CN113444035B - 一类具有抗癌作用的萘基脲类化合物及其制备方法和应用 - Google Patents

一类具有抗癌作用的萘基脲类化合物及其制备方法和应用 Download PDF

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CN113444035B
CN113444035B CN202110727896.3A CN202110727896A CN113444035B CN 113444035 B CN113444035 B CN 113444035B CN 202110727896 A CN202110727896 A CN 202110727896A CN 113444035 B CN113444035 B CN 113444035B
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cancer
stat3
naphthyl urea
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CN113444035A (zh
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徐学军
杨玉坡
杨争艳
徐红运
段超群
董嘉炜
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Henan Radiomedical Science And Technology Co ltd
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Abstract

本发明公开一类具有抗癌作用的萘基脲类化合物及其制备方法和应用，其含有的具有生物活性萘脲母核基团进一步化学修饰产生诸多生物活性更高的化合物群，拓展了此类化合物在生物医药上的广泛应用以及药物制剂开发前景。该类化合物在低剂量（亚微摩尔）即，可显著抑制JAK2/STAT3信号的活化，MTT、分子对接和免疫印迹实验结果显示，该化合物可以特异抑制JAK2信号活化及下游STAT3、CyclinD1、CyclinB1和MMP9等靶基因的表达，诱导细胞周期阻滞和凋亡，显著抑制乳腺癌、肝癌、肺癌、耐药的肺癌、结肠癌和白血病等多种肿瘤细胞株的增殖，表明该类化合物具有开发为JAKs/STAT3靶向抗癌药物的前景。

Description

一类具有抗癌作用的萘基脲类化合物及其制备方法和应用
技术领域
本发明属于肿瘤靶向治疗领域，具体涉及一类具有全新化学结构的萘基脲类化合物及其制备方法和应用。
背景技术
已有大量研究证明JAKs(Janus kinases)/STATs(Signal transducer andactivators of transcriptions)信号的异常活化与许多疾病相关，包括癌症及免疫相关疾病。JAKs激酶家族包括4个成员:JAK1、JAK2、JAK3和Tyk2，它们都包含7个结构域，JH1-JH7，其中JH1 结构域被认为具有酪氨酸激酶活性，可以催化底物(如STATs等)的磷酸化。当外源细胞因子刺激下，使细胞膜表面相互靠近的细胞因子受体构象发生变化，JAKs家族成员在胞内与相关受体相结合，使结合在受体上的JAKs成员也因相互靠近而使彼此关键的酪氮酸位点磷酸化(JAK1为Tyr1038/Tyr1039；JAK2为Tyr1007/Tyr1008；JAK3为Tyr980/Tyr981；Tyk2 为Tyr1054/Tyr1055)，这些位点磷酸化后使JAKs成员构象改变，从而有催化下游底物蛋白的磷酸化的作用。
JAK2/STAT3的过表达和组成型活化在多种实体瘤和血液系统癌症中最为常见。STAT3 是STATs家族的成员之一，是JAK2底物蛋白，已被证实与癌症的发生、发展和恶性转化密切相关。在正常情况下，STAT3以无活性的单体形式存在于胞浆中，并存在严格的负反馈调控机制。当JAK2或STAT3的负反馈调控机制异常或基因突变，可以导致STAT3磷酸化水平持续升高和内源性亢奋，与另外一个STAT3蛋白的SH2结构域形成同源二聚体或异源二聚体进入细胞核，通过DNA结合域结合到特定的基因启动子序列上，启动下游基因的转录，其中包括：BCL-2、BCL-XL、CyclinD1等一系列抗凋亡因子的表达。
由于CyclinD1,Bcl-xl,MMP9和c-Myc等众多促增殖、侵袭和抗凋亡的基因都是JAK2/STAT3信号的靶基因，在STAT3持续活化的动物肿瘤模型或体外培养的肿瘤细胞中，抑制JAK2或STAT3蛋白可以有效的抑制肿瘤细胞的生长或诱导肿瘤细胞调亡，并减少肿瘤细胞的转移。JAK2和STAT3已成为肿瘤治疗热门靶点。尽管目前国外已有三款JAK抑制剂在免疫性疾病中获批上市，多个JAKs抑制剂针对肿瘤治疗的研究在临床后期，针对 STAT3的一些靶向抑制剂也已进入临床研究阶段，JAKs/STAT3抑制剂在肿瘤市场的需求还远未被满足。
