CN111423446B - 具有光、声敏活性的二氢卟吩硝酸酯类化合物、制备方法与应用 - Google Patents
具有光、声敏活性的二氢卟吩硝酸酯类化合物、制备方法与应用 Download PDFInfo
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Abstract
本发明提供了一类具有光、声敏活性的二氢卟吩硝酸酯类化合物、制备方法与应用,属于化学医药技术领域。本发明所述的二氢卟吩硝酸酯类化合物制备方法简便,通过引入硝酸酯基团作为NO的供体,提高活性氧的产率,增强光、声敏化合物的活性。在体外抗肿瘤活性评价中对人宫颈癌细胞系Hela细胞具有不同程度的抑制作用,光、声活性要高于作为对照的Chlorin e6。可用于肿瘤的光动力治疗及声动力治疗中的光敏剂及声敏剂的制备。
Description
技术领域
本发明涉及一类具有光、声敏活性的二氢卟吩硝酸酯类化合物及其制备方法与应用,属于化学医药技术领域。
背景技术
光动力学治疗(Photodynamic therapy,PDT)与声动力学治疗(Sonodynamictherapy,SDT),分别是通过光敏剂(Photosensitizer)或声敏剂(Sonosensitizer)在光或超声激发下,产生单线态氧和其他活性氧物质,与附近的富电子生物分子反应,引起细胞死亡和组织破坏的一种医疗技术。同外科手术、化疗、放疗等传统的治疗方法相比,PDT及SDT具有对靶组织选择性高、副作用小、对内脏器官无损伤等优点,但是目前光、声敏剂还存在活性氧产生量低,在体内滞留时间长,易产生光毒性等缺点,因此亟待开发高效低毒的新型光、声敏剂,用于肿瘤的治疗,其中提高化合物活性氧的产率是设计方向之一,详见具有光、声敏活性的二氢卟吩青蒿琥酯结合物及其制备方法与应用,郭修晗等,中国发明专利,2017.08.04。
PDT及SDT对肿瘤细胞的杀伤作用高度依赖细胞内的活性氧(ROS)的存在,但是由于肿瘤组织周围氧气浓度低的特点,限制了活性氧的产生。NO分子作为一种活性氧分子,是氧化还原信号传导的关键调节剂,形成原始活性氧物质及超氧化物,产生细胞毒性,进一步诱导细胞凋亡,使肿瘤细胞对化疗,放射或免疫治疗敏感,逆转化疗耐药性,延缓血管生成和转移性级联。基于PDT及SDT的治疗原理,我们设计将硝酸酯基团引入到光、声敏剂结构中,通过NO的释放,增强活性氧的产生数量,提高化合物对肿瘤细胞的杀伤作用,同时克服肿瘤细胞对常规治疗剂具有的抗性,开发出活性更佳的光、声敏剂用于肿瘤治疗。
发明内容
本发明通过合成具有光、声敏活性的二氢卟吩硝酸酯类化合物,得到了活性更强的可用于光、声动力治疗的抗肿瘤化合物。
本发明的技术方案:
一种具有光、声敏活性的二氢卟吩硝酸酯类化合物,其具有如下通式I、II、III和IV:
其中:
R1,R2,R3选自H和甲基;
n为0~8中任一整数。
一种具有光、声敏活性的二氢卟吩硝酸酯类化合物的制备方法,步骤如下:①以pheophytin a为原料,在0℃下溶解于50wt.%甲醇钠甲醇溶液,浓度为0.1M,在室温下反应10h,得到131,152-Chlorin e6 dimethyl ester;再将131,152-Chlorin e6 dimethylester溶解于DMF,浓度为0.15M,依次加入EDCI、端基溴脂肪链状烷基伯胺盐和DIPEA,其中,131,152-Chlorin e6 dimethyl ester:EDCI:端基溴脂肪链状烷基伯胺盐:DIPEA的摩尔比为1:1~2:1~2:1~4,在室温下反应24h,得到化合物1;再将化合物1溶解于无水乙腈中,浓度为0.1M,加入硝酸银,其中化合物1:硝酸银的摩尔比为1:1~3,在60℃下反应4h,得到化合物2;所述的端基溴脂肪链状烷基伯胺盐的直链的碳的个数为2~10;反应式如下:
②以化合物2为原料,溶解于体积比3:1:1的THF、MeOH和H2O的混合液,浓度为0.1M,加入LiOH·H2O,化合物2:LiOH·H2O的摩尔比为1:2~5,在室温下反应24h,得到化合物2i;反应式如下:
③以Chlorin e6为原料,溶解于DMF,浓度为0.1M,依次加入EDCI、端基溴脂肪链状烷基伯胺盐和DIPEA,其中,Chlorin e6:EDCI:端基溴脂肪链状烷基伯胺盐:DIPEA的摩尔比为1:1~2:1~2:1~4,在室温下反应20h,得到化合物3;再将化合物3溶解于无水乙腈中,浓度为0.1M,加入硝酸银,其中化合物3:硝酸银的摩尔比为1:1~3,在60℃下反应6h,得到化合物4;反应式如下:
