CN109824641A - 一种具有抗癌活性的白杨素异亮氨酸衍生物 - Google Patents
一种具有抗癌活性的白杨素异亮氨酸衍生物 Download PDFInfo
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Abstract
本发明公开了一种具有对肺癌细胞A549和宫颈癌细胞Hela具有抑制活性的白杨素异亮氨酸衍生物,其能够特异性地阻断肺癌细胞和宫颈癌细胞分裂从而使肺癌细胞和宫颈癌细胞死亡,在杀死肺癌细胞和宫颈癌细胞的同时,对人体正常细胞无灭杀活性,可以有效避免因对人体正常细胞的灭杀带来的副作用。因而可以用做抗肺癌和宫颈癌药物的活性成分,具有良好的开发应用前景。
Description
技术领域
本发明涉及药物化学领域,具体地涉及一种具有抗癌活性的白杨素异亮氨酸衍生物、其制备方法及其用途。
背景技术
癌症发病率高,死亡率高,是严重威胁人类健康的疾病之一,据世界卫生组织统计,2012年全世界新增癌症患者超过1400万,因癌症死亡人数超过820万。化疗是目前治疗癌症最有效的方法之一。传统的化疗药物非特异性地阻断细胞分裂从而使细胞死亡,它们在杀死癌细胞的同时,也破坏了人体正常细胞的生长,带来许多毒副作用。近年来,随着全球生命科学领域的发展,癌症发生侵润和转移的过程正在逐步被阐明。如今愈多抗肿瘤药物,研发趋势转向以肿瘤细胞分化增殖相关的分子及信号通路中的某些环节为作用靶点,使肿瘤细胞发生特异性死亡,而不波及肿瘤细胞周围的正常细胞。
EGFR酪氨酸激酶是一种重要的跨膜受体,对细胞的生长、增殖和分化等生理过程发挥重要的作用,并在多种癌细胞中过度表达。目前,通过对表皮生长因子结构的分析,选择特定部位作为靶点,干扰其信号传导,已经成为开发抗癌和抗肿瘤药物的新思路(BehavBrain Funct, 2007, 3(1):31.)。
黄酮类化合物是从低毒或无毒的植物中提取,且具有多种生物活性。根据文献报道,黄酮类化合物通过介导细胞凋亡通路中的相关活性分子或蛋白,诱导肿瘤细胞凋亡(Med Res Rev, 2010, 23(4):519-534)。同时也有研究表明,黄酮类化合物具有二苯基色原酮结构,属于天然EGFR抑制剂(Eur J Med Chem, 2009, 44(5):1982-1988)。同时其结合EGFR模式与ATP类似,能够和EGFR蛋白主链活性位点以氢键的形式相结合(J Med Chem,1999, 42(6):1018-1026)。白杨素(5,7-二羟基黄酮)是一种在自然界广泛存在的黄酮化合物,具有抗菌、抗氧化、抗肿瘤、抗炎等广泛的生物活性。最近的研究表明其还可以预防顺铂引起的器官毒性和改善间歇性缺氧引起的认知缺陷和脑损伤。然而,由于其水溶性较差,肠道吸收邵,在体内容易代谢失活。为了提高其药理活性,对其进行结构修饰与改造,对于获得高效低毒的新型候选药物具有重要意义。已有文献报道合成具有优异的EGFR抑制活性的白杨素衍生物。
氨基酸是构成蛋白质的基本单元,作为人体内的重要的活性分子,参与多种生命活动。由于其自身具有一定的生物活性、低毒性及较好的生物相容性等特点被视为制备前体药物的理想载体。已有研究结果证明,一些氨基酸自身具备一定的生物活性,如精氨酸、谷酰胺酸、亮氨酸、色氨酸、苏氨酸在分子水平参与并调控基因的表达、蛋白质的合成及信号通路的传导( Amino Acids, 2015, 47(10):2037-2063.)。且与正常细胞相比,肿瘤细胞的的代谢活动更加旺盛和频繁,对氨基酸是的需求量也更大。有研究表明,L-型氨基酸转运蛋白家族(LAT1、LAT2、LAT3、LAT4),在细胞营养物质供给上起到重要作用,主要负责一些大分子中性氨基酸如支链氨基酸和芳香族氨基酸包括一些必须氨基酸的跨膜转运。其中LAT1在肿瘤的发展和扩散过程中扮演着重要的角色,它除了为肿瘤细胞的增殖提供了源源不断养料和能量外,还对肿瘤细胞特有的一些代谢通路起到了一定的调节作用。