为了开发JAK2/STAT3靶向抗肿瘤药物，我们近期合成了一类具有全新结构式的萘基脲类化合物。通过一些生物学技术分析，发现该类化合物能够显著抑制JAK2和STAT3信号的活化，抑制乳腺癌和肝癌细胞株的细胞增殖，诱导细胞发生G1/S或G2/M期阻滞，并促进肿瘤细胞凋亡，显示了极强的抑瘤活性。
本发明旨在揭示一类新型萘基脲类化合物及其衍生物的抗肿瘤作用及其潜在药理机制，以及此类化合物在银屑病、骨髓纤维化和风湿性关节炎临床治疗的潜在应用。
发明内容
本发明的目的是提供一类具有全新化学结构的萘基脲类化合物及其制备方法和应用。
基于上述目的，本发明采取如下技术方案：
一种萘基脲类化合物，结构式如通式I所示：
Figure BDA0003139283160000021
其中，R选自
Figure BDA0003139283160000022
Figure BDA0003139283160000023
Figure BDA0003139283160000031
L1、L2、L3、L4、L5、L6、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、 R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、R34、R35、R36、 R37、R38、R39、R40、R41、R42、R43、R44、R45、R46、R47、R48各自独立地选自H、F、Cl、 Br、-CN、-CH3、-CF3、-OCH3、-OCF3或Ph，
m,n代表CH2取代基的个数，m,n为1、2、3、4...10；
k,z代表CH2取代基的个数，k,z为0、1、2、3、4、5、6；
A为
Figure BDA0003139283160000032
其中p代表CH2取代基的个数，p为1、2、3；
X为O或S。
上述萘基脲类化合物，具体为如下结构的化合物：
Figure BDA0003139283160000033
Figure BDA0003139283160000041
上述萘基脲类化合物与乙酸、二氢叶酸、苯甲酸、柠檬酸、山梨酸、丙酸、草酸、富马酸、马来酸、盐酸、苹果酸、磷酸、亚硫酸、硫酸、香草酸、酒石酸、抗坏血酸、硼酸、乳酸和乙二胺四乙酸中的至少一种形成的生物学可接受的盐。
上述萘胺类化合物的制备方法，包括以下步骤：
(1)将
Figure BDA0003139283160000042
和三苯基膦溶于四氢呋喃中，-5℃～5℃慢慢加入偶氮二甲酸二异丙酯，室温搅拌反应至完全，后处理得到
Figure BDA0003139283160000051
(2)将
Figure BDA0003139283160000052
和叔丁醇钾溶于甲苯中，氮气保护下依次加入Pd2(dba)3和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽，110℃下反应至完全，经后处理得到
Figure BDA0003139283160000053
其中，所述
Figure BDA0003139283160000054
的制备过程如下：
(a)将
Figure BDA0003139283160000055
和三苯基膦溶于四氢呋喃中，-5℃～5℃保护气氛下加入偶氮二甲酸二异丙酯，室温搅拌反应至完全，经后处理得到
Figure BDA0003139283160000061
(b)将化合物
Figure BDA0003139283160000062
溶于四氢呋喃中，-5℃～5℃分批加入四氢铝锂，室温搅拌至反应完全，经后处理得到
Figure BDA0003139283160000063
优选地，所述步骤(1)中
Figure BDA0003139283160000064
三苯基膦与偶氮二甲酸二异丙酯的摩尔比为1:1:1.2:1.2；
步骤(2)中
Figure BDA0003139283160000065
叔丁醇钾、Pd2(dba)3和4,5-双 (二苯基膦)-9,9-二甲基氧杂蒽的摩尔比为1:1:1.3:0.05:0.1。
所述步骤(a)中，
Figure BDA0003139283160000066
三苯基膦、偶氮二甲酸二异丙酯的摩尔比为1:1.2:1.2:1.2；
步骤(b)中，
Figure BDA0003139283160000067
和四氢铝锂的摩尔比为1:1。
上述的萘基脲类化合物及其生物学可接受的盐在制备抗肿瘤药物中的用途，其中所述抗肿瘤药物为治疗与JAKs或STAT3信号传导相关的肿瘤的药物。
优选地，所述的抗肿瘤药物是指治疗乳腺癌、肝癌、肺癌、结肠癌和白血病的药物。
本发明的另一目的是提供一类具有靶向抗肿瘤活性的小分子化合物。
