CN109180521B - 一种抗肿瘤化合物及其制备方法、用途 - Google Patents

一种抗肿瘤化合物及其制备方法、用途 Download PDF

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CN109180521B
CN109180521B CN201811031515.2A CN201811031515A CN109180521B CN 109180521 B CN109180521 B CN 109180521B CN 201811031515 A CN201811031515 A CN 201811031515A CN 109180521 B CN109180521 B CN 109180521B
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欧阳勤
单长宇
惠文其
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Abstract

本发明属于药物技术领域，尤其涉及一种抗肿瘤化合物及其制备方法、用途，所述抗肿瘤化合物包括具有符合式Ⅰ所示的分子结构：
Figure DDA0001789865170000011
式Ⅰ，其中，R1、R2、R3分别独立选自取代或未取代的苯基、C1‑C6烷基、C1‑C6烷氧基、C1‑C6直链烷氨基、C1‑C6醇基、C3‑C6环烷基、含有N、S、O中的至少一种的C5‑C6芳族杂环基、吗啉基、萘基中的一种；本发明化合物具备优异的抑制肿瘤细胞增殖的潜能，并展示出抑制多种耐药肿瘤细胞增殖的生物活性，同时本发明化合物还具有诱导耐药肿瘤细胞株对抗肿瘤药增敏作用，具有良好的临床应用前景，为肿瘤治疗提供新的思路和希望，其制备方法简单。

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一种抗肿瘤化合物及其制备方法、用途
技术领域
本发明属于药物技术领域，尤其涉及一种抗肿瘤化合物及其制备方法、用途。
背景技术
肿瘤是严重危害人类健康的重大疾病，发病率呈逐年上升，一直是生物学和医学界研究的重心和难题。目前，细胞毒类抗肿瘤药物依然是临床上抗肿瘤治疗的主要选择，这些药物包括：1.作用于DNA化学结构的药物如：氮芥、环磷酰胺、塞替派、卡莫司汀、白消安、顺铂、丝裂霉素；2.影响核酸合成的药物如：甲氨蝶呤、卡培他滨、6-巯基嘌呤、羟基脲等、阿糖胞苷等；3.作用于核酸转录的药物如：柔红霉素、阿霉素等；4.DNA复制的拓扑异构酶Ⅰ抑制剂如：伊立替康、拓扑替康、羟基喜树碱等；5.主要作用于有丝分裂M期干扰微管蛋白合成的药物如：紫杉醇、长春新碱等。众所周知，近年来，越来越多的肿瘤对传统抗肿瘤药物的治疗产生了耐药，这使得肿瘤耐药已成为了目前临床恶性肿瘤治疗过程中面临的一个非常棘手的问题。所谓肿瘤耐药，就是由于肿瘤细胞群为了自我生存而抵抗肿瘤治疗药物形成的一种自我保护机制，其主要机制是肿瘤对相关细胞因子进行调控，从而降低细胞对化疗药物的敏感性。因此研发新型结构和功能的抗肿瘤药物，实现高效、低毒、稳定的治疗目标已成为目前抗癌药物研究的方向。
发明内容
本发明为了解决上述技术问题提供一种抗肿瘤化合物，本发明化合物具备优异的抑制肿瘤细胞增殖的潜能，并展示出抑制多种耐药肿瘤细胞增殖的生物活性，同时本发明化合物还具有诱导耐药肿瘤细胞株对抗肿瘤药增敏作用，具有良好的临床应用前景，为肿瘤治疗提供新的思路和希望，其制备方法简单。
本发明解决上述技术问题的技术方案如下。
本发明提供一种抗肿瘤化合物，包括具有符合式Ⅰ所示的分子结构：
Figure GDA0003072966590000021
其中，R1、R2、R3分别独立选自取代或未取代的苯基、C1-C6烷基、C1-C6烷氧基、C1-C6直链烷氨基、C1-C6醇基、C3-C6环烷基、含有N、S、O中的至少一种的C5-C6芳族杂环基、吗啉基、萘基中的一种。
本发明的有益效果是：本发明化合物具备优异的抑制肿瘤细胞增殖的潜能，并展示出抑制多种耐药肿瘤细胞增殖的生物活性，同时本发明化合物还具有诱导耐药肿瘤细胞株对抗肿瘤药增敏作用，具有良好的临床应用前景，为肿瘤治疗提供新的思路和希望，其制备方法简单。
在上述技术方案的基础上，本发明还可以做如下改进。
进一步，所述R1、R2、R3选自下述结构中的任意一种：
Figure GDA0003072966590000022
其中，*代表能够与母核结构键合的键合位点，n为1-5中任一整数；
所述R4、R5、R6、R7、R8选自下述结构中的任一种：-CF3、-NO2、-NH2、-CH3、-CH2CH3、-C(CH3)3、-OCH3、-OCH2CH3、-OH、-F、-Cl、-Br、-I、-H；
所述R为N；
所述Y为NH、O或S。
