CN113943304B - 靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物及其制备方法和应用 - Google Patents
靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种靶向Pim‑1激酶的酞菁‑5‑溴‑1‑苯并呋喃‑2‑羧酸配合物及其制备方法和应用,其是以3‑硝基邻苯二甲腈为原始原料,通过亲核反应得到3‑(4‑羧基甲酯苯氧基)邻苯二腈,再通过成环反应和亲核反应生成1‑(4‑羧基苯氧基)酞菁,最后通过亲核取代反应生成目标产物()。该配合物能增强对于三阴性乳腺癌细胞的杀伤作用,为提高光动力治疗提供一个新的思路。
Description
技术领域
本发明属于药物化学领域,具体涉及一种靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物及其制备方法与应用。
背景技术
癌症是危害人类健康的主要疾病。目前癌症的治疗手段有化疗、放疗、手术切除、光动力治疗,其中光动力治疗因为具有选择性、微创、毒性较小而具有较大的潜力。光动力治疗中用到的光敏剂主要是卟啉和酞菁,酞菁是一种大环平面的结构,自身靶向性能不足,这会严重降低光动力治疗的效果,所以提高酞菁靶向性能是急需解决的问题。
Pim-1激酶在一些肿瘤中高度表达,比如三阴性乳腺癌,但是在正常组织几乎不表达。临床数据表明Pim-1激酶和肿瘤的整个阶段都有关,从肿瘤的初期阶段到肿瘤的转移和扩散,因此Pim-1激酶是一个潜在的靶点。5-溴-1-苯并呋喃-2-羧酸是一种Pim-1激酶的抑制剂,其可以靶向到Pim-1激酶中。
基于Pim-1激酶在肿瘤发展中的重要作用,本发明提出了把酞菁和5-溴-1-苯并呋喃-2-羧酸的活性结构域结合在一起,利用5-溴-1-苯并呋喃-2-羧酸对Pim-1激酶的靶向性以增强配合物对于三阴性乳腺癌细胞的杀伤作用。
发明内容
本发明针对酞菁容易聚集的问题,提供一种靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物,其利用5-溴-1-苯并呋喃-2-羧酸对Pim-1激酶的靶向性,通过将酞菁和酶结合以增强酞菁的靶向性,提高单线态氧产率,进而提高治疗效率。
为实现上述发明目的,本发明采用如下技术方案:
一种靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物,其化学结构式为:
所述靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物的制备方法,包括以下步骤:
1)将3-硝基邻苯二甲腈、对羟基苯甲酸甲酯、K2CO3按摩尔比1:1:2溶于DMF(二甲基甲酰胺)中,常温搅拌反应24~48h后,往反应液里加入一定量的水,使其析出白色沉淀,过滤并烘干,得到化合物1a,其化学结构式为:其中,所用水和DMF的体积比为5:1;
2)将化合物1a、邻苯二甲腈溶于正戊醇,加热到110~130℃后加入锌源,搅拌均匀后再加入DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯),回流反应36~48h,之后旋干正戊醇,加入过量的20wt%氢氧化钠水溶液,回流反应24~48h,旋干溶液后加入20wt%盐酸水溶液调节pH至3.0,过滤得到蓝色固体,取蓝色固体过硅胶柱,以EA(乙醇)-DMF的体积比为100:1为洗脱剂冲洗至无酞菁,再以EA-DMF的体积比为20:1进行洗脱,收集目标产物2a,其化学结构式为:其中,所用化合物1a、邻苯二甲腈、DBU与锌源的摩尔比为1:7:8:4,所述锌源为氯化锌或醋酸锌;
3)将5-溴-1-苯并呋喃-2-羧酸(cas:10242-11-2)、NHS(N-羟基琥珀酰亚胺)、DCC(N,N-二环己基碳二亚胺)用DCM(二氯甲烷)溶解,常温搅拌反应24h~48h后旋干,产物过中性硅胶柱,以DCM作为洗脱剂,收集黄色固体3a,其化学结构式为:其中所用5-溴-1-苯并呋喃-2-羧酸、NHS、DCC的摩尔比为1:1:1;