所述肿瘤具体可为JAK2/STAT3高表达或组成型活化的肿瘤，包括但不限于肝癌、乳腺癌、肺癌、结肠癌和白血病等。
具体的说，本发明合成了一类具有全新结构的萘基脲类化合物IY210216D-1,ID210203C-1和IY210316B-1等。通过MTT法检测此类化合物对肿瘤细胞的增殖抑制作用，通过流式细胞术检测化合物对肿瘤细胞的细胞周期和凋亡的影响，并通过免疫印迹等方法明确其对JAK2/STAT3信号的抑制作用。
结果表明，本发明的化合物IY210216D-1,ID210203C-1和IY210316B-1等，可以有效抑制乳腺癌和肝癌细胞的增殖，诱导癌细胞G1/S或G2/M期阻滞和细胞凋亡。
总之，本发明提供了一种新的萘基脲类化合物以及它的衍生物在肿瘤治疗上的用途和潜在分子机制。
附图说明
图1是IY210216D-1、ID210203C-1和IY210316B-1等对乳腺癌细胞MDA-MB-468，肝癌细胞HepG2，肺癌细胞PC9，阿法替尼耐药的肺癌细胞PC9-AR，结肠癌细胞HT29和白血病细胞Jurkat等肿瘤细胞的半数抑制率(IC50值)的检测结果；
图2是Western blot检测ID210203C-1对JAK2/STAT3信号蛋白的表达调控作用；
图3是通过流式细胞术检测化合物IY210216D-1和ID210203C-1对乳腺癌和肝癌细胞的周期的影响；
图4是对图3结果的定量分析；
图5是通过流式细胞术检测化合物IY210216D-1,ID210203C-1和IY210316B-1对乳腺癌细胞和肝癌细胞的凋亡的影响；
图6是通过Q-PCR检测IY210216D-1和ID210203C-1对细胞周期和转移相关分子的mRNA水平的影响。
具体实施方式
为了使本发明的技术目的、技术方案和有益效果更加清楚，下面结合附图和具体实施例对本发明的技术方案作出进一步的说明。
在本发明合成式I化合物的方法中，反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的，或者是可以通过文献公知的方法制得的，或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识做适当改变的。
在本发明中，除非另外说明，其中：(i)温度以摄氏度(℃)表示，操作在室温环境下进行；更具体地，所述室温是指20-30℃；(ii)有机溶剂用常用干燥方法干燥，溶剂的蒸发使用旋转蒸发仪减压蒸发，浴温不高于50℃；展开剂和洗脱剂均为体积比；(iii)反应过程用薄层色谱(TLC)跟踪；(iv)终产物具有满意的质子核磁共振(1H-NMR)。
实施例1:化合物的合成
Figure BDA0003139283160000081
IY210316B-1：
Figure BDA0003139283160000082
n＝2，
Figure BDA0003139283160000083
X＝O；
ID210203C-1：
Figure BDA0003139283160000084
n＝2，
Figure BDA0003139283160000085
X＝O；
IY210313C-1：
Figure BDA0003139283160000086
n＝2，
Figure BDA0003139283160000087
X＝O；
IY210327B-1：
Figure BDA0003139283160000088
n＝2，
Figure BDA0003139283160000089
X＝O；
IY210316C-1：
Figure BDA00031392831600000810
n＝2，
Figure BDA00031392831600000811
X＝O；
ID210329B-1：
Figure BDA00031392831600000812
n＝2，
Figure BDA00031392831600000813
X＝O；
IY210314B-1：
Figure BDA00031392831600000814
n＝2，
Figure BDA00031392831600000815
X＝O；
IY210315C-1：
Figure BDA00031392831600000816
n＝2，
Figure BDA00031392831600000817
X＝O；
IY210126D-1：
Figure BDA0003139283160000091
n＝2，
Figure BDA0003139283160000092
X＝O；
ID210214A-1：
Figure BDA0003139283160000093
n＝2，
Figure BDA0003139283160000094
X＝O；
IY210224D-1：
Figure BDA0003139283160000095
n＝2，