进一步，所述式Ⅰ的具体化合物结构式为下述化合物A1至化合物A58中的一种：
Figure GDA0003072966590000031
Figure GDA0003072966590000041
Figure GDA0003072966590000051
Figure GDA0003072966590000061
本发明提供一种抗肿瘤化合物的制备方法，包括以下步骤：
A、将化合物1a、甲醇与酸混匀反应得到化合物1b，其反应方程式为：
Figure GDA0003072966590000062
B、将步骤A中得到的化合物1b、化合物2a与碱加入到有机溶剂中，反应得到化合物2b，其反应方程式为：
Figure GDA0003072966590000063
其中，Z为F、Cl、Br或I；
C、将步骤B中得到的化合物2b、化合物3a加入到有机溶剂中，反应得到化合物3b，其反应方程式为：
Figure GDA0003072966590000064
D、将步骤C中得到的化合物3b与硼氢化钠加入到有机溶剂中，反应得到化合物4b，其反应方程式为：
Figure GDA0003072966590000071
E、将步骤D中得到的化合物4b、化合物5a、催化剂与碱加入到有机溶剂中，反应得到本发明产品，其反应方程式为：
Figure GDA0003072966590000072
进一步，在步骤A中，所述反应温度为85-95℃，反应时间为2-24h；
在步骤B中，所述反应温度为70-80℃，反应时间为2-24h；
在步骤C中，所述反应温度为70-80℃，反应时间为3-6h；
在步骤D中，所述反应温度为24-25℃，反应时间为12-18h；
在步骤E中，所述反应温度为80-90℃，反应时间为2-24h。
进一步，在步骤A中，所述化合物1a与甲醇的摩尔比为1：(10-20)，所述酸为质量分数98.3％的浓硫酸，所述化合物1a与浓硫酸的摩尔比为1：(1.5-2.0)；
在步骤B中，所述化合物1b与所述化合物2a的摩尔比为1：(1-3)，所述碱为碳酸钾，所述化合物1b与碳酸钾的摩尔比为1：(2-3)，所述有机溶剂为甲苯或二甲基甲酰胺，该有机溶剂仅作为反应体系不参与反应作用。
进一步，在步骤C中，所述化合物2b与所述化合物3a的摩尔比为1：(1-3)，所述有机溶剂为甲苯，该有机溶剂仅作为反应体系不参与反应作用；
在步骤D中，所述化合物3b与硼氢化钠的摩尔比为1：(5-8)，所述有机溶剂为甲醇，该有机溶剂仅作为反应体系不参与反应作用；
在步骤E中，所述化合物4b与所述化合物5a的摩尔比为1：(1-3)，所述催化剂为三氟乙醇，所述化合物4b与三氟乙醇的摩尔比为1：(0.2-0.5)，所述碱为磷酸钾，所述化合物4b与磷酸钾的摩尔比为1：(1-2)；所述有机溶剂为四氢呋喃，该有机溶剂仅作为反应体系不参与反应作用。
本发明提供一种抗肿瘤化合物在制备治疗乳腺癌、胃癌和/或食管癌药物中的应用。
本发明还提供一种治疗乳腺癌、胃癌和/或食管癌的药物组合物，由上述抗肿瘤化合物与长春新碱或顺铂组成，所述抗肿瘤化合物与长春新碱的摩尔比为(3.33-53.33)：1，所述抗肿瘤化合物与顺铂的摩尔比为(0.27-0.8)：1。
进一步，所述长春新碱与抗肿瘤化合物A13的摩尔比为1：3.33、1:13.33、1:26.66、1:40、1:53.33；
所述长春新碱与抗肿瘤化合物A23的摩尔比为1：3.33、1:13.33、1:26.66、1:40、1:53.33；
所述顺铂与抗肿瘤化合物A13的摩尔比为1:0.27、1:0.4、1:0.53、1:0.67、1:0.8；
所述顺铂与抗肿瘤化合物A23的摩尔比为1:0.33、1:0.4、1:0.47、1:0.53、1:0.67。
附图说明
图1为本发明化合物A11的1H NMR图谱；
图2为本发明化合物A19的1H NMR图谱；
图3为本发明化合物A39的1H NMR图谱；
图4为本发明化合物A47的1H NMR图谱；
图5为本发明化合物A13的1H NMR图谱；
图6为本发明化合物A16的1H NMR图谱；
图7为本发明化合物A23的1H NMR图谱；
图8为本发明化合物A27的1H NMR图谱；
图9为本发明化合物A13、长春新碱及其二者联用时对Eca109/VCR耐药株增殖抑制作用柱状分析图；
图10为本发明化合物A23、长春新碱及其二者联用时对Eca109/VCR耐药株增殖抑制作用柱状分析图；
图11为本发明化合物A13、顺铂及其二者联用时对Eca109/VCR耐药株增殖抑制作用柱状图；
图12为本发明化合物A23、顺铂及其二者联用时对Eca109/VCR耐药株增殖抑制作用柱状分析图。
具体实施方式
以下对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。
实施例1：化合物A19的制备：
