化合物3-o-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成及其作为抗肿瘤药物的应用 Download PDFInfo
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Abstract
本发明公开了新化合物3‑O‑(2‑(5‑氟尿嘧啶‑1‑)乙酰)‑熊果酸的合成方法及其作为抗肿瘤药物的应用。该合成方法为将5‑氟尿嘧啶‑1‑基乙酸与熊果酸进行酯化反应即可获得3‑O‑(2‑(5‑氟尿嘧啶‑1‑)乙酰)‑熊果酸。该化合物对BEL‑7402和Hela癌细胞的生长具有很强的抑制作用。
Description
技术领域
本发明涉及化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成及其作为抗肿瘤药物的应用。
背景技术
1990年日本将熊果酸列为最有希望的癌化学预防药物之一。目前,国内外学者对熊果酸结构进行了各种修饰,并对其修饰物的毒理、药理、代谢等进行了研究,如在3位羟基、C12-C13位双键、28羧基和A环开环等分别进行或交叉进行结构修饰,得到的部分熊果酸衍生物的抗肿瘤活性提高了几十到几百倍。熊果酸通过多种机制发挥其抗肿瘤作用,具有多方面和全方位的特点,包括预防肿瘤形成,诱导肿瘤细胞分化和凋亡,抗氧化,抑制肿瘤血管新生,抑制肿瘤侵袭转移,增敏抗肿瘤化疗药物及逆转耐药,以及调节机体免疫功能等。但其机制没有达到细胞水平以及分子水平。
近几十年来,5-氟尿嘧啶(5-Fu)始终作为首选抗肿瘤代谢药物用于临床治疗食道癌、胃癌、结肠癌、卵巢癌、宫颈癌、肺癌和乳腺癌等多种癌症。尿嘧啶中的氢原子被氟原子取代后所得的5-Fu,由于氟的原子半径和氢相近,氟化物的体积与原化合物几乎相等,加之形成的C-F键特别稳定,在代谢过程中不易分解,能以分子形式参与正常代谢,可与胸腺嘧啶合成酶牢固结合,是该酶的有效抑制剂。5-Fu及其衍生物在体内首先转化为氟尿嘧啶脱氧核苷酸,然后与胸腺嘧啶合成酶结合,再与辅酶5,10-次甲基四氢叶酸作用。它能抑制胸腺嘧啶合成酶的作用,阻断脱氧嘧啶核苷酸转化成胸腺嘧啶核苷酸,干扰DNA的合成,从而抑制恶性肿瘤细胞的生长。但是由于5-Fu首过代谢明显,半衰期短,亲脂性弱,口服吸收不稳定,且治疗剂量和中毒剂量接近,因此对5-Fu进行结构修饰,延长5-Fu类药物在体内的滞留时间,增强其靶向性及选择性,最大限度地减小其毒副作用已经成为研究热点。
多年来国内外学者对5-Fu结构进行了各种修饰,并对其修饰物的毒理、药理、代谢等进行了研究,如在其结构上引入小分子的氨基酸、短肽、葡萄糖、甘油磷脂等加以修饰;将其与天然或合成的高分子键合,以达到药物缓释效果,延长药效;用卟啉类化合物修饰;与金属形成配合物;在其分子中引入稳定的氮氧自由基,等等。研究结果表明,对5-Fu的适当修饰可以克服其吸收性差的缺点,同时提高其选择性和生物利用度,减小其毒副作用。目前,国内外许多学者对熊果酸和5-氟尿嘧啶的结构修饰已经取得了较好的效果,但对熊果酸和5-氟尿嘧啶两者偶合的相关药物研究的报道很少。
发明内容
本发明的目的在于提供一种新化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
本发明的另一目的在于提供化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成方法。
本发明的再一目的在于提供化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸作为抗癌药物的应用。
本发明所采取的技术方案是:
化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸,其结构式为:
化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成方法包括以下步骤:将5-氟尿嘧啶-1-基乙酸与熊果酸进行酯化反应即可获得3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
进一步的,上述酯化反应过程中还加有催化剂和脱水剂,并对酯化反应产物进行纯化,即可获得3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
进一步的,上述酯化反应过程中,5-氟尿嘧啶-1-基乙酸与熊果酸的摩尔比为(0.8~1.2):(0.8~1.2)。
进一步的,上述催化剂为4-二甲氨基吡啶,所述的脱水剂为二环己基碳二亚胺。
进一步的,上述纯化的具体操作为:将反应产物中加入饱和食盐水,用乙酸乙酯萃取,再用饱和食盐水水洗有机相,洗后的有机相再经干燥、浓缩溶剂得白色混合物,白色混合物再过硅胶柱,淋洗收集目标组分,旋转蒸发,得到无色透明固体,即为3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
进一步的,上述淋洗过程中用到的淋洗剂为体积比为(2.5~3.5):1的石油醚和乙酸乙酯混合液。
化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸在制备治疗癌症药物中的应用。
进一步的,上述癌症为肝癌、宫颈癌。
本发明的有益效果是:
本发明提供了一种新的化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸及其合成方法,该化合物对BEL-7402和Hela癌细胞的生长具有很强的抑制作用,能作为这两种癌的治疗药物。
附图说明
图1为本发明化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸对Hela细胞及Bel-7402细胞抑制作用的量效关系曲线,横坐标表示浓度(μmol/L)。