Figure BDA0003139283160000096
X＝O；
IY210215C-1：
Figure BDA0003139283160000097
n＝2，
Figure BDA0003139283160000098
X＝S；
ID1217B-1：
Figure BDA0003139283160000099
n＝2，
Figure BDA00031392831600000910
X＝O；
IY210224C-1：
Figure BDA00031392831600000911
n＝2，
Figure BDA00031392831600000912
X＝O；
IY210304D-1：
Figure BDA00031392831600000913
n＝2，
Figure BDA00031392831600000914
X＝O；
ID1217C-1：
Figure BDA00031392831600000915
n＝2，
Figure BDA00031392831600000916
X＝S；
IY210317A-1：
Figure BDA00031392831600000917
n＝2，
Figure BDA00031392831600000918
X＝O；
ID210317C-1：
Figure BDA00031392831600000919
n＝2，
Figure BDA00031392831600000920
X＝O；
IY210317C-1：
Figure BDA00031392831600000921
n＝2，
Figure BDA00031392831600000922
X＝O；
IY210318A-1：
Figure BDA00031392831600000923
n＝2，
Figure BDA00031392831600000924
X＝O；
IY210319C-1：
Figure BDA00031392831600000925
n＝2，
Figure BDA00031392831600000926
X＝O；
ID210318A-1：
Figure BDA00031392831600000927
n＝2，
Figure BDA00031392831600000928
X＝O；
IY210320B-1：
Figure BDA0003139283160000101
n＝2，
Figure BDA0003139283160000102
X＝O；
IY210321C-1：
Figure BDA0003139283160000103
n＝2，
Figure BDA0003139283160000104
X＝O；
ID210421B-1：
Figure BDA0003139283160000105
n＝2，
Figure BDA0003139283160000106
X＝O,L2＝Me；
ID210422B-1：
Figure BDA0003139283160000107
n＝2，
Figure BDA0003139283160000108
X＝O,L1＝F；
ID210426B-1：
Figure BDA0003139283160000109
n＝2，
Figure BDA00031392831600001010
X＝O,L1＝Cl；
ID210428B-1：
Figure BDA00031392831600001011
n＝2，
Figure BDA00031392831600001012
X＝O,L2＝F；
IY210524A-1：
Figure BDA00031392831600001013
n＝2，
Figure BDA00031392831600001014
X＝O,L6＝Ph；
IY210524B-1：
Figure BDA00031392831600001015
n＝2，
Figure BDA00031392831600001016
X＝O,L5＝Cl；
IY210525A-1：
Figure BDA00031392831600001017
n＝2，
Figure BDA00031392831600001018
X＝O,L5＝Me；
IY210525C-1：
Figure BDA00031392831600001019
n＝2，
Figure BDA00031392831600001020
X＝O,L6＝F；
具体合成方法，以化合物IY210316B-1为例，结构式分别如下：
Figure BDA00031392831600001021
化合物IY210316B-1的名称为1-(4-((4-(2-(piperidin-1-yl)ethoxy)benzyl)oxy)naphthalen-1-yl)- 3-(pyridin-2-ylmethyl)urea，
其合成路线如下：
Figure BDA0003139283160000111