A、化合物1b的制备
Figure GDA0003072966590000091
取原料3.32g 5-甲酰水杨酸(20mmol)、10mL甲醇(247.4mmol)、2mL浓硫酸(11.1mmol)加入到反应容器中，而后90℃加热至回流，采用薄层色谱法(TLC)跟踪反应进程，5.0小时反应完毕后，将反应体系冷却至25℃，加入20％(20g/100mL)Na2CO3水溶液200mL，分液洗涤，将有机相用无水硫酸钠干燥，得到3.6g化合物1b，收率为99.98％。
B、化合物2b的制备
Figure GDA0003072966590000101
取步骤A中获得的化合物1b 0.9g(5mmol)、4-(三氟甲基)溴苄1.3g(5.5mmol)、碳酸钾1.38g(10mmol)加入到35mL二甲基甲酰胺中，加热至70℃反应，采用薄层色谱法(TLC)跟踪反应进程，5.0小时反应完毕后，将体系温度降低至25℃，然后用水洗涤，将有机相减压脱溶剂至无馏分，得到1.3g化合物2b，收率为76.90％。
C、化合物3b的制备
Figure GDA0003072966590000102
取步骤B中获得的化合物2b 1.014g(3mmol)和环己甲胺390μL(3mmol)加入到50mL甲苯中，75℃加热至回流，采用薄层色谱法(TLC)跟踪反应进程，3.0小时反应完毕后，将体系温度降低至25℃，将有机相减压脱溶剂至无馏分，然后用石油醚乙酸乙酯混合液对残留物进行柱层析纯化，其中石油醚与乙酸乙酯体积比为石油醚：乙酸乙酯＝1:1，得到1.001g化合物3b，收率为74.81％。
D、化合物4b的制备
Figure GDA0003072966590000103
取步骤C中获得的化合物3b 0.9g(2mmol)和硼氢化钠0.378g(10mmol)加入到60mL甲醇中，75℃加热至回流，25℃下反应，12.0小时反应完毕后，向反应体系中加入氯化铵5.0g，25℃下搅拌0.5h，而后加入乙酸乙酯100mL进行萃取，取有机相减压脱溶剂至无馏分，然后用石油醚乙酸乙酯混合液对残留物进行柱层析纯化，其中石油醚与乙酸乙酯体积比为石油醚：乙酸乙酯＝1:1，得到0.7455g化合物4b，收率为86.25％。
E、化合物A19的制备
Figure GDA0003072966590000111
取步骤D中获得的化合物4b 0.6483g(1.5mmol)、对甲基苄胺286μL(2.25mmol)、三氟乙醇22μL(0.3mmol)、磷酸钾318.4mg(1.5mmol)加入到128.4mL四氢呋喃中，加热至90℃反应，同时TLC跟踪反应进程，22.0小时反应完毕后，将体系冷却至25℃，对有机相减压脱溶剂至无馏分，然后用石油醚乙酸乙酯混合液对残留物进行柱层析纯化，其中石油醚与乙酸乙酯体积比为石油醚：乙酸乙酯＝1:1，得到0.6424g化合物A19，收率为81.69％。利用600MHz核磁氢谱确定化合物A19结构式：
1H NMR(600MHz,CDCl3)δ8.18(s,1H),8.01(s,1H),7.47(d,J＝7.5Hz,3H),7.35(d,J＝7.8Hz,2H),7.07(q,J＝7.8Hz,4H),6.98(d,J＝8.4Hz,1H),5.14(s,2H),4.53(d,J＝4.9Hz,2H),3.78(s,2H),2.45(d,J＝6.5Hz,2H),2.34(s,3H),1.68(dd,J＝27.0,12.7Hz,5H),1.47(s,1H),1.28-1.19(m,2H),1.14(d,J＝12.3Hz,1H),0.93-0.83(m,2H)。
实施例2：化合物A39的制备：
Figure GDA0003072966590000121
化合物2a换为间硝基溴苄，化合物3a换为对甲基苯甲氨，化合物5a换为己胺，其余同实施例一,得到产物A39，收率为76.13％。利用600MHz核磁氢谱确定化合物A39结构式：1HNMR(600MHz,CDCl3)δ8.32(s,1H),8.25(d,J＝8.1Hz,1H),8.08(d,J＝1.7Hz,1H),7.78(d,J＝7.6Hz,1H),7.63(d,J＝7.9Hz,1H),7.60(d,J＝4.9Hz,1H),7.52(dd,J＝8.4,1.7Hz,1H),7.23(d,J＝7.8Hz,2H),7.14(d,J＝7.7Hz,2H),7.01(d,J＝8.5Hz,1H),5.25(s,2H),3.86(d,J＝6.2Hz,4H),3.35(dd,J＝12.9,6.8Hz,2H),1.40-1.33(m,2H),1.18(dd,J＝15.9,8.2Hz,6H),0.83(t,J＝6.8Hz,3H)。
实施例3：化合物A11的制备
Figure GDA0003072966590000122