④以化合物4为原料,在0℃下溶解于DMF,浓度为0.1M,依次加入碳酸钾、碘甲烷,其中化合物4:碳酸钾:碘甲烷的摩尔比为1:6:6,室温下反应5h,得到化合物5,反应式如下:
⑤以Methyl pheophytin a为原料,溶解于DMF,浓度为0.1M,依次加入端基溴脂肪链状烷基伯胺盐和DIPEA,其中,Methyl pheophytin a:端基溴脂肪链状烷基伯胺盐:DIPEA的摩尔比为1:1~2:1~4,在室温下反应24h,得到化合物6;再将化合物6溶解于无水乙腈中,浓度为0.1M,加入硝酸银,其中化合物6:硝酸银的摩尔比为1:1~2,在60℃下反应6h,得到化合物7;反应式如下:
⑥以化合物7为原料,溶解于体积比3:1:1的THF、MeOH和H2O的混合液,浓度为0.1M,加入LiOH·H2O,化合物2:LiOH·H2O的摩尔比为1:2~5,在室温下反应24h,得到化合物7i;反应式如下:
⑦以Chlorin e6为原料,溶解于DMF,浓度为0.1M,依次加入HBTU、DIPEA和3-amino-1-propanol-nitrate,其中,Chlorin e6:HBTU:DIPEA:3-amino-1-propanol-nitrate的摩尔比为1:3~6:3~6:6~10,在室温下反应96h,得到化合物8;反应式如下:
所述的具有光、声敏活性的二氢卟吩硝酸酯类化合物用于制备抗肿瘤药物或作为活性组份制备药物复合物用于肿瘤的治疗。
本发明的有益效果:本发明所述的二氢卟吩硝酸酯类化合物制备方法简便,通过引入硝酸酯基团作为NO的供体,提高活性氧的产率,增强光、声敏化合物的活性。在体外抗肿瘤活性评价中对人宫颈癌细胞系Hela细胞具有不同程度的抑制作用,光、声活性要高于作为对照的Chlorin e6。可用于肿瘤的光动力治疗及声动力治疗中的光敏剂及声敏剂的制备。
附图说明
图1是溶液中化合物释放NO的量的测定图。
具体实施方式
以下结合附图和技术方案,进一步说明本发明的具体实施方式。
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。
实施例1
化合物1的合成
pheophytin a(100mg)在0℃溶解于50wt.%甲醇钠甲醇溶液(4ml),在室温下氮气保护反应10h,反应结束后,加入甲酸淬灭反应,减压浓缩除去甲醇,浓缩物二氯甲烷溶解,先后用水,饱和氯化钠溶液洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=80:1,得到化合物131,152-Chlorin e6 dimethylester。再将131,152-Chlorin e6 dimethyl ester溶解于DMF(2ml),依次加入EDCI(54.2mg)、溴丙胺氢溴酸盐(63.4mg)和DIPEA(0.1ml),在室温下反应24h,反应结束后反应液用二氯甲烷转移,先后用水,饱和氯化钠溶液洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=20:1,得到化合物1(70mg,56%)。1H-NMR(CDCl3,400MHz,ppm)δ:9.72(s,1H),9.53(s,1H),8.80(s,1H),7.91(dd,J=17.8,11.4Hz,1H),6.23(d,J=18.3Hz,1H),6.06(d,J=11.6Hz,1H),5.26(br,2H),4.41(br,2H),4.24(d,J=8.8Hz,2H),4.18(s,3H),3.86(br,2H),3.72(s,3H),3.53(s,3H),3.51(br,2H),3.37(s,3H),3.22(s,3H),2.91(dd,J=14.6,7.1Hz,1H),2.60(d,J=16.0Hz,2H),2.36~2.27(m,1H),2.11(d,J=11.3Hz,2H),1.73(d,J=6.7Hz,3H),1.66~1.60(m,3H),-1.50~-1.72(m,2H).HR-MS found:m/z:682.52[M-Br+H2O]+,calcd for C39H46BrN5O5,744.7310.