步骤1.methyl 4-(2-(piperidin-1-yl)ethoxy)benzoate(2)
将4-羟基苯甲酸甲酯(1.0g,6.57mmol,1.0eq)，N-羟乙基哌啶(1.02g,7.89mmol,1.2eq) 和三苯基膦(2.07g,7.89mmol,1.2eq)溶解到30mL无水四氢呋喃中，降温到0℃，氮气保护下慢慢滴加偶氮二甲酸二异丙酯(1.59g,7.89mmol,1.2eq)，然后室温反应16小时。TLC监测反应完毕后，减压浓缩除去四氢呋喃，固体用乙酸乙酯溶解，用1N的盐酸水溶液调节pH到1，乙酸乙酯萃取三次，水相用碳酸氢钠固体调节pH到8，再用乙酸乙酯萃取三次，有机相干燥旋干得到1.5g白色固体methyl 4-(2-(piperidin-1-yl)ethoxy)benzoate(2)，收率 86.7％。
1H NMR(CDCl3,300MHz)δ:8.0(d,J＝9.0Hz,2H),6.93(d,J＝9.0Hz,2H),4.17(t,J＝6.0Hz, 2H),3.90(s,3H),2.82(t,J＝6.0Hz,2H),2.58-2.55(m,4H),1.66-1.61(m,4H),1.50(t,J＝3.0Hz, 2H)
步骤2.(4-(2-(piperidin-1-yl)ethoxy)phenyl)methanol(3)
将化合物(2)(1.00g,3.80mmol,1.0eq)溶于40mL无水四氢呋喃，冷却到0℃，分批加入四氢铝锂(144mg,3.80mmol,1.0eq)，自然升温到室温反应0.5小时。TLC监测显示原料反应完毕，并有新点产生。将反应液冷却到0℃，依次加入1mLNaOH(15wt％)水溶液，1 mL水；硅藻土过滤，滤液旋干得到680mg(4-(2-(piperidin-1-yl)ethoxy)phenyl)methanol (3)，白色固体，收率88.7％。
1H NMR(CDCl3,300MHz)δ:7.30(d,J＝6.0Hz,2H),6.92(d,J＝6.0Hz,2H),4.64(s,2H),4.17 (t,J＝6.0Hz,2H),2.98(t,J＝6.0Hz,2H),2.74(m,4H),1.89-1.86(m,6H)
步骤3.1-(2-(4-(((4-bromonaphthalen-1-yl)oxy)methyl)phenoxy)ethyl)piperidine(4)
将化合物(3)(1.05g,4.48mmol,1.0eq),4-溴-1-萘酚(1.0g,4.48mmol,1.0eq)，三苯基膦 (1.41g,5.38mmol,1.2eq)溶解于50mL无水四氢呋喃中，冷却到0℃，慢慢加入偶氮二甲酸二异丙酯(1.09g,5.38mmol,1.2eq)，继续室温反应12小时。TLC监测反应完毕后，倒入100mL饱和氯化铵水溶液中，用乙酸乙酯萃取3次(100mL*3)，将有机相合并，用无水硫酸钠干燥，旋干过柱(二氯甲烷：甲醇＝60:1～20:1)得到710mg 1-(2-(4-(((4-bromonaphthalen-1-yl)oxy)methyl)phenoxy)ethyl)piperidine(4),黄色固体，收率47.6％。
步骤4.1-benzyl-3-(4-((4-(2-(piperidin-1-yl)ethoxy)benzyl)oxy)naphthalen-1-yl)urea(IY210316B- 1)
将化合物(4)(200mg,0.45mmol,1.0eq)，1-(pyridin-2-ylmethyl)urea(68.6mg,0.45mmol, 1.0eq)和叔丁醇钾(66.3mg,0.59mmol,1.3eq)溶于50毫升甲苯中，氮气保护下依次加入 Pd2(dba)3(50mg,0.03mmol,0.05eq),Xantphos(4,5-双(二苯基膦)-9,9-二甲基氧杂蒽，15 mg,0.06mmol,0.1eq)110℃反应12小时。TLC监测反应完毕后，直接旋干过柱(二氯甲烷：甲醇＝50:1～15:1)得到210mg 1-benzyl-3-(4-((4-(2-(piperidin-1- yl)ethoxy)benzyl)oxy)naphthalen-1-yl)urea(IY210316B-1),棕色固体，收率77.8％。
1H NMR(DMSO-d6,400MHz)δ:8.32(s,1H),8.19(d,J＝8.0Hz,1H),8.01(d,J＝8.0Hz,2H), 7.68(d,J＝8.0Hz,2H),7.58-7.26(m,8H),7.05-6.98(m,3H),6.82(m,1H),5.20(s,2H),4.34(d, J＝4.0Hz,2H),4.11(m,2H),2.52(m,2H),1.53(m,4H),1.40(m,2H),1.39-1.20(m,2H).