化合物2a换为对甲基溴苄，化合物5a换为2-吡啶甲基胺，其余同实施例1，得到产物A11，收率为73.61％，利用600MHz核磁氢谱确定化合物A11结构式：1H NMR(600MHz,cdcl3)δ8.86(t,J＝4.6Hz,1H),8.35(d,J＝4.5Hz,1H),8.16(s,1H),7.58(t,J＝7.7Hz,1H),7.52(d,J＝8.3Hz,1H),7.27(s,3H),7.21(d,J＝7.8Hz,1H),7.16-7.11(m,1H),7.09(d,J＝7.6Hz,2H),7.04(d,J＝8.5Hz,1H),5.15(s,2H),4.72(d,J＝5.0Hz,2H),3.88(s,2H),2.52(d,J＝6.8Hz,2H),2.32(s,3H),1.74(d,J＝12.6Hz,2H),1.68(d,J＝13.1Hz,2H),1.63(d,J＝13.2Hz,1H),1.58(s,1H),1.22(dd,J＝14.8,10.8Hz,2H),1.15-1.06(m,1H),0.92-0.83(m,2H).13CNMR(151MHz,cdcl3)165.05,156.95,156.69,148.92,138.26,136.61,133.58,133.03,132.40,129.40,127.90,121.97,121.75,121.54,113.38,71.30,53.85,51.48,45.33,36.31,30.98,26.26,25.71,21.20。
实施例4：化合物A47的制备
Figure GDA0003072966590000131
化合物3a换为2-羟基乙胺，化合物5a换为3-甲基苄胺，其余同实施例1,得到产物A4，收率为79.33％。利用600MHz核磁氢谱确定化合物A4结构式：1H NMR(600MHz,cdcl3)δ8.21(d,J＝1.8Hz,1H),8.07(s,1H),7.46(d,J＝7.8Hz,3H),7.34(d,J＝8.0Hz,2H),7.14(t,J＝7.5Hz,1H),7.08(d,J＝7.7Hz,1H),7.04(s,1H),6.99(t,J＝7.4Hz,2H),5.15(s,2H),4.54(d,J＝5.3Hz,2H),3.83(s,2H),3.70-3.60(m,2H),2.89-2.75(m,2H),2.28(s,3H)。
实施例5：化合物A13的制备
Figure GDA0003072966590000132
化合物2a换为对甲基溴苄，化合物5a换为己胺，其余同实施例1,得到产物A13，收率为82.64％。利用600MHz核磁氢谱确定化合物A13结构式：1HNMR(600MHz,cdcl3)δ8.13(d,J＝2.1Hz,1H),7.91(t,J＝4.9Hz,1H),7.49(dd,J＝8.4,2.1Hz,1H),7.30(d,J＝7.9Hz,2H),7.20(d,J＝7.8Hz,2H),7.02(d,J＝8.5Hz,1H),3.80(s,2H),3.30(dd,J＝12.5,6.9Hz,2H),2.46(d,J＝6.8Hz,2H),2.37(s,3H),1.74(d,J＝12.6Hz,2H),1.67(d,J＝13.1Hz,2H),1.62(d,J＝12.5Hz,1H),1.57–1.48(m,1H),1.31(dd,J＝14.0,7.0Hz,2H),1.25–1.09(m,9H),0.93–0.86(m,2H),0.84(t,J＝7.2Hz,3H).13CNMR(151MHz,cdcl3)δ164.86,156.19,138.62,132.87,132.44,132.43,129.52,129.50,128.17,121.53,112.83,71.39,54.94,52.37,39.80,37.12,31.46,31.23,29.02,26.58,26.46,25.88,22.42,21.20。
实施例6：化合物A16的制备
Figure GDA0003072966590000141
化合物2a换为间硝基溴苄，化合物5a换为己胺，其余同实施例1,得到产物A16，收率为77.92％。利用600MHz核磁氢谱确定化合物A16结构式：1HNMR(600MHz,cdcl3)δ8.34(s,1H),8.26(d,J＝8.2Hz,1H),8.10(d,J＝2.0Hz,1H),7.79(d,J＝7.6Hz,1H),7.62(dd,J＝14.2,6.3Hz,2H),7.44(dd,J＝8.4,2.0Hz,1H),6.98(d,J＝8.4Hz,1H),5.26(s,2H),3.76(s,2H),3.38(dd,J＝12.8,7.0Hz,2H),2.44(d,J＝6.7Hz,2H),1.75–1.62(m,8H),1.50–1.43(m,1H),1.38(dd,J＝13.9,6.9Hz,2H),1.22–1.16(m,7H),0.90(dt,J＝21.4,6.1Hz,2H),0.83(d,J＝7.0Hz,2H)。