4)将产物2a、NHS、EDCI(碳化二亚胺)用THF(四氢呋喃)溶解,常温搅拌反应48h~72h之后,往溶液中加入己二胺化合物,回流反应1小时,旋干溶液,往圆底烧瓶里面加入少量水,摇匀后把水倒掉,之后旋干,加入黄色固体3a和DMF,100~120℃反应2h,旋干后过硅胶柱,以DCM-CH3OH的体积比为100:1进行洗脱除掉杂质,再用DCM-CH3OH的体积比为30:1进行洗脱纯化,收集产物,用同样的洗脱除杂、纯化条件重复过柱2~3次之后,得到纯的目标产物;其中,所用产物2a、NHS、EDCI、己二胺化合物、黄色固体3a的摩尔比为1:1:1:5:1。
所述靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物可用于合成光动力抗肿瘤药物。
本发明的有益效果在于:
1)本发明所合成的配合物结构稳定,无异构体,容易合成;
2)本发明中5-溴-1-苯并呋喃-2-羧酸活性结构域的引入可以增强肿瘤细胞对于配合物的摄取,且5-溴-1-苯并呋喃-2-羧酸活性结构域可以靶向Pim-1激酶,增强配合物对于三阴性乳腺癌细胞的杀伤作用,从而增强光动力治疗的效果。
附图说明
图1为本发明合成酞菁-5-溴-1-苯并呋喃-2-羧酸配合物BF-Pc的工艺路线图。
图2为对比例合成H-Pc的工艺路线图。
图3为实施例所合成BF-Pc(A)和H-Pc(B)在DMF中的紫外可见吸收光谱图。
图4为BF-Pc和H-Pc在光照条件下对于4T1细胞和HELF细胞的毒性对比图。
具体实施方式
为了使本发明所述的内容更加便于理解,下面结合具体实施方式对本发明所述的技术方案做进一步的说明,但是本发明不仅限于此。
实施例BF-Pc的制备
以3-硝基邻苯二甲腈为原始原料,通过亲核反应得到3-(4-羧基甲酯苯氧基)邻苯二腈,再通过成环反应和碱解反应生成1-(4-羧基苯氧基)酞菁锌,再通过1-(4-羧基苯氧基)酞菁锌、己二胺、5-溴-1-苯并呋喃-2-羧酸活性酯之间的亲核取代反应生成BF-Pc的目标产物。
具体步骤如下:
1)将2.00g(11.6mmol)3-硝基邻苯二甲、1.757g(11.6mmol)对羟基苯甲酸甲酯、3.202g(23.2mmol)K2CO3溶于20ml DMF中,常温反应24h后,往反应液里加入100ml水,使其析出白色沉淀,过滤并烘干,得到2.5g化合物1a,其产率为78%,1H NMR(400MHz,Chloroform-d)δ8.13(d,J=8.2Hz,2H),7.64(t,J=8.2Hz,1H),7.54(d,J=7.7Hz,1H),7.16(dd,J=17.6,8.2Hz,3H),3.93(s,3H);
2)将0.500g(1.8mmol)化合物1a、1.448g(12.6mmol)邻苯二甲腈溶于50ml正戊醇中,加热到130℃后,加入1.318g(7.2mmol)醋酸锌,搅拌均匀后再加入2.189g(14.4mmol)DBU,此时溶液颜色变绿,然后回流反应36h,之后旋干正戊醇,往里加入20ml 20wt%氢氧化钠水溶液,回流反应48h,旋干溶液后往里面加入50ml 20wt%盐酸水溶液,以调节pH至3.0,过滤得到蓝色的固体;取300mg蓝色固体上硅胶柱,以EA:DMF=100:1(v/v)冲洗至无锌酞菁,再用EA:DMF=20:1(v/v)洗脱,收集得到200mg目标产物2a,其产率为15%,1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),9.12–8.76(m,6H),8.49(s,1H),8.26–7.69(m,10H),7.40(s,2H)。
3)将0.672g(2.8mmol)5-溴-1-苯并呋喃-2-羧酸、0.327g(2.8mmol)N-羟基琥珀酰亚胺、0.576g(2.8mmol)N,N-二环己基碳二亚胺用20mL DCM溶解,常温反应24h后旋干,用DCM作为洗脱剂,过中性硅胶柱,收集得到0.6g白色固体3a,其产率为64%,1H NMR(500MHz,CDCl3)δ7.88(s,1H),7.75(s,1H),7.62(s,1H),7.50(s,1H),2.92(s,4H).