其他化合物的合成方法参照实施例1，区别在于，在步骤4中换成相应R取代的脲或者在步骤1中将4-羟基苯甲酸甲酯换成L1、L2、L3或L4取代的4-羟基苯甲酸甲酯，或者在步骤3中将4-溴-1-萘酚换成L5或L6取代的4-溴-1-萘酚即可。
实施例2、IY210216D-1、ID210203C-1和IY210316B-1等对乳腺癌和肝癌等细胞的增殖抑制作用
分别收集对数生长期的肿瘤细胞，调整细胞悬液浓度为5×104个/mL，加入96孔细胞培养板，每孔体积100ul。以DMSO为溶剂对照，WP1066(中文名称：(2E)-3-(6-溴-2-吡啶基)-2-氰基-N-[(1S)-1-苯基乙基]-2-丙烯酰胺,CAS:857064-38-1，结构为
Figure BDA0003139283160000121
)为阳性对照，将本发明所述的新型萘脲类化合物IY210216D-1、ID210203C-1和IY210316B-1等用DMSO稀释后加入培养孔，使体系中化合物的终浓度分别为0.1、0.3、1、3、10、30、100和300(μmol/L)。继续培养48h后，每孔加入MTT溶剂(5mg/ml)10μL，37℃孵育4h，吸弃培养上清，每孔加入150μl DMSO，摇床震荡脱色 10min，酶标仪读值，测定在吸收波长为490nm下的OD值，记录结果，以化合物的剂量为横坐标，吸光值为纵坐标绘制细胞生长曲线。所述的IY210216D-1、ID210203C-1和IY210316B-1等对肿瘤细胞的半数抑制率(IC50值)的统计结果如图1所示。
图1的结果表明：与阳性对照药物WP1066相比，IY210216D-1、ID210203C-1和IY210316B-1等对乳腺癌和肝癌等肿瘤细胞均有良好的增殖抑制作用，特别是在乳腺癌和肝癌细胞的抑瘤活性更强，我们重点对这3种化合物在乳腺癌和肝癌的抗肿瘤效应进行了进一步研究。
实施例3、Western blot检测ID210203C-1对JAK2/STAT3信号轴的蛋白表达的调控作用
将对数生长期的MDA-Mb-468或HepG2细胞接种至6孔细胞培养板中，每孔8×105个细胞。待细胞贴壁后，加入ID210203C-1，使其终浓度分别为0、0.5、1或0、0.5、1、2、4 和8μM。约48h后，用RIPA裂解液裂解细胞收集蛋白，进行Western blot分析。分别通过抗JAK2、p-JAK2、STAT3、p-STAT3、CyclinD1、p-AKT、p-ERK和β-actin抗体检测相应蛋白表达量。
结果如图2显示，与溶剂对照孔相比，ID210203C-1处理后，可以显著抑制p-JAK2、p- STAT3和CyclinD1的表达水平，并具有剂量依赖性。表明化合物ID210203C-1可以靶向抑制JAK2和STAT3蛋白磷酸化和下游靶基因的表达。
实施例4、IY210216D-1和ID210203C-1可以显著诱导乳腺癌和肝癌细胞的周期阻滞
取对数生长期的MDA-MB-468或HepG2细胞，消化后离心并将细胞制成单细胞悬液。计数后将细胞铺入1个12孔板，两种细胞均每孔接种2×105个细胞，铺3个孔做平行对照。铺板16h后，加化合物处理细胞。以DMSO为化合物的溶剂，化合物IY210216D-1和 ID210203C-1在HepG2细胞悬液的终浓度分别为0、2、4和8μM，化合物IY210216D-1和 ID210203C-1在MDA-MB-468细胞悬液的终浓度分别为0和2μM。加药48h后，用胰酶分别消化各空细胞，重悬之后计数，将各孔细胞浓度调整为5×105个。消化完成后离心弃上清，再用PBS洗细胞两遍(2000rpm，离心5min)，之后弃尽上清，每管加入980μl的 70％冷乙醇和20μl的5％BSA(添加少量BSA可以减少操作过程中的细胞损失)在 4℃条件下固定过夜。弃固定液，用PBS洗3遍以去除残余的固定液(1000rpm，离心3 min)。细胞洗涤完成后，按DNA含量检测试剂盒(北京索莱宝公司产品)的说明书的要求进行后续操作。每个样品分别用100μl Rnase A于37度孵育30min，然后每个样品中加入 500μl已经配制好的PI(碘化丙啶)工作液，室温避光孵育30min。最后，通过流式细胞仪测定细胞周期。采用ModFit软件对实验结果进行分析，通过Graphpad prism 6.0进一步分析得到两种细胞各自的细胞周期比例。