实施例7：化合物A23的制备
Figure GDA0003072966590000142
化合物5a换为环己甲胺，其余同实施例1,得到产物A23，收率为73.39％。利用600MHz核磁氢谱确定化合物A23结构式：1H NMR(600MHz,cdcl3)δ8.13(d,J＝2.2Hz,1H),7.73(s,1H),7.70(d,J＝8.1Hz,2H),7.58(d,J＝8.0Hz,2H),7.44(dd,J＝8.4,2.2Hz,1H),6.99(d,J＝8.4Hz,1H),5.20(s,2H),3.76(s,2H),3.21(t,J＝6.2Hz,2H),2.44(d,J＝6.7Hz,2H),1.77–1.68(m,4H),1.65(d,J＝12.4Hz,1H),1.59(d,J＝9.5Hz,4H),1.52(d,J＝13.5Hz,2H),1.49–1.42(m,1H),1.30(dd,J＝7.0,3.6Hz,1H),1.23(dt,J＝15.6,10.9Hz,2H),1.18–1.12(m,1H),1.05(d,J＝8.5Hz,2H),0.94–0.85(m,2H),0.78(t,J＝11.7Hz,2H)。
实施例8：化合物A27的制备
Figure GDA0003072966590000151
化合物5a换为间甲基苄胺，其余同实施例1,得到产物A27，收率为84.26％。利用600MHz核磁氢谱确定化合物A27结构式：1H NMR(600MHz,cdcl3)δ8.19(d,J＝2.0Hz,1H),8.06(s,1H),7.50(dd,J＝8.3,1.8Hz,1H),7.45(d,J＝8.1Hz,2H),7.33(d,J＝8.0Hz,2H),7.13(t,J＝7.5Hz,1H),7.07(d,J＝7.5Hz,1H),7.04(s,1H),6.98(t,J＝7.0Hz,2H),5.13(s,2H),4.53(d,J＝5.3Hz,2H),3.82(s,2H),2.47(d,J＝6.7Hz,2H),2.28(s,3H),1.75(d,J＝12.6Hz,2H),1.70(d,J＝13.0Hz,2H),1.65(d,J＝12.6Hz,1H),1.52(dtd,J＝11.1,7.5,3.7Hz,1H),1.26–1.21(m,2H),1.17–1.12(m,1H),0.90(td,J＝12.3,9.4Hz,2H).13CNMR(151MHz,cdcl3)δ164.79,155.52,139.16,138.28,137.96,132.92,132.48,130.46,128.75,128.54,128.23,127.63,125.73,125.71,125.68,125.66,124.91,121.50,112.72,70.44,55.48,52.68,44.08,37.44,31.32,26.54,25.94,21.22。
实验例9：化合物抑制人乳腺癌细胞MCF-7增殖实验
(1)细胞收集
a.乳腺癌细胞株MCF-7(购于美国模式培养物集存库(ATCC))用完全培养基(含有10％体积胎牛血清和1％体积青链双抗的DMEM培养基)在37℃，5％CO2条件下培养48小时后，显微镜观察细胞生长状态，待细胞融汇度达到80％-90％后从孵箱取出；
b.真空泵吸出培养基，用PBS缓冲液洗涤细胞一次，吸出PBS，向培养皿中加入1mL预热至室温的胰酶消化液，37℃孵箱消化2分钟；
c.加入5mL预热至37℃的完全培养基终止消化，并用移液枪反复轻柔吹打培养皿底，使细胞脱落形成细胞悬液；
d.将细胞悬液转入15mL离心管中，并用培养基补齐至10mL，用低速离心机以800rpm转速离心5min后吸出上清，加入10mL完全培养基重悬细胞。
(2)细胞铺板
a.取96孔板一块，于四周36个孔中各加入PBS缓冲液100μL封板，在中央的60个孔中各加入90μL上述细胞悬液，此时各孔中细胞数为5000个/孔；
b.将接种好细胞的96孔板放回37℃孵箱继续培养过夜使细胞贴壁。
(3)加药处理
a.精密称量本发明合成的(A1-A50)化合物后用二甲基亚砜(DMSO)配制成50mmol的药物母液，并用完全培养基(含有10％体积胎牛血清和1％体积青链双抗的DMEM培养基)稀释至10、20、40、80、160、320、640微摩尔/升的系列浓度梯度药液；
b.将以上稀释后的药液按照10μL/孔的剂量加入到对应的细胞接种孔中，每个浓度设置3个复孔(此时各孔中化合物终浓度为1、2、4、8、16、32、64μmol/L)，同时设置阴性对照孔(加入体积分数0.1％的二甲基亚砜完全培养基溶液)和空白对照孔(不含细胞和药液)；
c.加完药后充分振摇孔板，使药液充分混匀，后放回37℃孵箱继续培养24h。