具体实施方式
化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成方法,包括以下步骤:将5-氟尿嘧啶-1-基乙酸与熊果酸进行酯化反应即可获得3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
优选的,上述酯化反应过程中还加有催化剂和脱水剂,并对酯化反应产物进行纯化,即可获得3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
优选的,上述酯化反应过程中,5-氟尿嘧啶-1-基乙酸与熊果酸的摩尔比为(0.8~1.2):(0.8~1.2)。
优选的,上述催化剂为4-二甲氨基吡啶,所述的脱水剂为二环己基碳二亚胺。
优选的,上述酯化反应过程中,还用到了溶剂,所述溶剂为N,N-二甲基甲酰胺。
优选的,上述纯化的具体操作为:将反应产物中加入饱和食盐水,用乙酸乙酯萃取,再用饱和食盐水水洗有机相,洗后的有机相再经干燥、浓缩溶剂得白色混合物,白色混合物再过硅胶柱,淋洗收集目标组分,旋转蒸发,得到无色透明固体,即为3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
优选的,上述淋洗过程中用到的淋洗剂为体积比为(2.5~3.5):1的石油醚和乙酸乙酯混合液。
化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸在制备治疗癌症药物中的应用。
优选的,上述癌症为肝癌、宫颈癌。
下面结合具体实施例对本发明作进一步的说明,但并不局限于此。
实施例1:化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成方法
化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成路线如下所示:
结合上述合成路线进一步阐述3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的具体操作步骤:
1)5-氟尿嘧啶-1-基乙酸的合成
5-氟尿嘧啶-1-基乙酸的合成方法可参考“扈靖,刘彦钦,韩士田等,5-氟尿嘧啶-1-基乙酸合成方法的改进[J].化学试剂,2005,27(8),500;509”,将计量摩尔比为1:1.5的5-FU(5-氟尿嘧啶)和溴乙酸溶液加入KOH溶液中,在50℃下反应完全后,冷却至室温,用浓盐酸调节pH至5.5,放于冰箱中冷藏2h,滤除沉淀物,再加浓盐酸将溶液pH值调至2,放于冰箱中冷冻6h,过滤,得到固体物质,即为5-氟尿嘧啶-1-基乙酸,所得产率为72%。
2)3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成
在5mL 5-氟尿嘧啶-1-基乙酸的DMF溶液(0.2mol/L)中加入10mg 4-二甲氨基吡啶(DMAP),搅拌溶解后,加入10mL熊果酸的DMF溶液(0.1mol/L),搅拌10min,将5mL脱水剂二环己基碳二亚胺(DCC)的DMF溶液(0.2mol/L)缓慢滴入其中,室温反应4小时后,TLC(薄层色谱法)检测反应完后将反应液加入到5倍量的饱和食盐水中,用乙酸乙酯萃取,饱和食盐水水洗有机相,无水硫酸镁干燥有机相,浓缩溶剂得白色混合物。用硅胶装柱,石油醚和乙酸乙酯(3:1,v/v)作为淋洗剂,收集目标组分,旋转蒸发,得到无色透明固体,即为3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸,产率为68.1%。
对上述产物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸进行1H核磁共振(1H-NMR)分析,结果如下:1H NMRδH(MeOH-d4):7.860(1H,d,J=6Hz,H-6”),5.227(1H,t,J=3.5Hz,H-12),4.56(1H,t,J=6Hz,H-3),4.480(2H,d,J=2.5Hz,H-2’),2.202(1H,d,J=11Hz,H-18),1.940(2H,dd,J1=3.5Hz,J2=17.5Hz,H-11),1.130(CH3,s,H-27),0.990(CH3,s,H-25),0.969(CH3,s,H-26),0.904(CH3,d,J=5Hz,H-29),0.887(CH3,d,J=11.5Hz,H-30),0.853(2CH3,s,H-23,H-24).13C NMRδC(MeOH-d4):181.727(C-28),169.116(C-1’),151.622(C-4”),140.775(C-2”),139.825(C-13),131.702(C-5”),131.431(C-12),126.865(C-6”),84.417(C-3),56.805(C-2’),54.470(C-5),50.618(C-9),43.394(C-11),40.920(C-17),40.553(C-18,C-8),39.521(C-20),38.982(C-4),38.240(C-15),38.159(C-7),34.317(C-16),31.904(C-10),30.923(C-19),29.345(C-1),28.732(C-21),25.446(C-22),24.597(C-11),24.502(C-2),24.279(C-25),21.737(C-26),19.429(C-6),17.906(C-23),17.832(C-24),17.330(C-27),16.145(C-29),14.618(C-30).
