CN113149897B - 一种2,6-取代-4-氧基萜酚吡啶类化合物及其制备方法和用途 - Google Patents
一种2,6-取代-4-氧基萜酚吡啶类化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种如式I所示的2,6‑取代‑4‑氧基萜酚吡啶类化合物及其制备方法和通途，其是一种新的化合物，通过合成获得，且通过细胞实验发现，该化合物具有较好的抗肿瘤细胞增殖活性，尤其在肝癌细胞中，抑制肿瘤细胞增殖效果明显。且通过本发明方法得到的该化合物纯度高，稳定性好，且具备良好的生物活性。并且同顺铂联合使用时，抑制肿瘤细胞增殖效果更加明显。
Description
技术领域
本发明涉及一种药物化合物，具体涉及一种2,6-取代-4-氧基萜酚吡啶类化合物及其制备方法和用途。
背景技术
癌症(恶性肿瘤)是指由于调控细胞增殖机制的失常而引发的疾病，不同的生活习惯和环境因素等原因导致癌症的发生率逐渐升高。常见的癌症治疗方法有外科手术法、化疗法、放射治疗、免疫治疗和单克隆抗体治疗，化疗仍是最主要的治疗手段。肿瘤多药耐药性的发生是导致临床上化疗失败的主要原因。为了达到治疗目的，临床上常采用联合用药(Drug combination)，但联合用药往往会发生体内或体外药物的相互影响。对于某些药物组合，联合治疗还允许产生最佳组合剂量来使副作用最小化。
顺铂是常见的细胞周期非特异性药物，中心以二价铂同两个氯原子和两个氨分子结合的重金属络合物，具有细胞毒性，可抑制癌细胞的DNA复制过程，并损伤其细胞膜上结构，有较强的广谱抗癌作用。临床对卵巢癌、前列腺癌、睾丸癌、肺癌、鼻咽癌、食道癌、恶性淋巴瘤、头颈部鳞癌、甲状腺癌及成骨肉瘤等多种实体肿瘤均能显示疗效。但其表现的毒副作用包括：耳毒性、肾毒性、神经毒性、骨髓抑制和恶心呕吐等。毒副反应和耐药性常限制了顺铂的临床应用。
吡啶类化合物具有与吲哚、氮杂吲哚等类似的特殊结构和良好的生物活性，在医药领域有着广泛的应用。例如稠环化合物吡唑并[3,4-b]吡啶-6-酮为骨架的新型抗肿瘤先导化合物能抑制肿瘤细胞活性、影响微管形成，阻滞癌细胞的细胞周期于G2/M期并诱导细胞凋亡；治疗心血管疾病药物普拉格雷作为一种噻吩并吡啶类药物能更强地抑制血小板聚集且个体差异小，疗效优于氯吡格雷。随着创新性新理念和新方法在吡啶类药物的设计和开发，吡啶类药物在医药、农业等领域应用日益凸显并具有广泛的开发前景。
发明内容
本发明的目的是提供一种通过合成而得的具有抑制肿瘤细胞活性作用的化合物。
本发明的另一个目的是提供制备该化合物的方法。
本发明的再一个目的是提供该化合物在制备抗肿瘤药物中的应用。
本发明的再一个目的是提供该化合物和顺铂联用在制备抗肿瘤药物上的用途。
有鉴于此，本发明的目的之一是获得了一种化合物，该化合物可用以制备抗肿瘤药物，该化合物通过合成获得。
本发明为实现其目的采用的技术方案是：
如式I所示的2,6-取代-4-氧基萜酚吡啶类化合物或其立体异构体或其前药或其药学上可接受的盐或其药学上可接受的溶剂合物；
其中，R1、R2分别独立选自：
1)氢、羟基、卤素；
2)任选被取代的C1-C6烷氧基酰基、羟基酰基、酰卤基、任选被取代的 C6-C10芳醚基酰基、任选被取代的杂芳醚基酰基，其取代基选自：卤素原子、氨基、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6含氟烷基；
2)酰氨基或一个或两个氮上任选被取代的氨基酰基，取代基选自C1-C6 烷基、C1-C6烷氧基、C1-C6含氟烷基、C3-C7环烷基；
3)芳氨基酰基或杂芳氨基酰基，其中的芳基或杂芳基任选地被C1-C6烷基、C1-C6烷氧基、C1-C3含氟烷基、C3-C6环烷基、卤素、氨基、羟基、任选被取代的杂环基取代；
作为本发明的优选方案，R1选自:
R2优选自：H,COOMe。除非特殊说明，上述基团和取代基具有药物化学领域的普通含义。
