CN112898379B - 二氧六环修饰的四氢咔啉-3-甲酰-The-HGE、其制备、抗肿瘤活性和应用 - Google Patents
二氧六环修饰的四氢咔啉-3-甲酰-The-HGE、其制备、抗肿瘤活性和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu化合物,涉及它的制备方法,涉及它的抗肿瘤活性。因而本发明涉及该化合物在抗肿瘤药物以及抗肿瘤转移药物中的应用。
背景技术
肿瘤已经成为严重威胁人类健康的常见病。例如2015年新增的肿瘤患者大约有392.9万,其中有233.8万肿瘤患者死亡。平均每天有超过1万人被确诊为肿瘤。目前,临床应用治疗癌症的方法主要有放射疗法,化学疗法,抗体治疗和免疫治疗等。然而由于严重的副作用,药物治疗后产生多药耐药性以及昂贵的治疗价格,使得癌症的治疗再度陷入困境。发明新型的抗肿瘤药物是药物研究的前沿之一。
3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸是具有多种生物活性的药效团,茶氨酸也是具有多种生物活性的药效团。在一项关联发明中,发明人发现3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸与茶氨酸两个药效团融合形成的下式左的3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The具有抗肿瘤生长的作用。在进一步的研究中,发明人认识到在3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The的羧基端引入尿毒素三肽His-Gly-Glu生成的下式右的3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu可具有更强的抗肿瘤作用和抗肿瘤转移作用。根据这种认识,发明人提出了本发明。根据这种认识,发明人提出了本发明。
发明内容
本发明的第一个内容是提供下式的3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu。
本发明的第二个内容是提供3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu的制备方法,该方法包括:
1)合成(3S)-1,1-二羟甲基-四氢-β-咔啉-3-羧酸苄酯;
2)合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯;
3)合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸;
4)采用二环己基碳二亚胺(DCC)为缩合剂,1-羟基苯并三唑(HOBt)为催化剂的液相缩合的方法,合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-OBzl;
5)合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The;
6)采用DCC为缩合剂,HOBt为催化剂的液相缩合的方法,合成HCl·His-Gly-Glu(OBzl)-OBzl;
7)采用DCC为缩合剂,HOBt为催化剂的液相缩合的方法,合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(OBzl)-OBzl;
8)合成3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu;
本发明的第三个内容是评价3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu对S180小鼠肿瘤生长的抑制作用。
本发明的第四个内容是评价3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu的抗肿瘤转移的作用其中包括:
1.评价3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu抑制肿瘤细胞迁移及侵袭的能力
2.评价3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu体内抑制Lewis肺癌小鼠肿瘤转移活性
附图说明
图1.3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu的合成路线:i)三氟乙酸,1,3-二羟基丙酮;ii)浓硫酸,丙酮;iii)钯碳(Pd),H2;iv)二环己基碳二亚胺(DCC),1-羟基苯并三唑(HOBt),N-甲基吗啉(NMM);v)氯化氢的乙酸乙酯溶液(4M)。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1制备(3S)-1,1-二羟甲基-四氢-β-咔啉-3-羧酸苄酯(1)
往10mL二氯甲烷中加入2g(7.2mmol)L-色氨酸苄酯,充分搅拌使其溶解。冰浴条件下,往溶液中缓慢滴加1mL三氟醋酸。然后再往该溶液中加0.78g(8.6mmol)1,3-二羟基丙酮,室温反应7小时。TLC显示L-色氨酸苄酯消失(二氯甲烷/甲醇:30:1)。冰浴条件下,往溶液中加入50mL饱和NaHCO3溶液,充分搅拌,然后留下二氯甲烷层,再用饱和NaHCO3溶液(30mL×3)洗,再用饱和NaCl溶液(30mL×3)洗,二氯甲烷层用无水硫酸钠干燥12小时。过滤,滤液减压浓缩得到2.03g(77%)标题化合物,为黄色粉末。ESI-MS(m/e):367[M+H]+。
实施例2制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(2)