化合物2的合成
将化合物1(30mg)溶解于无水乙腈(1ml),加入硝酸银(12mg),氮气保护在60℃下反应4h,反应结束后,减压除去溶剂,浓缩得到固体用二氯甲烷溶解,用饱和食盐水洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得到固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=80:1,得到化合物2(21.4mg,73%)。1H-NMR(CDCl3,400MHz,ppm)δ:9.70(s,1H),9.57(s,1H),8.73(s,1H),8.05(dd,J=17.9,11.6Hz,1H),6.36(d,J=17.9Hz,1H),6.16(d,J=11.2Hz,1H),5.28(br,2H),4.50(br,2H),4.26(s,5H),3.77(s,3H),3.65(br,2H),3.57(s,3H),3.47(s,3H),3.30(s,3H),3.07~2.90(br,4H),2.34(s,1H),2.04~1.76(br,3H),1.71(t,J=7.6Hz,3H),1.42(m,3H),-1.43(m,2H).HR-MS found:m/z:682.3570[M-NO2+2H]+,calcd for C39H46N6O8,726.8310.
实施例2
化合物3的合成
将Chlorin e6(60mg)溶解于DMF(2ml),依次加入EDCI(20mg)、溴丙胺氢溴酸盐(27mg)和DIPEA(0.05ml),氮气保护在室温下反应20h,反应结束后反应液用二氯甲烷转移,先后用水,饱和氯化钠溶液洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=40:1,得到化合物3(46.8mg,65%)。1H-NMR(CDCl3,400MHz,ppm)δ:9.65(s,1H),9.53(s,1H),8.79(s,,1H),8.00(dd,J=11.5Hz,1H),7.75(s,1H),6.32(d,J=17.9Hz,1H),6.14(d,J=11.5Hz,1H),5.18(br,2H),4.71~4.19(m,4H),3.73(d,J=7.1Hz,2H),3.54(s,3H),3.43(s,3H),3.26(s,3H),2.99(s,1H),2.89(d,J=22.6Hz,1H),2.57(d,J=6.3Hz,1H),2.36~2.00(m,2H),1.96~1.73(m,4H),1.67(br,4H),-1.16~-2.20(m,2H).HR-MS found:m/z:634.51[M-HBr-H]-,calcd for C37H42BrN5O5,716.6770.
化合物4的合成
将化合物3(34mg)溶解于无水乙腈(2ml),加入硝酸银(8.5mg),氮气保护在60℃下反应6h,反应结束后,减压除去溶剂,浓缩得到固体用二氯甲烷溶解,用饱和食盐水洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得到固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=50:1,得到化合物4(24mg,72%)。1H-NMR(CDCl3,400MHz,ppm)δ:9.62(s,1H),9.49(s,1H),8.71(s,1H),7.98(dd,J=11.5Hz,1H),7.60(s,1H),6.29(d,J=17.8Hz,1H),6.11(d,J=11.5Hz,1H),5.07(br,2H),4.51~3.95(br,4H),3.71(d,J=6.5Hz,2H),3.50(s,3H),3.36(s,3H),3.23(s,3H),2.94(s,2H),2.53(s,2H),2.10(br,2H),1.79(d,3H),1.66(m,3H),1.26(s,2H),-1.64(s,2H).HR-MS found:m/z:634.51[M-HBr-H]-,calcd forC37H42N6O8,698.7770.
实施例3
化合物5的合成
将化合物4(20mg)在0℃下溶解于DMF(1ml),依次加入碳酸钾(24mg)、碘甲烷(0.05ml),氮气保护室温下反应5h,反应结束后反应液用二氯甲烷转移,先后用水,饱和氯化钠溶液洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=20:1,得到化合物5(18mg,87%)。1H-NMR(CDCl3,400MHz,ppm)δ:9.72(s,1H),9.55(s,1H),8.84(s,1H),8.01(s,1H),7.57(m,1H),6.26(br,2H),5.36(dd,J=47.2,18.3Hz,2H),4.60(br,2H),4.25(m,2H),3.76(t,J=26.0Hz,5H),3.59(s,3H),3.46(s,3H),3.30(s,3H),3.19(s,3H),2.88~2.66(m,2H),2.31(br,3H),2.05(br,1H),1.75(br,6H),1.56(d,J=5.1Hz,2H),-1.15~-1.73(m,2H).HR-MS found:m/z:682.3570[M-NO2+2H]+,calcd for C39H46N6O8,726.8310.