需要说明的是，C1-C6含氧烷基是指C1-C6烷基骨架被一个或多个C1-C6 烷氧基取代所成的基团，例如，甲氧基乙基，甲氧基乙氧基甲基等。
术语"芳基"是指C6-10的单-、二-或多-碳环烃，其具有任选地进一步通过单键彼此稠合或连接的1至2个环系统，其中所述碳环中至少一个是“芳族的”，其中术语“芳族的”是指完全共轭的π-电子键系统。芳基环可以任选地进一步稠合或连接于芳族的和非芳族的碳环和杂环的环。所述芳基的非限制性的实例是苯基、α-或β-萘基。
术语"杂芳基"是指芳族的杂环，通常为具有1至3个选自N、O或S的杂原子的5-至8-元的杂环；杂芳基环可以任选地进一步稠合或连接于芳族和非芳族的碳环和杂环。所述杂芳基的非限制性的实例为例，如吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、咪唑基、噻唑基、异噻唑基、噻噁唑基、吡咯基、苯基-吡咯基、呋喃基、苯基-呋喃基、噁唑基、异噁唑基、吡唑基、噻吩基、苯并噻吩基、异二氢吲哚基、苯并咪唑基、吲唑基、喹啉基、异喹啉基、1,2,3- 三唑基、1-苯基-1,2,3-三唑基、2,3-二氢吲哚基、2,3-二氢苯并呋喃基、2,3- 二氢苯并噻吩基、苯并吡喃基、2,3-二氢苯并噁嗪基、2,3-二氢喹喔啉基等。
术语“杂环基”(也称作“杂环烷基”)指的是3-、4-、5-、6-和7-元饱和或部分不饱和碳环，其中一个或多个碳原子被杂原子例如氮、氧和硫替代。杂环基的非限制性实例是，例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、噻唑啉、噻唑烷、二氢呋喃、四氢呋喃、1,3-二氧戊环、哌啶、哌嗪、吗啉、吗啡啉基、四氢吡咯基、硫吗啉基等。
术语“任选被取代的杂环基”指的是上述“杂环基”被一个或多个“C1-C6 烷基”、“C1-C3烷基”、“C3-C6环烷基”等取代。
术语“C1-C6烷基”指的是任意的含有1－6个碳原子的直链或支链基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基等。
本发明的目的是由以下技术方案进一步达到的，上述通式为I的化合物与一定物质的量的酸(如等物质的量)成药学上可接受的盐，其中所述药学上可接受的盐为无机酸盐或有机酸盐，其中，所述无机酸盐为盐酸盐、氢溴酸盐、硝酸盐、硫酸盐或磷酸盐，所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。
本发明的目的是由以下技术方案进一步达到的，本发明提供一种制备通式为I的化合物及其盐的方法，其特点是包括如下步骤：
玻璃反应瓶，加入底物CBD、氯代物、溶剂DMF，混合均匀后除氧，加入 Cs2CO3，然后将反应瓶置于100℃油浴中至反应完毕；置于冰水浴中，往体系加入1N HCl调pH至3～5,乙醚分液萃取，合并有机相，用饱和食盐水洗以及无水硫酸钠干燥，减压浓缩，经反相制备得目标化合物。反应路线如下所示：
其中R1、R2如前面所定义。
为了更好的实现本发明，上柱层析洗脱体系为正己烷：乙酸乙酯＝4：1 等梯度洗脱；反相制备洗脱体系为乙腈：水＝5：1等梯度洗脱。
本发明还提供了式I所示化合物在制备抗肿瘤药物上的用途。
为了更好的实现本发明，所述肿瘤为肝癌。
本发明还提供了一种抗肿瘤药物，包括活性成分和药学上可接受的辅料，所述活性成分包括式I所示化合物。
为了更好的实现本发明，所述抗肿瘤药物包括但不限于肿瘤细胞增殖抑制剂。
本发明还提供了式I所示化合物和顺铂联用在制备抗肿瘤药物上的用途。即一种含有顺铂的抗肿瘤药物组合，同时给药作用于肝癌细胞，顺铂和麻类化合物式Ⅰ之间的质量浓度比为0.16：1至0.5：1。
本发明的有益效果是：本发明提供了一种如式I所示的2,6-取代-4-氧基萜酚吡啶类化合物，其是一种新的化合物，通过合成获得，且通过细胞实验发现，该化合物具有较好的抗肿瘤细胞增殖活性，尤其在肝癌细胞中，抑制肿瘤细胞增殖效果明显。且通过本发明方法得到的该化合物纯度高，稳定性好，且具备良好的生物活性。并且同顺铂联合使用时，抑制肿瘤细胞增殖效果更加明显。