史兰香等(CN108101892A)通过将白杨素与非天然氨基酸结合,并在分子中引入三氮唑,得到了一系列白杨素衍生物 ,活性测试结果显示其对于人肝癌细胞HepG2和人胃癌细胞MGC-803具有良好的抑制活性;胡昆等(CN101774993A)将白杨素与含氨基的基团通过分子拼合的方法,得到了一系列白杨素含氮衍生物,活性测试结果显示部分化合物对于HCT-116、Hela、DU-145、K562和SGC-7901细胞株具有一定的抑制活性;本发明的发明人刘运美等(CN106632193A)公开了一系列白杨素氨基酸衍生物,部分化合物对于HepG2和MGC-803具有良好的抑制活性,然而部分化合物对于肺癌细胞A549的活性表现不佳,同时对于HVECs(人正常血管内皮细胞)表现出不期望的抑制活性。
综上所述,虽然目前利用氨基酸结构修饰的白杨素已有文献报道,然而这些化合物仅提供了对部分癌细胞的抑制活性,然而并未公开修饰后的化合物能够特异性阻断癌细胞分裂从而使癌细胞死亡,使得其在杀死癌细胞的同时,对人体正常细胞无灭杀活性。因此,开发和研究具备特异性抗癌活性的化合物仍然具备重要意义。
发明内容
本发明所要解决的技术问题是:提供了一种白杨素异亮氨酸衍生物,其能够特异性地抑制癌细胞,尤其是A549和Hela细胞株,对人体正常细胞无灭杀活性。
本发明的发明人在前期工作的基础上,为了得到具有特异性抑制癌细胞的白杨素氨基酸衍生物,进行了大量的工作,设计并合成了一系列白杨素氨基酸衍生物,筛选出了与EGFR激酶能够较好地结合的化合物,并考量了化合物对细胞周期、细胞凋亡、细胞迁移和人正常血管内皮细胞的毒性等因素,最终筛选得到了本发明的化合物。
本发明的第一个方面,是提供一种式I所示化合物及其药学上可接受的盐,其具有如下结构:
式I;
优选地,所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、草酸盐、酒石酸盐、柠檬酸盐、三氟乙酸盐、甲烷磺酸盐、乙烷磺酸盐、对甲苯磺酸盐或水杨酸盐;
本发明的另一方面提供一种制备式I化合物的方法,其合成路线如下:
。
具体反应步骤如下:
步骤一:向白杨素(1)的丙酮溶液中加入无水碳酸钾,60℃下搅拌30 min,滴加7-溴庚酸乙酯(2)以及催化剂碘化钾,在60℃条件下继续搅拌回流,TLC检测反应完成后,经后处理得到化合物3;
步骤二:将化合物3,氢氧化钾和甲醇依次加入到反应瓶中,60℃搅拌回流,TLC检测反应结束后,反应液过滤,调节滤液pH在2-3,置于冰水中1-3小时,待完全析晶后抽滤,滤饼分别用3.8 % 盐酸溶液、饱和氯化钠溶液和蒸馏水各洗涤三次,真空干燥,得到化合物4;
步骤三:在冰浴条件下将化合物4,1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCl),1-羟基苯并三唑(HOBt)以及溶剂DMF加入到三颈烧瓶中,搅拌1-1.5 h,加入异亮氨酸甲酯盐酸盐的DMF溶液,滴加含缚酸剂N,N’-二异丙基乙胺(DIPEA)、4-二甲氨基吡咯(DMAP)的DMF溶液,冰浴下反应30 min后逐渐升至室温反应,TLC检测反应结束后,将反应液投入到装有冰水的烧杯中,将烧杯放入冰水中静置,抽滤,滤饼分别用饱和氯化钠溶液、蒸馏水各洗涤三次,用硅胶色谱柱分离纯化,得到化合物5;
步骤四:将化合物5、无水乙醇依次加入到反应瓶中,加入氢氧化钾水溶液调节反应液的pH至10-11,室温下搅拌反应,TLC检测原料水解完全,将反应液抽滤,滤液用硫酸调节pH至2-3,随着酸的加入逐渐析出淡黄色固体,放入冰水中静置,抽滤,水洗,真空干燥得到化合物I。
优选地,步骤一中白杨素与7-溴庚酸乙酯的摩尔比为:(0.5-2):(1-2),优选为1:1-1.2;
步骤三中化合物4与异亮氨酸甲酯盐酸盐的摩尔比为:(1-1.5):(1-2),优选为1: 1-1.5;
步骤四中氢氧化钾水溶液为0.1 mol·L-1的水溶液,硫酸为0.5 mol·L-1的硫酸溶液。
本发明的另一方面提供一种药物组合物,其包含式I所示的化合物或其药学上可接受的盐,以及药学上可接受的载体、赋形剂。
本发明另一方面涉及一种式I化合物及其药学上可接受的盐或包含其药物组合物在制备抗癌药物中的用途;
优选地,所述癌症为肺癌或宫颈癌;尤其是,人肺癌细胞株A549或人宫颈癌细胞株Hela。
定义:
在某些实施方案中,药学上可接受的形式是药学上可接受的盐,药学上可接受的盐在本领域中是熟知的。药学上可接受的盐的实例是诸如盐酸、氢溴酸、磷酸、硫酸、高氯酸、乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、丁二酸或丙二酸、乙酸、丙酸、乙醇酸、丙酮酸、草酸、乳酸、三氟乙酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸等与化合物形成盐的形式。
“药学上可接受的载体”或“药学上可接受的赋形剂”包括任何和所有溶剂、分散介质、包覆剂、等张剂和吸收延迟剂等。药学上可接受的载体或赋形剂不破坏公开的化合物的药理学活性,并且在以足以递送治疗量的化合物的剂量施用时是无毒的。药物活性物质的所述介质和试剂的使用在本领域中是熟知的。
与现有技术相比,本发明的有益效果是:
(1)本发明提供了一类新的具有抗癌活性的白杨素异亮氨酸衍生物,拓宽了现有抗癌化合物的范围,可作为先导化合物继续优化;
(2)本发明化合物可以特异性地抑制癌细胞的增殖和迁移,而对人体正常细胞无灭杀活性,可以减少化疗药物对于人体的毒副作用。通过对比试验的方法,表明了本发明的化合物能够特异性地抑制肺癌和宫颈癌细胞,而对人正常细胞无生理毒性,减少了成药副作用;
(3)本发明化合物通过延长酰胺键和氧原子之间的碳链长度,使得化合物的抗癌活性增加。
附图说明
图1是化合物I对MGC-803细胞集落的形成和迁移的影响。(A)不同浓度的I处理MGC-803细胞集落10天。(B)给予MGC-803细胞浓度分别为0,20,40 μM的化合物I药液处理48h。对照组的划痕随着时间的推移而愈合,宽度减小;给药组的划痕由于药物的作用,划痕愈合的宽度宽于对照组。
图2是化合物I对MGC-803细胞的周期和凋亡的影响。(A)MGC-803细胞经过化合物I处理48 h后,MGC-803细胞周期分布发生明显变化。(B)周期结果统计柱状图。(C)I处理MGC-803细胞48 h 后,I对细胞凋亡的影响。(D)凋亡结果统计柱状图;与对照组48 h处理结果相比,“*” p<0.05, “**” p<0.01。
具体实施方式
下面通过实施例来具体说明本发明的内容。在本发明中,以下实施例是为了更好地阐述本发明,并不是用来限制本发明的范围。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1 N-[7-(5-羟基-2-苯基-4H-苯并吡喃酮-7-O)庚酰基]-L-异亮氨氨酸(化合物I)
。
步骤一:在搅拌条件下向白杨素(2524.4 mg)的丙酮(100 mL)溶液中加入无水碳酸钾(2073.2 mg)。60℃下搅拌30 min。用恒压滴液漏斗缓慢滴加7-溴庚酸乙酯(2544 μL)以及催化剂碘化钾(166.0 mg),在60℃条件下继续搅拌回流。TLC检测反应结束后,冷却,过滤,滤渣用少量丙酮洗涤,将得到的滤液在旋转蒸发仪上除去有机溶剂。再经过硅胶层析柱层析分离纯化(二氯甲烷/丙酮=50:1),得到化合物3。 产率: 65%。m.p.83-86 ℃。1H NMR(500 MHz, CDCl3) δ 12.73 (s, 1H), 7.95 – 7.86 (m, 2H), 7.60 – 7.49 (m, 3H),6.69 (s, 1H), 6.52 (d, J = 2.1 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 4.19 – 4.12(m, 2H), 4.05 (t, J = 6.5 Hz, 2H), 2.39 – 2.31 (m, 2H), 1.71 (d, J = 7.6 Hz,2H), 1.63 (s, 3H), 1.52 (d, J = 7.5 Hz, 2H), 1.44 (d, J = 7.2 Hz, 2H), 1.28(s, 2H)。