往5mL无水丙酮中加入0.2g(0.55mmol)(3S)-1,1-二羟甲基-四氢-β-咔啉-3-羧酸苄酯(1)。在冰浴条件下,往里加入100μL浓硫酸,之后,室温搅拌3小时。TLC显示化合物1消失(石油醚/乙酸乙酯,4:1)。冰浴条件下,用饱和NaHCO3溶液调节反应液pH值为7,得到的溶液减压浓缩除去丙酮,残留液再加乙酸乙酯萃洗3遍,乙酸乙酯层用饱和NaCl溶液洗至中性。乙酸乙酯层用无水硫酸钠干燥12小时。过滤,滤液减压浓缩得到的棕黄色固体,经柱层层析分离(石油醚/乙酸乙酯,4:1)得到0.08g(35.8%)标题化合物,为白色国体。ESI-MS(m/e):407[M+H]+。
实施例3制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸(3)
往10mL甲醇中加入0.20g(0.5mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(2)和0.02g Pd/C。搅拌并通12h氢气,TLC显示化合物2消失(石油醚/乙酸乙酯,4:1)。过滤除去钯碳(Pd/C),滤液减压浓缩。残留物用乙醚磨洗,得到0.14g(90%)标题化合物,为无色固体。ESI-MS(m/e):317[M+H]+。
实施例4制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-OBzl(4)
往20mL四氢呋喃中加入0.19g(0.6mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-羧酸(3),0.15g(0.72mmol)N,N'-二环己基碳二亚胺(DCC)和0.09g(0.72mmol)1-羟基苯并三唑(HOBt)。冰浴下搅拌30分钟。之后,再向反应液中加入0.20g(0.66mmol)HCl·The-OBzl。之后,向反应液中滴加N-甲基吗啉(NMM)调节反应液的pH值为9。室温搅拌6小时,TLC显示化合物3消失(二氯甲烷/甲醇,30/1)。滤除二环己基脲(DCU),滤液减压浓缩,得到的残留物用30mL乙酸乙酯溶解,溶液再过滤除去DCU。滤液依次用5%NaHCO3水溶液萃洗(15mL×3),饱和NaCl水溶液洗(15mL×3),5%KHSO4水溶液洗(15mL×3),饱和NaCl水溶液洗(15mL×3),5%NaHCO3水溶液洗(15mL×3),饱和NaCl水溶液洗(15mL×3),用无水硫酸钠干燥12小时。过滤,滤液减压浓缩,得到的黄色粉末经硅胶柱层析纯化(石油醚/乙酸乙酯,10/1),得到0.27g(80%)标题化合物,为无色粉末。ESI-MS(m/e):563[M+H]+;1H-NMR(300MHz,DMSO-d6):δ/ppm=10.94(s,1H),8.28(t,J=7.2Hz,1H),7.79(s,1H),7.37(m,6H),7.07(m,1H),7.02(m,1H),5.16(s,1H),5.12(s,1H),4.40(m,1H),4.21(m,1H),3.99(m,1H),3.75(m,1H),3.61(m,2H),3.02(m,2H),2.12(m,2H),1.82(m,2H),1.65(s,3H),1.42(s,3H),1.22(m,2H),1.01(m,3H)。
实施例5制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The(5)
往10mL甲醇中加入0.28g(0.5mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-OBzl(4)和0.02g钯碳(Pd/C)。搅拌并通12h氢气,TLC显示化合物4消失(二氯甲烷/甲醇,30/1)。过滤除去Pd/C,滤液减压浓缩。残留物用乙醚磨洗,得到0.21g(90%)标题化合物,为黄色固体。ESI-MS(m/e):473[M+H]+,1H-NMR(300MHz,DMSO-d6):δ/ppm=10.98(s,1H),8.18(d,J=7.5Hz,1H),7.79(s,1H),7.40(dt,J1=4.8Hz,J2=8.1Hz,2H),7.02(td,J1=8.1Hz,J2=4.8Hz,2H),4.40(m,1H),4.28(m,1H),4.12(m,1H),4.02(m,1H),3.81(m,1H),3.61(m,1H),3.02(m,2H),2.14(m,2H),1.82(m,2H),1.65(s,3H),1.41(s,3H),1.22(m,2H),1.03(m,3H)。
实施例6制备Boc-Gly-Glu(OBzl)-OBzl
采用实施例4的方法,从0.88g(5mmol)Boc-Gly和2.00g(5.5mmol)Hcl·Glu(OBzl)-OBzl得到1.93g(80%)标题化合物,为无色固体。
实施例7制备HCl·Gly-Glu(OBzl)-OBzl
冰浴下将1.45g(3mmol)Boc-Gly-Glu(OBzl)-OBzl用20mL氯化氢的乙酸乙酯溶液(4M)溶解并反应4小时。TLC监测显示反应完全(体系为二氯甲烷/甲醇,30/1)。反应混合物减压浓缩,残留物用无水乙酸乙酯溶解,得到的溶液再减压浓缩。该操作重复3次。得到的白色粉末样物质用无水乙醚充分磨洗,得到1.14g(90%)标题化合物,为无色固体。
实施例8制备Boc-His(Boc)-Gly-Glu(OBzl)-OBzl
采用实施例4的方法从1.77g(5mmol)Boc-His(Boc)和2.52g(6mmol)HCl·Gly-Glu(OBzl)-OBzl得到2.56g(67%)标题化合物,为无色固体。ESI-MS(m/e):722[M+H]+。
实施例9制备HCl·His-Gly-Glu(OBzl)-OBzl
采用实施例7的方法从1.44g(2mmol)Boc-His(Boc)-Gly-Glu(OBzl)-OBzl得到1.03g(92%)标题化合物,为无色固体。