附图说明
图1为式I-4所示化合物用CKK8比色法检测联合用药对肿瘤细胞存活性能的影响；
图2为式I-4所示化合物用CCK8比色法检测联合用药对肿瘤细胞存活性能的影响；
图3为式I-4所示化合物用细胞划痕实验检测联合用药对肿瘤细胞迁移性能的影响；
图4为式I-4所示化合物用细胞克隆形成实验检联合用药对肿瘤细胞增殖的影响。
具体实施方式
下面结合实施例对本发明作进一步地详细说明，但本发明的实施方式不限于此，在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段，做出各种替换和变更，均应包括在本发明的范围内。
具体实施例化合物汇总表(Table 1)：
合成实验部分
就如下涉及的实施例而言，使用本文所述的方法或本领域众所周知的其他方法合成本发明的化合物。
通用纯化和分析方法：
在硅胶GF254预涂覆板(merck)上进行薄层色谱。在中压下经硅胶 (300-400目，Greagent)进行柱色谱分离。成分通过UV光(254nm)和通过碘蒸气、碱性KMnO4溶液(KMnO4：K2CO3：NaOH：H2O＝1.5g：10g：0.125g： 200ml)磷钼酸溶液(10g磷钼酸+200ml乙醇)显影。必要时，将化合物通过 HPLC纳谱分析(Chromcore 8-120C18,8um,10×250mm)柱纯化，流动相为乙腈/H2O(70％～100％),流速：10ml/min。
将1H-NMR谱在400MHz操作的Bruker Avance 400谱仪(对于1H而言) 进行记录。将四甲基硅烷信号用作参比。化学位移以百万分率(ppm)进行报道且偶合常数(J)以Hz计。以下缩写用于峰裂分:s＝单；br.s.＝宽信号；d＝双； t＝三；m＝多重；dd＝双双。
电喷雾(ESI)质谱经Finnigan LCQ离子阱获得。
试剂纯化参考Purification of Laboratory Chemicals(Perrin,D.D.,Armarego, W.L.F.and Perrins Eds,D.R.；Pergamon Press:Oxford,1980)一书进行。石油醚是60-90℃馏分、乙酸乙酯、甲醇、二氯甲烷均为分析纯。
实施例1:
取10mL反应瓶，依次加入CBD(100mg，0.32mmol)、氯代物(108.6mg， 0.32mmol)，溶剂DMF(1mL)，混合均匀后除氧，加入Cs2CO3(104mg， 0.32mmol),置于90℃油浴中，反应24h，TLC检测反应完毕，冷却至室温，置于冰水浴中，往体系加入1N HCl调pH至3～5,乙醚分液萃取，合并有机相，饱和碳酸氢钠洗一次，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩，柱层析分离(200～300目硅胶；正己烷：乙酸乙酯＝2：1)得到粗品，在用(300～400 目硅胶；正己烷：丙酮＝2：1)得目标化合物(17.6mg，产率11％)。1H NMR (400MHz,CDCl3)δ8.59(d,J＝5.6Hz,2H),7.63(s,2H),6.93(d,J＝3.3Hz, 2H),6.73(s,2H),4.89(s,1H),4.49(s,1H),4.47(s,1H),4.41(t,J＝6.9Hz,4H),3.68(d,J＝10.4Hz,1H),2.82–2.71(m,1H),2.55(t,2H),1.98–1.74(m,6H), 1.71–1.59(m,2H),1.57–1.51(m,2H),1.46(4,7H),1.42(s,3H),1.34–1.26(m,4H),1.12(s,3H),0.97(t,J＝7.4Hz,6H),0.87(t,J＝6.8Hz,3H).MS(ESI)m/z: 508[M+H]+.