4)将100mg(0.14mmol)2a、16.1mg(0.14mmol)N-羟基琥珀酰亚胺、26.74mg(0.14mmol)EDCI用20ml THF溶解,常温反应48h之后,往溶液中加入81.2mg(0.70mmol)己二胺,回流反应1小时,旋干溶液,往圆底烧瓶里面加入50ml水,稍微晃几下后把水倒掉,之后旋干,往瓶子里加入47.18mg(0.14mmol)3a和10ml DMF,100℃反应2h,旋干DMF后,用DCM:CH3OH=100:1(v/v)洗脱除掉杂质,再用DCM:CH3OH=30:1(v/v)洗脱纯化,收集产物,用同样的洗脱除杂、纯化条件重复过柱3次之后,得到20mg纯的产物BF-Pc,其产率为14%,1H NMR(500MHz,DMSO-d6)δ9.00(d,J=22.7Hz,6H),8.61(s,1H),8.48(s,1H),8.20(s,1H),8.04(s,1H),7.98(d,J=7.2Hz,5H),7.88(d,J=27.6Hz,4H),7.73(s,1H),7.49-7.42(m,2H),7.30(s,1H),7.27(s,1H),7.23(s,1H),7.13(s,1H),1.13(s,17H);HRMS(ESI):Calcd forC54H37BrN10O4Zn[M+H]+:1033.1547,found:1033.1518.
对比例H-Pc的合成
将100mg(0.14mmol)2a、16.1mg(0.14mmol)N-羟基琥珀酰亚胺、26.74mg(0.14mmol)EDCI用10ml THF溶解,常温反应48h之后,往溶液中加入14.14mg(0.14mmol)正己胺,回流反应1小时,旋干溶液,用DCM:CH3OH=110:1(v/v)洗脱除掉杂质,再用DCM:CH3OH=45:1(v/v)洗脱纯化,收集产物,用同样的洗脱除杂、纯化条件重复过柱3次之后,得到30mg较纯的产物H-Pc,其产率为30%,1H NMR(400MHz,Chloroform-d)δ9.15(d,J=44.7Hz,6H),8.79(s,1H),8.31–7.70(m,10H),7.63(s,2H),3.54(s,2H),1.40(s,9H),0.98(s,3H),HRMS(ESI):Calcd C45H33N9O2Zn[M+H]+:796.2121,found:796.2083,H-Pc的化学结构式如下:
细胞毒性实验
MTT法又称比色法,是一种检测细胞存活状态的方法。活细胞线粒体中的琥珀酸脱氢酶能使外源性的MTT还原为不溶于水的甲臜并沉积在细胞中,死去的细胞则不能使MTT还原为甲臜。二甲基亚砜可以溶解细胞中的甲臜,用酶标仪测定其在570nm处的波长值,可间接反映活细胞的数量。在一定细胞数范围内,MTT结晶形成的量与细胞数成正比。
在显微镜底下选取生长状态良好的细胞4T1和HELF细胞,当细胞密度长到90%左右时,用1ml胰酶(含EDTA)消化3分钟(其中Hela细胞消化1分钟),之后加入2ml培养基终止消化,吹打均匀,之后用细胞计数板计数,用DMEM培养基稀释细胞溶液至6万Cell/ml,往96孔板中每孔加入100μL上述细胞培养基溶液,BF-Pc和H-Pc药物每个浓度设置6个复孔,并设置细胞空白组和溶剂空白组(每组6个复孔),将96孔板至于37℃培养箱中24h。
加药:用5%CEL的DMSO溶液分别稀释BF-Pc和H-Pc至7种不同浓度,之后再用DMEM培养基将上述7种浓度的药物稀释100倍,用排枪吸出96孔板中的旧培养基,往细胞对照组中加入稀释100倍的5%CEL的DMSO溶液,溶剂对照组加入DMFM培养基,剩下的药物对照组分别加入上述配制的溶液,继续把96孔板放于培养箱中24h。
光毒:取出96孔板,用排枪小心的吸出孔里的含药培养基,之后用生理盐水洗涤每个孔3遍去除未被摄取的药物,最后往每孔加入100μL的培养基,之后用670nm的LED灯照射2min,之后把光照后的板放回培养箱。