实施例2:3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸作为抗癌药物的应用
取实施例1制备的3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸对癌细胞进行处理,采用MTT法研究该化合物在体外对肿瘤细胞的抑制作用。
方法:首先将培养成单层的靶细胞(人肝癌细胞BEL-7402和人宫颈癌细胞Hela)经胰酶消化后,利用细胞计数器进行计数,加入适当的RPMI-1640培养基使细胞数达到105个每毫升时,取0.1mL于96孔细胞培养板中,然后将接种好的细胞板在37℃,5%CO2的培养箱中培养24h。
然后,将长满单层细胞的96孔培养板中,每孔加入0.1mL不同浓度的化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸,检测化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的浓度为10-6~10-4M的药效作用,对照组中的培养孔加入0.1mL培养基,不加本发明的化合物,将96孔培养板放入37℃,5%CO2的培养箱中培养48h后,吸去培养液,用PBS洗涤一次。每孔加20μL 5mg/mL的MTT染料溶液,在37℃,5%CO2的培养箱中培养4h后,加入0.1mL含有50%DMF的缓冲液和20%的十二烷基磺酸钠溶液,溶解细胞中形成的甲瓒。用酶标仪在490nm处检测各孔OD值,计算活细胞数目。通过对数曲线法可以计算出50%细胞存活时化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的浓度(IC50)。
结果与结论:检测结果如图1所示,本发明3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸对BEL-7402和Hela细胞的IC50为6.8±0.6μmol/L和6.6±0.4μmol/L,可见化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸对肿瘤细胞BEL-7402和Hela具有很强的抑制作用。说明本发明化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸对人肝癌细胞和宫颈癌细胞具有一定的抑制作用。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (9)
1.化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸,其结构式为:
。
2.权利要求1所述的化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸的合成方法,其特征在于:包括以下步骤:将5-氟尿嘧啶-1-基乙酸与熊果酸进行酯化反应即可获得3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
3.根据权利要求2所述的合成方法,其特征在于:所述酯化反应过程中还加有催化剂和脱水剂,并对酯化反应产物进行纯化,即可获得3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸。
4.根据权利要求3所述的合成方法,其特征在于:所述酯化反应过程中,5-氟尿嘧啶-1-基乙酸与熊果酸的摩尔比为(0.8~1.2):(0.8~1.2)。
5.根据权利要求3所述的合成方法,其特征在于:所述的催化剂为4-二甲氨基吡啶,所述的脱水剂为二环己基碳二亚胺。
6.根据权利要求3所述的合成方法,其特征在于:所述纯化的具体操作为:将反应产物中加入饱和食盐水,用乙酸乙酯萃取,再用饱和食盐水水洗有机相,洗后的有机相再经干燥、浓缩溶剂得白色混合物,白色混合物再过硅胶柱,淋洗收集目标组分,旋转蒸发,得到无色透明固体,即为3-O-(2-( 5-氟尿嘧啶-1-)乙酰)-熊果酸。
7.根据权利要求6所述的合成方法,其特征在于:所述淋洗过程中用到的淋洗剂为体积比为(2.5~3.5):1的石油醚和乙酸乙酯混合液。
8.权利要求1所述的化合物3-O-(2-(5-氟尿嘧啶-1-)乙酰)-熊果酸在制备治疗癌症药物中的应用。
9.根据权利要求8所述的应用,其特征在于:所述的癌症为肝癌、宫颈癌。
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