实施例2：
化合物I-2合成步骤参考实施例1，得目标化物I-2(17.8mg，产率11.6％)。1H NMR(400MHz,CDCl3)δ8.57(d,J＝5.6Hz,1H),7.63(d,J＝2.3Hz,1H), 6.92(dd,J＝5.6,2.5Hz,1H),6.59(s,1H),6.33(s,1H),6.04(brs,1H),5.46(brs,1H),5.38–5.24(m,1H),4.52(s,1H),4.40(s,1H),3.70–3.55(m,1H),2.57– 2.41(m,3H),2.30–2.14(m,1H),2.12–1.99(m,1H),1.84–1.63(m,5H),1.57–1.51(m,2H),1.48(s,3H),1.41(d,J＝6.3Hz,6H),1.34–1.26(m,4H),0.86(t, J＝6.9Hz,3H).MS(ESI)m/z:478[M+H]+.
实施例3:
化合物I-3合成步骤参考实施例1，得目标化物I-3(21mg，产率13.4％)。1H NMR(400MHz,CDCl3)δ8.56(d,J＝5.6Hz,1H),7.63(d,J＝2.3Hz,1H), 6.93(dd,J＝5.5,2.4Hz,1H),6.60(s,1H),6.33(s,1H),6.05(brs,1H),5.46(brs,1H),4.51(s,1H),4.41(s,1H),4.39(t,J＝6.8Hz,2H),3.70–3.55(m,1H),2.55– 2.43(m,3H),2.29–2.14(m,1H),2.12–1.98(m,1H),1.84–1.63(m,7H),1.59 –1.51(m,2H),1.51–1.37(m,5H),1.34–1.21(m,4H),0.96(t,J＝7.4Hz,3H),0.87(t,J＝6.9Hz,3H).MS(ESI)m/z:492[M+H]+.
实施例4：
化合物I-4合成步骤参考实施例1，得目标化物I-4(28mg，产率20％)。1H NMR(400MHz,CDCl3)δ8.34(d,J＝5.6Hz,1H),8.00(d,J＝4.8Hz,1H), 7.71(d,J＝2.4Hz,1H),6.87(dd,J＝5.6,2.5Hz,1H),6.58(s,1H),6.33(d,J＝1.2Hz,1H),6.04(brs,1H),5.47(brs,1H),4.53(s,1H),4.40(s,1H),3.68–3.53(m,1H),3.02(d,J＝5.1Hz,3H),2.55–2.41(m,3H),2.20(s,1H),2.11–1.98(m, 1H),1.82–1.62(m,5H),1.58–1.52(m,2H),1.51(s,3H),1.36–1.21(m,4H),0.87(t,J＝6.9Hz,3H).MS(ESI)m/z:449[M+H]+.
实施例5：
化合物I-5合成步骤参考实施例1，得目标化物I-5(41.6mg，产率26.5％)。1H NMR(400MHz,CDCl3)δ8.34(d,J＝5.6Hz,1H),8.10–7.97(m,1H),7.71 (d,J＝2.4Hz,1H),6.86(dd,J＝5.6,2.5Hz,1H),6.58(s,1H),6.33(d,J＝1.3Hz, 1H),6.04(brs,1H),5.47(brs,1H),4.54(s,1H),4.40(s,1H),3.66–3.53(m,1H),3.51–3.38(m,2H),2.58–2.40(m,3H),2.28–2.14(m,1H),2.08–1.95(m,1H), 1.81–1.48(m,12H),1.47–1.37(m,2H),1.34–1.23(m,4H),0.95(t,J＝7.3Hz,3H),0.87(t,J＝6.9Hz,3H).MS(ESI)m/z:491[M+H]+.