图3是用ModFit软件分析IY210216D-1和ID210203C-1对HepG2和MDA-MB-468细胞的周期分布的结果。图4是通过Graphpad prism 6.0对图3结果的进一步定量分析。图3 和图4结果表明，与溶剂对照组(DMSO)相比，化合物IY210216D-1和ID210203C-1均可以诱导肝癌细胞的G2期比率显著增加，G1期的比率显著减少。化合物IY210216D-1和 ID210203C-1均可以诱导乳腺癌细胞的S期比率显著增加，G1期的比率相应减少。
实施例5、IY210216D-1,ID210203C-1和IY210316B-1诱导肿瘤细胞凋亡
取对数生长期的MDA-MB-468或HepG2细胞，消化后离心并将细胞制成单细胞悬液。计数后将细胞铺入1个12孔板，两种细胞均每孔接种2×105个细胞，铺3个孔做平行对照。铺板16h后，加化合物处理细胞。以DMSO为化合物的溶剂，化合物IY210216D-1 和ID210203C-1在HepG2细胞悬液的终浓度分别为0、2、4和8μM。化合物IY210316B-1 在MDA-MB-468细胞悬液的终浓度分别为0和0.12μM。加药48h后，用不含EDTA的胰酶消化细胞，重悬之后计数，将细胞浓度调整为1×106个。用Annexin V FITC-PI细胞凋亡检测试剂盒(北京索莱宝公司产品)的说明书的要求进行用后续操作。具体为：1×PBS 洗细胞2遍(6000rpm，离心0.5min)，用1×Binding buffer洗细胞1遍(6000rpm，离心 0.5min)之后弃尽上清，以500μl的1×Binding buffer重悬细胞，每管加入5μl Annexin V-FITC，避光孵育10min。随后，每管加入5μl的PI，避光孵育5min。避光上机检测。
图5是流式细胞术检测IY210216D-1,ID210203C-1和IY210316B-1对肿瘤细胞凋亡的影响。结果显示，与对照组相比，IY210216D-1,ID210203C-1和IY210316B-1均可以剂量依赖的方式诱导细胞凋亡增加。特别是IY210316B-1，仅0.12uM处理48h,即可以诱导乳腺癌细胞发生43.86％的凋亡。
实施例6、IY210216D-1和ID210203C-1影响细胞周期调控分子和转移相关基因的表达
将肝癌HepG2细胞接种于6孔板，每孔1×106个细胞。加化合物IY210216D-1和ID210203C-1(浓度为0和4μM)处理24h。按照TRIzol一步法提取细胞总RNA，测定 RNA浓度和纯度。以总RNA为模板，按Promega公司反转录试剂盒说明书合成cDNA。半定量RT-PCR和实时定量RT-PCR扩增检测CCND1、CCNB1和MMP9，以ACTB为内参照。所用引物见表1。
表1
Figure BDA0003139283160000151
实时定量RT-PCR：
反应体系:
Figure BDA0003139283160000152
每组样品设3个复孔。
反应条件：
95℃预变性5min。
变性 95℃ 15sec
退火 60℃ 15sec
延伸 72℃ 30sec
扩增40个循环，以β-actin的CT值作为初始值进行数据分析。
图6是通过Q-PCR检测IY210216D-1和ID210203C-1对细胞周期和转移相关分子的mRNA水平的影响。结果表明，IY210216D-1和ID210203C-1以0和4μM处理24h后，与内存蛋白β-actin的基因(ATCB)的表达水平相比，细胞周期G2期调控分子Cyclin D1(基因名：CCND1)和G2期调控分子Cyclin B1(基因名：CCNB1)的mRNA水平约下调10 倍以上，细胞转移相关标志物MMP9(基因名：MMP9)的表达下调接近10倍。表明 IY210216D-1和ID210203C-1可以通过从mRNA水平下调Cyclin D1、Cyclin B1和MMP9 的表达，诱导细胞周期阻滞，抑制肿瘤细胞生长和转移。
综上结果表明，以IY210216D-1,ID210203C-1和IY210316B-1为代表的此种萘脲类化合物可以显著抑制乳腺癌和肝癌细胞增殖和转移，诱导肿瘤细胞发生周期阻滞和细胞凋亡，显示了良好的抗癌作用。
按照药物开发的一般途径(先进行常规的抗肿瘤体外筛选，然后进行针对性的研究)，本发明的化合物可以应用到与细胞增殖异常相关的癌症治疗药物中，可通过与人体可接受的成盐或与药用载体混合制备抗肿瘤药物。