实施例10制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(OBzl)-OBzl(6)
往30mL无水四氢呋喃中加入0.47g(1mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The(5)、0.25g(1.2mmol)DCC和0.16g(1.2mmol)HOBt,冰浴下,搅拌30分钟。之后,向反应液中加入0.62g(1.1mmol)HCl·His-Gly-Glu(OBzl)-OBzl。滴入N-甲基吗啉(NMM)调节反应液的pH值为9。室温反应8小时。TLC显示化合物5消失(二氯甲烷/甲醇,15/1),滤除二环己基脲(DCU),滤液减压浓缩。残留物用100mL乙酸乙酯溶解,溶液再过滤除去DCU。滤液依次用5%NaHCO3水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),5%KHSO4水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),5%NaHCO3水溶液洗(30mL×3),饱和NaCl水溶液洗(30mL×3),用无水硫酸钠干燥12小时。过滤,滤液减压浓缩,得到黄色粉末,经硅胶柱层析纯化(二氯甲烷/甲醇,15/1),得到0.71g(70%)标题化合物,为黄色粉末。ESI-MS(m/e):977[M+H]+;1H-NMR(300MHz,DMSO-d6):δ/ppm=10.99(s,1H),8.35(m,1H),8.27(m,1H),8,16(m,1H),7.79(m,1H),7.49(m,2H),7.35(m,12H),7.00(m,2H),5.13(s,2H),5.06(s,2H),4.41(m,2H),4.21(m,1H),4.02(m,1H),3.81(m,1H),3.65(m,2H),3.04(m,3H),2.92(m,2H),2.44(m,2H),2.09(m,2H),1.95(m,2H),1.85(m,2H),1.72(m,2H),1.62(s,3H),1.39(s,3H),1.23(m,2H),0.97(t,J=7.2Hz,3H)。
实施例11制备3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(7)
往10mL甲醇中加入0.048g(0.05mmol)3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(OBzl)-OBzl的制备(6)和0.005gPd/C,搅拌并通12h氢气,TLC显示化合物6消失(乙酸乙酯:水:冰醋酸,4:1:1)。过滤除去钯碳(Pd/C),滤液减压浓缩。残留物用乙醚磨洗,得到0.033g(85%)标题化合物,为无色固体。ESI-MS(m/e):795[M-H]-,1H-NMR(300MHz,DMSO-d6):δ/ppm=10.96(s,1H),8.34(m,1H),8.29(m,1H),8,15(m,1H),8.02(m,1H),7.79(m,1H),7.54(s,1H),7.39(m,1H),7.04(m,1H),6.98(m,1H),6.83(s,1H),4.44(m,3H),4.24(m,2H),4.12(m,2H),4.02(m,1H),3.03(m,3H),2.93(m,2H),2.27(m,2H),2.07(m,2H),1.93(m,2H),1.84(m,2H),1.62(s,3H),1.39(s,3H),1.20(m,2H),0.97(t,J=7.2Hz,3H);13C-NMR(125MHz,DMSO-d6):δ/ppm=173.64,171.83,171.80,171.67,169.31,135.22,120.62,119.33,118.23,111.76,109.32,98.15,64.75,53.92,51.57,42.55,33.80,32.24,30.79,29.60,22.97,22.91,15.17。
实施例12评价化合物7抑制肿瘤增长的活性
实验动物:
ICR小鼠,雄性,20±2g,购自北京维通利华实验动物技术有限公司。
瘤源为小鼠S180肉瘤,购自北京大学医学部动物实验中心,自行传代维持。
给药剂量及给药方式:
本发明的化合物3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(化合物7)的口服剂量为0.23μmol/kg,阳性对照阿霉素的注射剂量为2μmol/kg,阴性对照为生理盐水。
实验方法:实验采用S180移植性小鼠肉瘤模型。
实验操作:
于无菌条件下抽取接种生长旺盛的S180腹水瘤瘤液,用生理盐水稀释成(1:2)的液体充分混合,将肿瘤细胞悬液用新鲜配制的0.2%台盼蓝染色,混匀后按白细胞计数方法计数,染蓝色者为死细胞,不染色者为活细胞,并按如下公式计算细胞浓度和细胞存活率。
细胞浓度=4大方格内活细胞数/4×104×稀释倍数=细胞数/mL
细胞存活率=活细胞数/(活细胞数+死细胞数)×100%
将存活率大于90%的瘤液用匀浆法制备成1.5×107个/mL的细胞悬液,于鼠腋皮下接种,0.1mL/10g/只,制造S180荷瘤小鼠。7天后小鼠右侧腋下长出绿豆大小的实体瘤,按照肿瘤体积将小鼠随机分组,使各组小鼠的肿瘤体积均匀分布。随后开始给药,共给药10次。第17天后,乙醚麻醉小鼠,脱颈椎处死,然后用镊子固定小鼠右腋肿瘤生长部位,剪开皮肤,暴露肿瘤,钝性剥离,称重,瘤重用表示,经t-test统计学方法进行组间差异的比较。
实验结果:
实验结果列入表1:
表1.化合物7抑制肿瘤增长的活性
注:n=12,阿霉素为腹腔注射给药,其他均为灌胃方式给药,经t检验;a)与生理盐水组相比P<0.01且与阿霉素组相比,P>0.05.