实施例6：
化合物I-6合成步骤参考实施例1，得目标化物I-6(46mg，产率28％)。1H NMR(400MHz,CDCl3)δ8.37(d,J＝5.7Hz,1H),6.92(d,J＝2.3Hz,1H), 6.74(dd,J＝5.7,2.4Hz,1H),6.58(s,1H),6.36(d,J＝1.4Hz,1H),6.04(brs,1H),5.44(brs,1H),4.53(s,1H),4.39(brs,1H),3.89–3.74(m,1H),3.67–3.58(m, 1H),3.56–3.46(m,1H),2.55–2.40(m,3H),2.30–2.15(m,1H),2.10–1.97(m,1H),1.87–1.40(m,19H),1.33–1.26(m,4H),1.17(t,J＝5.6Hz,3H),0.87(t,J ＝6.9Hz,3H).MS(ESI)m/z:519[M+H]+.
实施例7：
化合物I-7合成步骤参考实施例1，得目标化物I-7(52mg，产率31％)。1H NMR(400MHz,CDCl3)δ8.36(t,J＝5.9Hz,1H),8.33(d,J＝5.6Hz,1H), 7.74(d,J＝2.4Hz,1H),7.39–7.27(m,5H),6.87(dd,J＝5.6,2.5Hz,1H),6.59(s,1H),6.34(d,J＝1.2Hz,1H),6.04(brs,1H),5.47(brs,1H),4.65(d,J＝6.0Hz, 2H),4.54(s,1H),4.40(s,1H),3.68–3.53(m,1H),2.55–2.43(m,3H),2.27–2.14(m,1H),2.09–1.99(m,1H),1.83–1.61(m,5H),1.58–1.46(m,5H),1.35–1.22(m,4H),0.87(t,J＝6.9Hz,3H).MS(ESI)m/z:525[M+H]+.
实施例8：
化合物I-8合成步骤参考实施例1，得目标化物I-8(22mg，产率15.6％)。1H NMR(400MHz,CDCl3)δ8.54(d,J＝5.6Hz,1H),7.64(d,J＝2.3Hz,1H), 6.95(dd,J＝5.5,2.4Hz,1H),6.60(s,1H),6.33(s,1H),6.05(brs,1H),5.46(brs,1H),4.52(s,1H),4.40(s,1H),3.99(s,3H),3.68–3.55(m,1H),2.56–2.40(m, 3H),2.31–2.14(m,1H),2.11–1.98(m,1H),1.83–1.51(m,7H),1.49(s,3H),1.35–1.21(m,4H),0.87(t,J＝6.9Hz,3H).MS(ESI)m/z:450[M+H]+.
实施例9：
测定2,6-取代-4-氧基萜酚吡啶类化合物对肿瘤细胞增殖活性的影响：
(1)CKK8比色法检测各化合物对肿瘤细胞存活性能的影响
取对数生长期人肝癌细胞(HepG2)，用DMEM培养液配制适宜浓度细胞悬液，细胞密度约70000个/mL(即每100μL培养液中约含7000个细胞)，以每孔100μL细胞悬液将细胞接种于96孔板，37℃培养箱中培养至细胞贴壁。以DMSO为溶剂分别配制浓度20mg/mL的式I-1～I-8所示化合物溶液和顺铂溶液，实验时用培养液稀释至所需工作浓度。96孔板弃培养液后，实验组分别加入浓度为2.5μg/mL、5μg/mL、10μg/mL、20μg/mL、40μg/mL的待测化合物溶液100μL，空白对照组加入培养液100μL，阳性对照组加入同样浓度的抗肿瘤药物顺铂(DDP)溶液100μL，将96孔板放置培养箱中24h后用CCK8试剂检测细胞存活率，96孔板继续放置培养箱中48h后用MTT试剂检测细胞存活率，实验重复3次取平均值。通过GraphPad Prism软件绘制剂量抑制曲线，并计算出化合物对HepG2肿瘤细胞的IC50值，结果如表1所示。