(4)细胞增殖活力检测
a.向各孔加入10μL3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)溶液(5mg/mL)，充分振摇孔板后放回37℃孵箱继续培养4h；
b.用真空泵小心吸出各孔上清液，避免吸走孔底的紫色结晶；
c.向各孔加入150μL DMSO，将孔板放置在平板震荡仪上低速震荡10min，使孔底结晶充分溶解；
d.用酶标仪在490nm波长处读取各孔OD值；
e.计算各化合物抑制乳腺癌细胞株MCF-7增殖的半数抑制浓度(EC50)。
实验结果显示：化合物A1-A50均能发挥抑制乳腺癌细胞株MCF-7增殖的生物学活性，其EC50值如下表1所示，说明系列化合物均能对MCF-7细胞的增殖产生抑制作用，其中化合物A13、A16、A19、A23、A27、A45生物活性较高，EC50值达到5μmol/L以下。
Figure GDA0003072966590000171
表1
Figure GDA0003072966590000172
Figure GDA0003072966590000181
实验例10：化合物抑制耐药肿瘤细胞株增殖实验
(1)细胞收集
a.耐阿霉素乳腺癌细胞株MCF-7/ADR、耐紫杉醇肺癌细胞株A549/TAX、耐长春新碱胃癌细胞株SGC-7901/VCR、耐顺铂胃癌细胞株SGC-7901/VCR、耐长春新碱食管癌细胞株Eca109/VCR、以及上述细胞株的亲本细胞：MCF-7、A549、SGC-7901、Eca109用完全培养基(含有10％体积胎牛血清和1％体积青链双抗)在37℃，5％CO2条件下培养48小时后，显微镜观察细胞生长状态，待细胞融汇度达到80％-90％后从孵箱取出；(以上亲本细胞MCF-7、A549购于美国模式培养物集存库(ATCC)，SGC-7901、Eca109细胞系购于中国科学院典型培养物保藏委员会细胞库；耐药肿瘤细胞株MCF-7/ADR、A549/TAX、SGC-7901/VCR、SGC-7901/VCR、Eca109/VCR购于上海美轩生物科技有限公司。)
b.真空泵吸出培养基，用PBS缓冲液洗涤细胞一次，吸出PBS，向培养皿中加入1mL预热至室温的胰酶消化液，37℃孵箱消化2分钟；
c.加入5mL预热至37℃的完全培养基终止消化，并用移液枪反复轻柔吹打培养皿底，使细胞脱落形成细胞悬液；
d.将细胞悬液转入15mL离心管中，并用培养基补齐至10mL，用低速离心机以800rpm转速离心5min后吸出上清，加入10mL培养基重悬细胞。
(2)细胞铺板
a.取96孔板一块，于四周36个孔中各加入PBS缓冲液100μL封板，在中央的60个孔中各加入90μL上述细胞悬液，此时各孔中细胞数为5000个/孔；
b.将接种好细胞的96孔板放回37℃孵箱继续培养过夜使细胞贴壁。
(3)加药处理
a.精密称量本发明合成的A13、A16、A19、A23、A27化合物后用二甲基亚砜(DMSO)配制成50mmol/L的药物母液，并用完全培养基(含有10％体积胎牛血清和1％体积青链双抗的DMEM培养基)稀释至10-200微摩尔/升的系列浓度梯度药液，长春新碱(VCR)配成3微摩尔/升的药液，顺铂(DDP)配成150微摩尔/升的药液，紫杉醇(TAX)配成1.5微摩尔/升的药液，阿霉素(ADR)配成50微摩尔/升的药液；
b.将以上稀释后的药液按照10μL/孔的剂量加入到对应的细胞接种孔中，每个浓度设置3个复孔，同时设置阴性对照孔(加入体积分数0.1％的二甲基亚砜完全培养基溶液)和空白对照孔(不含细胞和药液)；
此外耐阿霉素乳腺癌细胞株MCF-7/ADR、耐紫杉醇肺癌细胞株A549/TAX、耐长春新碱胃癌细胞株SGC-7901/VCR、耐顺铂胃癌细胞株SGC-7901/VCR、耐长春新碱食管癌细胞株Eca109/VCR五种耐药肿瘤细胞株同时设置联合给药组，即MCF-7/ADR细胞同时给予10-200微摩尔/升的系列浓度梯度药液和50微摩尔/升的阿霉素各10μL；A549/TAX细胞同时给予10-200微摩尔/升的系列浓度梯度药液和1.5微摩尔/升的紫杉醇各10μL；SGC-7901/DDP细胞同时给予10-200微摩尔/升的系列浓度梯度药液和150微摩尔/升的顺铂各10μL；SGC-7901/VCR细胞同时给予10-200微摩尔/升的系列浓度梯度药液和3微摩尔/升的长春新碱各10μL；Eca109/VCR细胞同时给予10-200微摩尔/升的系列浓度梯度药液和3微摩尔/升的长春新碱各10μL(此时各孔中化合物A13、A16、A19、A23、A27的终浓度为1-20μmol/L，VCR的终浓度为0.3μmol/L，DDP的终浓度为15μmol/L,TAX的终浓度为0.15μmol/L，ADR的终浓度为5μmol/L，VCR与A13的摩尔比例为1:3.33,1:13.33,1:26.66,1:40,1:53.33,VCR与A23的摩尔比例为1:3.33,1:13.33,1:26.66,1:40,1:53.33，DDP与A13的摩尔比例为1：0.27,1:0.4,1:0.53,1:0.67,1:0.8，DDP与A23的摩尔比例为1：0.33,1:0.4,1:0.47,1:0.53,1:0.67)。