测试OD值:往96孔板的每孔加入10μl 5mg/ml的MTT溶液,再把96孔板放于37℃培养箱中4h,之后用排枪吸出每孔的溶液,再次往每孔加入100μl的DMSO溶液,用摇床摇30min,用酶标仪测试570nm处的吸光度。
计算:用测定的吸光度计算细胞的存活率,计算公式如下:
细胞存活率(%)=(样品组吸光度-溶剂空白组吸光度)/(细胞空白组吸光度-溶剂空白组吸光度)×100。
图4为BF-Pc和H-Pc在光照条件下对于4T1细胞的和HELF细胞的毒性对比图。从图中可见,5-溴-1-苯并呋喃-2-羧酸的引入可以增强BF-Pc对于肿瘤细胞的毒性作用。
以上所述仅为本发明的较佳实施例,凡是利用本发明说明书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内。
Claims (5)
1.一种用于光动力抗乳腺癌的靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物的制备方法,其特征在于:包括以下步骤:
1)将3-硝基邻苯二甲腈、对羟基苯甲酸甲酯、K2CO3溶于DMF中,常温搅拌反应24~48h后,往反应液里加入水,使其析出白色沉淀,过滤并烘干,得到化合物1a,其化学结构式为:
;
2)将化合物1a、邻苯二甲腈溶于正戊醇,加热到一定温度后加入锌源,搅拌均匀后再加入1,8-二氮杂双环[5.4.0]十一碳-7-烯DBU,回流反应36~48h,之后旋干正戊醇,加入过量的20wt%氢氧化钠水溶液,回流反应24~48h,旋干溶液后调节pH,过滤得到蓝色固体,取蓝色固体过硅胶柱,洗脱冲洗至无酞菁,收集目标产物2a,其化学结构式为:
,其中的M为Zn;
3)将5-溴-1-苯并呋喃-2-羧酸、N-羟基琥珀酰亚胺NHS、N,N-二环己基碳二亚胺DCC用二氯甲烷DCM溶解,常温搅拌反应24h~48h后旋干,产物过中性硅胶柱,以DCM作为洗脱剂,收集黄色固体3a,其化学结构式为:;
4)将产物2a、NHS、碳化二亚胺EDCI用四氢呋喃THF溶解,常温搅拌反应48h~72h之后,往溶液中加入己二胺化合物,回流反应1小时,旋干溶液,往圆底烧瓶里面加入水,摇匀后把水倒掉,之后旋干,加入黄色固体3a和DMF,高温反应,旋干后过硅胶柱,洗脱除掉杂质,再进行洗脱纯化,收集产物,用同样的洗脱除杂、纯化条件重复过柱2~3次之后,得到纯的目标产物,其化学结构式为:
;
步骤2)中加热到一定温度具体为加热到110~130℃;
步骤4)中所用产物2a、NHS、EDCI、己二胺、黄色固体3a的摩尔比为1:1:1:5:1,高温反应具体为100~120℃反应2h。
2.根据权利要求1所述的靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物的制备方法,其特征在于:步骤1)中所用3-硝基邻苯二甲腈、对羟基苯甲酸甲酯与K2CO3的摩尔比为1:1:2,所用水和DMF的体积比为5:1。
3.根据权利要求1所述的靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物的制备方法,其特征在于:步骤2)中化合物1a、邻苯二甲腈、DBU与锌源的摩尔比为1:7:8:4;所述锌源为氯化锌或醋酸锌。
4.根据权利要求1所述的靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物的制备方法,其特征在于:步骤2)中调节pH具体是加入20wt%盐酸水溶液调节pH至3.0。
5.根据权利要求1所述的靶向Pim-1激酶的酞菁-5-溴-1-苯并呋喃-2-羧酸配合物的制备方法,其特征在于:步骤3)中所用5-溴-1-苯并呋喃-2-羧酸、NHS、DCC的摩尔比为1:1:1。
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