表1.化合物I-1～I-8对肝癌细胞HepG2增殖的IC50
联合用药抗肿瘤细胞增殖活性的测定方法：
(1)CKK8比色法检测联合用药对肿瘤细胞存活性能的影响
取对数生长期人肝癌细胞(HepG2)，用DMEM培养液配制适宜浓度细胞悬液，细胞密度约50000个/mL(即每100μL培养液中约含5000个细胞)，以每孔100μL细胞悬液将细胞接种于96孔板，37℃培养箱中培养至细胞贴壁。以DMSO为溶剂分别配制浓度20mg/mL的式I-1～I-8所示化合物溶液和顺铂化合物溶液，实验时用培养液稀释至所需工作浓度。96孔板弃培养液后，单药组分别加入工作浓度为2.5μg/mL、5μg/mL、10μg/mL、20μg/mL、30μ g/mL的顺铂溶液100μL；另一单药组加入同样浓度梯度的式I所示化合物溶液100μL，联药组含顺铂和式I所示化合物溶液100μL，联药的工作浓度为 (2.5μg/mL+2.5μg/mL)、(5μg/mL+5μg/mL)(10μg/mL+10μg/mL)、(20 μg/mL+20μg/mL)、(30μg/mL+30μg/mL)；将96孔板继续放置培养箱中48h 后用CCK8试剂检测细胞存活率，实验重复3次取平均值。协同指数参考金式公式计算Q值，通过Q值判断两种药物联合使用后的治疗效果，如果Q在0.85-1.15之间为单纯相加(+)，在1.15-20之间为增强(++)，Q>20为显著增强(+++)，在0.85-0.55之间为拮抗，Q<0.55为明显拮抗(--)；根据生物实验大约有15％的误差，将效应相加的Q值扩展为0.85-1.15；Q>1.15即为协同作用。
与对照组相比，随着式I-4所示化合物及顺铂的浓度增加，人肝癌细胞 (HepG2)的存活率越低，当两药联合使用时，细胞存活率比单药组更低，说明联药对人肝癌细胞(HepG2)存活性能的抑制作用越强。通过Q值计算，说明低浓度的顺铂和式Ⅰ化合物联用作用HepG2细胞48h时，对HepG2细胞有协同抑制作用，结果如图1所示。
(2)CCK8比色法检测联合用药对肿瘤细胞存活性能的影响
细胞铺板方法同上，本实验中联合用药浓度设置根据(1)中实验结果，设置单一浓度式I-4化合物与浓度梯度顺铂联用。单药组加固定浓度5μg/mL 的顺铂溶液100μL,另一单药组加工作浓度为2.5μg/mL、5μg/mL、10μ g/mL、20μg/mL、30μg/mL的式I-4所示化合物溶液100μL；联药组含式I-4 所示化合物额顺铂溶液100μL，联药的工作浓度为(2.5μg/mL+5μg/mL)、 (5μg/mL+5μg/mL)(10μg/mL+5μg/mL)、(20μg/mL+5μg/mL)、(30μ g/mL+5μg/mL)；将96孔板继续放置培养箱中48h后用CCK8试剂检测细胞存活率，实验重复3次取平均值，协同指数计算同上。
结果如图2所示，与对照组相比，随着式I-4所示化合物浓度的增加，人肝癌细胞(HepG2)的存活率越低，不同浓度的式I-4所示化合物与5μg/mL 顺铂联用时，对HepG2细胞抑制率更高。通过Q值计算，说明低浓度式Ⅰ-4 化合物同顺铂联用作用HepG2细胞48h时，对HepG2细胞有协同抑制作用。
(3)细胞划痕实验检测联合用药对肿瘤细胞迁移性能的影响