c.加完药后充分振摇孔板，使药液充分混匀，后放回37℃孵箱继续培养24h。
(4)细胞增殖活力检测
a.向各孔加入10μL 3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)溶液(5mg/mL)，充分振摇孔板后放回37℃孵箱继续培养4h；
b.用真空泵小心吸出各孔上清液，避免吸走孔底的紫色结晶；
c.向各孔加入150μL DMSO，将孔板放置在平板震荡仪上低速震荡10min，使孔底结晶充分溶解；
d.用酶标仪在490nm波长处读取各孔OD值；
e.计算化合物A13、A16、A19、A23、A27及以化合物与抗肿瘤药共处理时抑制各细胞株增殖的半数抑制浓度(EC50)。
其实验结果数据如下表2、表3、表4与表5所示：
表2
Figure GDA0003072966590000211
表3
Figure GDA0003072966590000212
Figure GDA0003072966590000221
表4
Figure GDA0003072966590000222
表5
Figure GDA0003072966590000223
从表2-5实验结果显示：化合物A13、A16、A19、A23、A27耐药肿瘤细胞株的增殖有显著的抑制活性，其EC50范围在4-20μmol/L；从附图9-12验结果显示：化合物A13、A23在低浓度时(＜10μmol/L)与15μmol/L的顺铂和0.3μmol/L的长春新碱共处理SGC-7901/DDP和Eca109/VCR肿瘤耐药株后，能够使15μmol/L的顺铂和0.3μmol/L的长春新碱对SGC-7901/DDP和Eca109/VCR肿瘤耐药株增殖的抑制率显著增加，提示化合物A13、A23可与抗肿瘤药物产生协同效应，在低浓度(＜10μmol/L)时能够提升SGC-7901/DDP和Eca109/VCR肿瘤耐药株对顺铂和长春新碱的敏感性。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (8)

1.一种抗肿瘤化合物，其特征在于，该抗肿瘤化合物的具体化合物结构式为下述化合物中的一种：
Figure FDA0003072966580000011
Figure FDA0003072966580000021
Figure FDA0003072966580000031
2.一种抗肿瘤化合物的制备方法，其特征在于，包括以下步骤：
A、将化合物1a、甲醇与酸混匀反应得到化合物1b，其反应方程式为：
Figure FDA0003072966580000032
B、将步骤A中得到的化合物1b、化合物2a与碱加入到有机溶剂中，反应得到化合物2b，其反应方程式为：
Figure FDA0003072966580000033
其中，Z为F、Cl、Br或I，R1为
Figure FDA0003072966580000041
Figure FDA0003072966580000042
其中，*代表能够与母核结构键合的键合位点；
C、将步骤B中得到的化合物2b、化合物3a加入到有机溶剂中，反应得到化合物3b，其反应方程式为：
Figure FDA0003072966580000043
其中，R2为
Figure FDA0003072966580000044
Figure FDA0003072966580000045
其中，*代表能够与母核结构键合的键合位点；
D、将步骤C中得到的化合物3b与硼氢化钠加入到有机溶剂中，反应得到化合物4b，其反应方程式为：
Figure FDA0003072966580000046
E、将步骤D中得到的化合物4b、化合物5a、催化剂与碱加入到有机溶剂中，反应得到本发明产品，其反应方程式为：
Figure FDA0003072966580000047
其中，R3为
Figure FDA0003072966580000051
Figure FDA0003072966580000052
Figure FDA0003072966580000053
其中，*代表能够与母核结构键合的键合位点。
3.根据权利要求2所述抗肿瘤化合物的制备方法，其特征在于，在步骤A中，反应温度为85-95℃，反应时间为2-24h；
在步骤B中，反应温度为70-80℃，反应时间为2-24h；
在步骤C中，反应温度为70-80℃，反应时间为3-6h；
在步骤D中，反应温度为24-25℃，反应时间为12-18h；