结果表明,0.23μmol/kg剂量下口服化合物7治疗的小鼠的体内抗肿瘤瘤重(1.82±0.86g)与阴性对照组生理盐水有显著性差别(3.31±0.73g,P<0.01);且与阳性对照组阿霉素组没有显著性差别(1.69±0.28g,P>0.05)。可见,化合物7在口服剂量低至0.23μmol/kg时,只有阿霉素腹腔注射剂量的约1/10时,仍具有抑制小鼠肿瘤增长的活性,说明本发明具有突出的技术效果。
实施例13用Transwell小室实验评价化合物7抑制肿瘤细胞迁移的能力
实验方法:
取生长状态良好处于对数生长期的A549细胞,0.25%胰酶消化,镜下观察,加入血清终止消化并3000rpm离心3min,计数,配成单细胞悬液,密度为2×106个/mL。Transwell小室上室每孔加入100μL细胞悬液,同时加入化合物7的溶液,使终浓度为20μM。下室加入600μL的含10%FBS的1640培养基,在37℃和5%CO2培养箱中培养6小时,用棉签擦去基质胶和上室内的细胞,用4%的多聚甲醛固定细胞30min,吸除固定液,用PBS洗3次;用0.1%的结晶紫染液染色15min,吸除染色液,用PBS洗3次,在每个小室选取9个视野进行拍照并计数,细胞数以表示。
实验结果:
实验结果列入表2:
表2化合物7抑制A549细胞迁移的活性
注:n=6,给药方式均为灌胃,经t检验,a)表示与PBS组相比P<0.01且与RGDS组相比P<0.01.
结果表明,加入化合物7的组别的细胞迁移数(153.56±22.65)与阴性对照组生理盐水有显著性差别(243.00±44.92,P<0.01)且与阳性对照组RGDS也有显著差别(193.77±14.78,P<0.01),可见,20μmol/L浓度的化合物7可抑制人非小细胞肺癌细胞A549的迁移,并较同浓度下的RGDS抑制癌细胞迁移活性更好。
实施例14用Transwell小室实验评价化合物7抑制肿瘤细胞侵袭的能力
实验方法:
包被基质胶:预先将保存在-20℃冰箱中呈黄色固态的Matrigel基质胶置于4℃冰箱约12h使之成为粉红色具有良好流动性的液态。尽快取240μL Matrigel基质胶加入到960μL相应肿瘤细胞所需的无血清培养基中,吹打将其稀释5倍分散均匀,上室每孔加100μL后于37℃,5%CO2的细胞孵箱中孵育5h,使基质胶均匀铺至聚碳酸酯膜小孔中。
水化基底膜:使用移液枪小心吸除上室残液,加入50μL相应无血清培养基,再次于37℃,5%CO2的细胞孵箱中孵育30min后,使用移液枪小心吸除上室残液备用。
取生长状态良好处于对数生长期的A549细胞,0.25%胰酶消化,镜下观察,加入血清终止消化并3000rpm离心3min,计数,配成单细胞悬液,密度为2×106个/mL。Transwell小室上室每孔加入100μL细胞悬液,同时加入化合物7的溶液,使终浓度为20μM。下室加入600μL的含10%FBS的1640培养基,,置于37℃5%CO2的细胞孵箱内培养(A549细胞培养12h),待各细胞株所需时间过后进行后处理,用棉签擦去基质胶和上室内的细胞,用4%的多聚甲醛固定细胞30min,吸除固定液,用PBS洗3次;用0.1%的结晶紫染液染色15min,吸除染色液,用PBS洗3次,在每个小室选取9个视野进行拍照并计数,细胞数以表示。
实验结果:
实验结果列入表3:
表3化合物7抑制A549细胞侵袭的活性
注:n=6,给药方式均为灌胃,经t检验;a)表示与空白对照组相比P<0.01且与RGDS组相比P>0.05.