步骤二:将化合物3(1943 mg),1 mol/L 氢氧化钾(12.5 mL)和甲醇50 mL依次加入到100 mL三口烧瓶中,60℃搅拌回流。TLC检测反应结束后,反应液过滤,向滤液中滴加0.5 mol/L硫酸,随着酸的加入逐渐析出淡黄色固体,调节滤液pH在2-3,置于冰水中2小时,待完全析晶后抽滤,滤饼分别用3.8 % 盐酸溶液、饱和氯化钠溶液和蒸馏水各洗三次,真空干燥,得到化合物4。产率: 87%。m.p.146-149 ℃。1H NMR (500 MHz, DMSO) δ12.82 (s,1H), 12.01 (s, 1H), 8.18 – 8.08 (m, 2H), 7.69 – 7.57 (m, 3H), 7.07 (s, 1H),6.85 (d, J = 2.2 Hz, 1H), 6.42 (d, J = 2.2 Hz, 1H), 4.13 (t, J = 6.5 Hz, 2H),2.25 (t, J = 7.3 Hz, 2H), 1.76 (dd, J = 14.4, 6.7 Hz, 2H), 1.62 – 1.49 (m,2H), 1.48 – 1.31 (m, 4H)。
步骤三:在冰浴条件下将化合物4(396.0 mg),1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCl) (766.8 mg),1-羟基苯并三唑(HOBt)(540.6 mg)以及溶剂N, N-二甲基甲酰胺(DMF)(20 mL)加入到 50 mL三颈烧瓶中,搅拌1h,加入异亮氨酸甲酯盐酸盐(363.2mg)的DMF溶液4 mL, 用恒压滴液漏斗逐滴加入含缚酸剂N,N’-二异丙基乙胺(DIPEA)(700μL)、4-二甲氨基吡咯(DMAP)(146.4 mg)的DMF溶液2 mL, 冰浴下反应30 min后逐渐升至室温反应约13 h。TLC检测反应结束后,将反应液投入到装有50 mL冰水的烧杯中,将烧杯放入冰水中静置,抽滤,滤饼分别用饱和氯化钠溶液、蒸馏水各洗涤三次,用硅胶色谱柱分离纯化(二氯甲烷/丙酮=50:1),得到淡黄色固体5。产率:54%, m.p. 144.1-147.0 ℃.1H NMR(500 MHz, CDCl3) δ 7.93 (dd, J = 7.9, 1.7 Hz, 2H), 7.63 – 7.51 (m, 3H), 6.71(s, 1H), 6.54 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 5.98 (d, J = 8.4Hz, 1H), 4.67 (dd, J = 8.6, 4.9 Hz, 1H), 4.07 (t, J = 6.5 Hz, 2H), 3.78 (s,3H), 2.30 (t, J = 7.5 Hz, 2H), 1.86 (dd, J = 14.4, 6.7 Hz, 2H), 1.77 – 1.71(m, 2H), 1.46 (dd, J = 10.1, 5.0 Hz, 2H), 1.33 – 1.14 (m, 2H), 0.97 (s, 3H),0.94 (s, 3H).
步骤四:将白杨素异亮氨酸甲酯化合物5(0.25 mmol),无水乙醇50 mL依次加入到100mL 单口圆底烧瓶中,加入0.1 mol·L-1氢氧化钾(KOH)溶液调节反应液的pH至 10~11。室温下搅拌3.5小时左右,TLC监测原料水解完全。将反应液抽滤,滤液用0.5 mol·L-1硫酸调节pH至2~3,随着酸的加入逐渐析出淡黄色固体,放入冰水静置,抽滤,滤饼用蒸馏水洗涤三次,真空干燥得淡黄色固体6(I)。产率:54%, m.p. 130.0-133.0 ℃.1H NMR (500 MHz,DMSO) δ 12.85 (s, 1H), 8.17 (s, 1H), 8.16 – 7.86 (m, 2H), 7.70 – 7.59 (m,4H), 7.10 (s, 1H), 6.88 (s, 1H), 6.45 (s, 1H), 4.16 (s, 3H), 2.22 (s, 2H),1.80 (s, 2H), 1.58 – 1.30 (m, 8H), 0.88 (d, J = 5.1 Hz, 6H)。
对比实施例1
参照实施例1的方法,在步骤一中以6-溴己酸乙酯代替7-溴庚酸乙酯作为反应原料,制备得到对比实施例化合物II,其结构如下:
。
对比实施例2
参照实施例2方法,在步骤三中以亮氨酸甲酯盐酸盐代替异亮氨酸甲酯盐酸盐作为反应原料,制备得到对比实施例化合物III,其结构如下:
。
实施例2 体外活性测试
细胞株选用A549(人乳腺癌细胞)、Hela(人宫颈癌细胞)和HVECs(人正常血管内皮细胞)。
培养液为DMEM+10% FBS+ 5 mL双抗