最后所应说明的是：上述实施例仅用于说明而非限制本发明的技术方案，任何对本发明进行的等同替换及不脱离本发明精神和范围的修改或局部替换，其均应涵盖在本发明权利要求保护的范围。

Claims (9)

1.一类具有抗癌作用的萘基脲类化合物，其特征在于，结构式如通式I所示：
Figure FDA0003591514130000011
其中，R选自
Figure FDA0003591514130000012
Figure FDA0003591514130000013
Figure FDA0003591514130000014
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、R34、R35、R36、R37、R38、R39、R40、R41、R42、R43、R44、R45、R46、R47、R48各自独立地选自H、F、Cl、Br、-CN、-CH3、-CF3、-OCH3、-OCF3，
m,n代表CH2取代基的个数，m,n为1、2、3、4；
k,z代表CH2取代基的个数，k,z为0、1、2、3、4、5、6；
A为
Figure FDA0003591514130000015
其中p代表CH2取代基的个数，p为1、2、3；
X为O或S。
2.一种萘基脲类化合物，其特征在于，具体为如下结构的化合物：
Figure FDA0003591514130000021
3.权利要求1或2所述的萘基脲类化合物与乙酸、二氢叶酸、苯甲酸、柠檬酸、山梨酸、丙酸、草酸、富马酸、马来酸、盐酸、苹果酸、磷酸、亚硫酸、硫酸、香草酸、酒石酸、抗坏血酸、硼酸、乳酸和乙二胺四乙酸中的至少一种形成的生物学可接受的盐。
4.权利要求1或2所述的萘基脲类化合物的制备方法，其特征在于，包括以下步骤：
(1)将
Figure FDA0003591514130000031
和三苯基膦溶于四氢呋喃中，-5℃～5℃慢慢加入偶氮二甲酸二异丙酯，室温搅拌反应至完全，后处理得到
Figure FDA0003591514130000032
(2)将
Figure FDA0003591514130000033
和叔丁醇钾溶于甲苯中，氮气保护下依次加入Pd2(dba)3和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽，110℃下反应至完全，经后处理得到
Figure FDA0003591514130000034
5.根据权利要求4所述的萘基脲类化合物的制备方法，其特征在于，所述
Figure FDA0003591514130000035
的制备过程如下：
(a)将
Figure FDA0003591514130000036
和三苯基膦溶于四氢呋喃中，-5℃～5℃保护气氛下加入偶氮二甲酸二异丙酯，室温搅拌反应至完全，经后处理得到
Figure FDA0003591514130000037
(b)将化合物
Figure FDA0003591514130000041
溶于四氢呋喃中，-5℃～5℃分批加入四氢铝锂，室温搅拌至反应完全，经后处理得到
Figure FDA0003591514130000042
6.根据权利要求4所述的萘基脲类化合物的制备方法，其特征在于，所述步骤(1)中
Figure FDA0003591514130000043
三苯基膦与偶氮二甲酸二异丙酯的摩尔比为1:1:1.2:1.2；
步骤(2)中
Figure FDA0003591514130000044
叔丁醇钾、Pd2(dba)3和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽的摩尔比为1:1:1.3:0.05:0.1。
7.根据权利要求5所述的萘基脲类化合物的制备方法，其特征在于，步骤(a)中，
Figure FDA0003591514130000045
三苯基膦、偶氮二甲酸二异丙酯的摩尔比为1:1.2:1.2:1.2；
步骤(b)中，
Figure FDA0003591514130000046
和四氢铝锂的摩尔比为1:1。
8.权利要求1至3任一项所述的萘基脲类化合物及其生物学可接受的盐在制备抗肿瘤药物中的用途，其特征在于，所述抗肿瘤药物为治疗与JAKs或STAT3信号传导相关疾病的药物。
9.根据权利要求8所述的用途，其特征在于，所述的抗肿瘤药物具体指治疗乳腺癌、肝癌、肺癌、结肠癌或白血病的药物。
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