结果表明,加入化合物7的组别的细胞侵袭数(197.78±26.00)与阴性对照组生理盐水有显著性差别(252.78±17.49,P<0.01),且与阳性对照组RGDS的抑制细胞侵袭数(205.33±24.78,P>0.05)无显著性差异。可见,20μmol/L浓度的化合物7可抑制人非小细胞肺癌细胞A549的侵袭,并与同浓度下的RGDS的抑制癌细胞侵袭的活性相当。
实施例15评价化合物7抑制小鼠肿瘤转移的活性
实验动物:
C57BL/6小鼠,雄性,20±2g,购自北京维通利华实验动物技术有限公司。
给药剂量及给药方式:
本发明的化合物3S-1-(1,1-二甲基-1,3-二氧六环-6-螺基)-1,2,3,4-四氢-β-咔啉-3-甲酰-The-His-Gly-Glu(化合物7)的口服剂量为0.23μmol/kg,阳性对照RGDS四肽的注射剂量为20μmol/kg,阴性对照为生理盐水。
实验方法:实验采用小鼠Lewis抗肺癌转移模型。
实验操作:
Lewis小鼠肺癌细胞(LLC),购自ATCC。选用DMEM培养基,其中含10%经灭活的胎牛血清,1×105U/L青霉素和100mg/L链霉素。按照贴壁细胞培养方法,每两天传代一次,富集细胞。待细胞生长状态良好,处于对数生长期时,消化细胞。用生理盐水调整细胞浓度至2×107个/mL,胎盘蓝(Tryanblue)染色计数,活细胞数>95%。取近交系C57BL/6雄性小鼠,左手固定小鼠,用75%乙醇消毒小鼠右前肢腋窝皮肤,右手持1mL无菌注射器于小鼠腋部皮下注射LLC肿瘤细胞悬液0.2mL/只。小鼠接种后10天可以长出直径约4-5mm的肿瘤,作为瘤源备用。
取接种8-10天生长良好的Lewis肺癌荷瘤小鼠,乙醚麻醉,脱颈椎处死,用75%的乙醇浸泡消毒10min,在超净工作台上剥离瘤体,选择生长良好的肿瘤组织,在无菌平皿中剪碎,放置于玻璃组织匀浆器内,按瘤块重(g):生理盐水体积(mL)为1:3的比例加入4℃预冷的生理盐水轻轻研磨,制成细胞悬液,过200目细胞筛制成单细胞悬液,用生理盐水调整细胞浓度为2×107个/mL,胎盘蓝染色计数,活细胞数>95%。
取近交系C57BL/6雄性小鼠,左手固定小鼠,用75%乙醇消毒小鼠右前肢腋窝皮肤,右手持1mL无菌注射器于小鼠腋部皮下注射LLC肿瘤细胞悬液0.2mL/只。接种10天后长出直径约4-5mm的肿瘤,测量肿瘤体积,按肿瘤平均体积随机分组,
从接种肿瘤第10天后开始给药,共给药10次,每隔两天测量并记录肿瘤体积。第22天后,乙醚麻醉小鼠,脱颈椎处死,取出肿瘤称重,并记录肿瘤的肺部转移率和转移瘤结数。
实验结果:
实验结果列入表4:
表4化合物7抑制肿瘤肺转移的活性
注:n=12,RGDS为腹腔注射给药,其他均为灌胃方式给药,经t检验;a)与生理盐水组相比,P<0.05且与RGDS组相比,P<0.05.
结果表明,0.23μmol/kg剂量下口服化合物7治疗的小鼠的体内抗肿瘤转移瘤结数(2.80±2.53)与阴性对照组生理盐水有显著性差别(9.38±2.62,P<0.05),且与阳性对照组RGDS也有显著性差别(4.50±2.25,P<0.05)可见,化合物7在口服剂量低至0.23μmol/kg时较腹腔注射剂量为20μmol/kg/天的RGDS的抑制肿瘤转移的活性更好。可见,本发明有突出的技术效果。
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