取对数生长期人肝癌细胞(HepG2)，用DMEM培养液配制适宜浓度细胞悬液，细胞密度约200000个/mL，以每孔1mL细胞悬液将细胞接种于24孔板， 37℃培养箱中培养至细胞贴壁。以DMSO为溶剂配制浓度20mg/mL的式I-4 所示化合物溶液，实验时用培养液稀释至所需工作浓度。24孔板弃培养液后，用200μL的枪头沿着孔中央作直划痕，用PBS轻轻洗去划痕产生的细胞团，实验组中单药组分别加入工作浓度为5μg/mL的顺铂溶液1mL、5μg/mL的式 I-4化合物溶液1mL、联药组加入含5μg/mL顺铂和5μg/mL的式I-4化合物溶液1mL，空白对照组加入培养液1mL；拍照并记录0h、24h、48h各孔的划痕宽度并计算每孔平均值，最后计算平均划痕修复率，实验重复3次取平均值，组间使用T-test分析差异显著性，P＜0.05有统计学意义。
划痕修复率(％)＝(0小时划痕面积-Nh划痕面积)/0小时划痕面积*100
结果如图3所示，划痕实验结果表明，与对照组相比，低浓度式I-4所示化合物及低浓度顺铂均能抑制HepG2细胞的迁移作用，两药联合时，划痕修复率比单药组更低，说明两种药物联用时，能显著抑制HepG2细胞迁移能力。
(4)细胞克隆形成实验检联药对肿瘤细胞增殖的影响
取对数生长期人肝癌细胞(HepG2)，用DMEM培养液配制适宜浓度细胞悬液，细胞密度约117个/mL(即每1mL培养液中约含117个细胞)，以每孔3mL 细胞悬液将细胞接种于6孔板，37℃培养箱中培养至细胞贴壁。以DMSO为溶剂配制浓度20mg/mL的式I-4所示化合物溶液，实验时用培养液稀释至所需工作浓度。6孔板弃培养液后，实验组中单药组分别加入工作浓度为5μg/mL 的顺铂溶液3mL、5μg/mL的式I-4化合物溶液3mL、联药组加入含5μg/mL 顺铂和5μg/mL的式I-4化合物溶液3mL，空白对照组加入培养液3mL；将 6孔板继续放置培养箱中，每2-3天更换新鲜的培养液或含药物的培养液，持续培养两周左右，持续观察细胞形态，当培养皿中出现肉眼可见的克隆时，终止培养。弃培养液，用PBS小心浸洗2次，加入4％多聚甲醛(PFA)1mL 固定细胞30min。弃PFA后每孔加入1mL 0.1％的结晶紫染色30min，超纯水洗去染色液，6孔板晾干后拍照并计算克隆形成率，组间使用T-test分析差异显著性，P＜0.05有统计学意义。
结果如图4所示，与对照组相比，低浓度式I-4所示化合物及低浓度顺铂均能抑制HepG2细胞的克隆形成，两药联合时，克隆形成率比单药组更低，说明两种药物联用时，对HepG2增殖具有显著的协同抑制作用。
尽管已经对上述各实施例进行了描述，但本领域内的技术人员一旦得知了基本创造性概念，则可对这些实施例做出另外的变更和修改，所以以上所述仅为本发明的实施例，并非因此限制本发明的专利保护范围，凡是利用本发明说明书及附图内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围之内。
Claims (7)
1.一种的2,6-取代-4-氧基萜酚吡啶类化合物或其药学上可接受的盐，其特征在于，选自如下化合物中的一种：
2.根据权利要求1所述的2,6-取代-4-氧基萜酚吡啶类化合物或其药学上可接受的盐在制备抗肿瘤药物上的用途。
3.根据权利要求2所述的用途，其特征在于，所述肿瘤为肝癌。
4.一种抗肿瘤药物，其特征在于，包括活性成分和药学上可接受的辅料，所述活性成分包括权利要求1所述的2,6-取代-4-氧基萜酚吡啶类化合物。
5.根据权利要求4所述的抗肿瘤药物，其特征在于，所述抗肿瘤药物包括肿瘤细胞增殖抑制剂。
6.根据权利要求1所述的2,6-取代-4-氧基萜酚吡啶类化合物和顺铂联用在制备抗肿瘤药物上的用途。
7.根据权利要求6所述的用途，其特征在于，同时给药时，顺铂和所述的2,6-取代-4-氧基萜酚吡啶类化合物之间的质量浓度比为0.16：1至0.5：1。
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