样品液配制:用DMSO(Merck)溶解后,浓度为33333.33 μmol/L
1.种板 将细胞悬液加入96孔板,每孔100 μL(每孔的细胞含量约为8000个/孔),置于37℃、5% CO2培养箱培育24 h;
2.加药 用培养基配制样品液梯度浓度(256,128,64,32,16,8,4,2 μmol/L),再弃去96孔板上原有培养基,加入药物不同浓度的培养基,每孔100 μL,每个浓度做5个副孔。其余孔用含有3‰的DMSO的培养基做对照,置37℃、5%培养箱培育48 h;
3.MTT法测试 取出96孔板,避光条件下每孔加入10 μL MTT (3-(4,5- 二甲基噻唑-2-基)-2,5-二苯基四唑翁溴化物,5 mg/mL)溶液,再放入培养箱内放置4 h;4 h后弃去培养液,每孔加入150 μL DMSO溶解震荡,用MK-2全自动酶标仪测490 nm OD值,计算半数抑制浓度IC50。
ND:Not detected。
由上表可以看,化合物I抗肺癌A549和抗宫颈癌Hela活性显著,且IC50优于对比实施例化合物II和III,与阳性对照药五氟尿嘧啶5-FU活性相当。细胞毒性实验表明,化合物I对人正常血管内皮细胞HVECs无明显毒性。
Claims (9)
1.一种式I所示化合物及其药学上可接受的盐,其具有如下结构:
式I。
2.根据权利要求1所述的式I化合物或其药学上可接受的盐,所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、草酸盐、酒石酸盐、柠檬酸盐、三氟乙酸盐、甲烷磺酸盐、乙烷磺酸盐、对甲苯磺酸盐或水杨酸盐。
3.一种制备如权利要求1所述的式I化合物的方法,其反应路线如下:
。
4.根据权利要求3所述的制备方法,其特征在于包括如下步骤:
步骤一:向白杨素(1)的丙酮溶液中加入无水碳酸钾,60℃下搅拌30 min,滴加7-溴庚酸乙酯(2)以及催化剂碘化钾,在60℃条件下继续搅拌回流,TLC检测反应完成后,经后处理得到化合物3;
步骤二:将化合物3,氢氧化钾和甲醇依次加入到反应瓶中,60℃搅拌回流,TLC检测反应结束后,反应液过滤,调节滤液pH在2-3,置于冰水中1-3小时,待完全析晶后抽滤,滤饼分别用3.8 % 盐酸溶液、饱和氯化钠溶液和蒸馏水各洗涤三次,真空干燥,得到化合物4;
步骤三:在冰浴条件下将化合物4,1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCl),1-羟基苯并三唑(HOBt)以及溶剂DMF加入到三颈烧瓶中,搅拌1-1.5 h,加入异亮氨酸甲酯盐酸盐的DMF溶液,滴加含缚酸剂N,N’-二异丙基乙胺(DIPEA)、4-二甲氨基吡咯(DMAP)的DMF溶液,冰浴下反应30 min后逐渐升至室温反应,TLC检测反应结束后,将反应液投入到装有冰水的烧杯中,将烧杯放入冰水中静置,抽滤,滤饼分别用饱和氯化钠溶液、蒸馏水各洗涤三次,用硅胶色谱柱分离纯化,得到化合物5;
步骤四:将化合物5、无水乙醇依次加入到反应瓶中,加入氢氧化钾水溶液调节反应液的pH至10-11,室温下搅拌反应,TLC检测原料水解完全,将反应液抽滤,滤液用硫酸调节pH至2-3,随着酸的加入逐渐析出淡黄色固体,放入冰水中静置,抽滤,水洗,真空干燥得到化合物I。
5.根据权利要求3或4所述的制备方法,其特征在于:
步骤一中白杨素与7-溴庚酸乙酯的摩尔比为:(0.5-2):(1-2),优选为1: 1-1.2;
步骤三中化合物4与异亮氨酸甲酯盐酸盐的摩尔比为:(1-1.5):(1-2),优选为1: 1-1.5;
步骤四中氢氧化钾水溶液为0.1 mol·L-1的水溶液,硫酸为0.5 mol·L-1的硫酸溶液。
6.一种药物组合物,其包含权利要求1-2中任一项所述式I化合物或其药学上可接受的盐,以及药学上可接受的载体、赋形剂。
7.权利要求1-2中任一项所述的化合物或其药学上可接受的盐或权利要求6所述的药物组合物在制备治疗癌症的药物中的用途。
8.如权利要求7所述的用途,其中所述癌症为肺癌和宫颈癌。
9.如权利要求7所述的用途,所述癌症为人肺癌细胞A549导致的癌症和人宫颈癌细胞Hela导致的癌症。
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