在步骤E中，反应温度为80-90℃，反应时间为2-24h。
4.根据权利要求3所述抗肿瘤化合物的制备方法，其特征在于，在步骤A中，所述化合物1a与甲醇的摩尔比为1：(10-20)，所述酸为质量分数98.3％的浓硫酸，所述化合物1a与浓硫酸的摩尔比为1：(1.5-2.0)；
在步骤B中，所述化合物1b与所述化合物2a的摩尔比为1：(1-3)，所述碱为碳酸钾，所述化合物1b与碳酸钾的摩尔比为1：(2-3)，所述有机溶剂为甲苯或二甲基甲酰胺。
5.根据权利要求3所述抗肿瘤化合物的制备方法，其特征在于，在步骤C中，所述化合物2b与所述化合物3a的摩尔比为1：(1-3)，所述有机溶剂为甲苯；
在步骤D中，所述化合物3b与硼氢化钠的摩尔比为1：(5-8)，所述有机溶剂为甲醇；
在步骤E中，所述化合物4b与所述化合物5a的摩尔比为1：(1-3)，所述催化剂为三氟乙醇，所述化合物4b与三氟乙醇的摩尔比为1：(0.2-0.5)，所述碱为磷酸钾，所述化合物4b与磷酸钾的摩尔比为1：(1-2)；所述有机溶剂为四氢呋喃。
6.一种如权利要求1所述抗肿瘤化合物在制备治疗乳腺癌、胃癌与食管癌药物中的应用。
7.一种治疗乳腺癌、胃癌与食管癌的药物组合物，其特征在于，由权利要求1所述抗肿瘤化合物与长春新碱或顺铂组成，所述抗肿瘤化合物与长春新碱的摩尔比为(3.33-53.33)：1，所述抗肿瘤化合物与顺铂的摩尔比为(0.27-0.8)：1。
8.根据权利要求7所述一种治疗乳腺癌、胃癌与食管癌的药物组合物，其特征在于，
所述长春新碱与抗肿瘤化合物A23的摩尔比为1：3.33、1:13.33、1:26.66、1:40、1:53.33；
所述顺铂与抗肿瘤化合物A23的摩尔比为1:0.33、1:0.4、1:0.47、1:0.53、1:0.67。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5872138A (en) * 1996-09-13 1999-02-16 Merck & Co., Inc. Thrombin inhibitors
CN104292154A (zh) * 2009-09-29 2015-01-21 葛兰素集团有限公司 新化合物
CN104592091A (zh) * 2015-01-27 2015-05-06 冉瑞琼 一种含吲哚乙酸核心结构的化合物及其应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9487500B2 (en) * 2012-10-04 2016-11-08 Inhibikase Therapeutics, Inc. Compounds and compositions thereof
WO2015042275A1 (en) * 2013-09-18 2015-03-26 Sloan-Kettering Institute For Cancer Research Methods and compositions for imaging disorders using polyspecific agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5872138A (en) * 1996-09-13 1999-02-16 Merck & Co., Inc. Thrombin inhibitors
CN104292154A (zh) * 2009-09-29 2015-01-21 葛兰素集团有限公司 新化合物
CN104592091A (zh) * 2015-01-27 2015-05-06 冉瑞琼 一种含吲哚乙酸核心结构的化合物及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo;J Teramachi，等;《Leukemia》;20151002;第30卷(第2期);第390-398页 *
Chloromethylation of salicylic acid and of the corresponding phenol ethers. Preparation of 2-carbamoyl-4-aminomethylphenols and phenol ethers. Preparation of diphenylmethanes, benzophenones, and benzoylbenzophenones;Raymond Quelet，等;《Bulletin de la Societe Chimique de France》;19691231(第5期);第1699页化合物17、化合物26 *

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