实施例4
化合物6的合成
将Methyl pheophytin a(100mg)溶解于DMF(2ml),依次加入溴丙胺氢溴酸盐(72.2mg)和DIPEA(0.1ml),氮气保护在室温下反应24h,反应结束后反应液用二氯甲烷转移,先后用水,饱和氯化钠溶液洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=40:1,得到化合物6(64mg,52%)。1H-NMR(CDCl3,400MHz,ppm)δ:9.53(s,1H),9.35(s,1H)8.62(s,1H),7.98(dd,J=11.5Hz,1H),6.23(d,J=50.5Hz,2H),5.49(s,1H),5.34(s,1H),4.39(br,2H),4.17(br,2H),3.76(t,5H),3.70(s,3H),3.66(s,3H),3.61(s,3H),3.40(s,3H),3.17(s,3H),2.60(br,2H),2.41~1.9(br,4H),1.78~1.42(m,6H),-1.63~-2.06(m,2H).HR-MS found:m/z:744.41[M+H]+,calcd forC39H46BrN5O5,744.7310.
化合物7的合成
将化合物6(23mg)溶解于无水乙腈(1ml),加入硝酸银(10mg),氮气保护在60℃下反应6h,反应结束后,减压除去溶剂,浓缩得到固体用二氯甲烷溶解,用饱和食盐水洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得到固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=50:1,得到化合物7(16mg,71%)。1H-NMR(CDCl3,400MHz,ppm)δ:9.64(s,1H),9.53(s,1H),8.71(s,1H),8.03(s,1H),6.38(s,1H),6.17(d,J=11.3Hz,1H),5.53~5.14(m,2H),4.45(d,J=7.0Hz,2H),3.78(d,J=7.2Hz,2H),3.58(s,3H),3.54(s,3H),3.50(s,2H),3.47(s,3H),3.30(s,3H),2.96(s,3H),2.90(s,2H),2.54(s,1H),2.27~2.07(br,3H),1.84(d,J=6.5Hz,3H),1.73(t,J=7.1Hz,3H),1.62(s,2H),-1.21(s,2H).HR-MS found:m/z:727.1674[M+H]+,calcd for C39H46N6O8,726.8310.
实施例5
化合物8的合成
将Chlorin e6(100mg)溶解于DMF(3ml),在0℃下依次加入HBTU(253.3mg)、DIPEA(0.15ml)和3-amino-1-propanol-nitrate(122.7mg),氮气保护在室温下反应4d,反应结束后反应液用二氯甲烷转移,先后用水,饱和氯化钠溶液洗,有机层用无水硫酸钠干燥,过滤,减压浓缩得固体,硅胶柱层析分离,洗脱条件为二氯甲烷/甲醇=40:1,得到化合物8(48mg,32%)。1H-NMR(CDCl3,400MHz,ppm)δ:9.67(s,1H),9.64(s,1H),8.76(s,1H),8.08(dd,J=11.9Hz,1H),7.51(s,1H),6.38(d,J=17.7Hz,1H),6.18(d,J=11.4Hz,1H),4.96(dd,17.1Hz,2H),4.60(t,J=5.7Hz,2H),4.40(dd,J=21.0,1H),4.28(d,J=22.6Hz,2H),4.09(d,J=4.9Hz,1H),3.90(s,2H),3.76(s,2H),3.65(s,2H),3.59~3.52(m,1H),3.48(s,3H),3.44(s,3H),3.37~3.21(m,5H),3.15(dd,J=6.1Hz,1H),2.54(s,1H),2.33(s,1H),2.08(d,J=5.5Hz,2H),1.74(d,J=6.3Hz,9H),1.54(d,J=6.6Hz,3H),-1.70(s,1H),-1.95(s,1H).HR-MS found:m/z:903.4002[M+H]+,calcd for C43H54N10O12,902.9630.
应用例1
①体外抗癌活性评价:
光动力活性:
将化合物2,4,5,7,8,Chlorin e6,用DMSO溶解,-20℃保存;使用时,用细胞培养液稀释至DMSO的最终浓度<0.1%。
将处于对数生长期的Hela宫颈癌细胞,以5×103个/空接种于96孔板中,每孔加入细胞悬液100μL,培养24h后,加入100μL药液,终浓度分别为100μmol/L、33μmol/L、11μmol/L、3.7μmol/L、1.2μmol/L、0.4μmol/L的待测化合物,设置空白组(含培养液,无细胞)、对照组(培养细胞不加药),细胞在37℃培养箱(5%CO2)中孵育24h后,进行光毒性实验。培养板距离光源高度为20cm,光强1.7J/cm2,波长660nmLED,时间2min,再放入37℃培养箱(5%CO2)中孵育24h后,每孔加入浓度为5mg/mL的MTT溶液20μL,继续培养4h,吸走上清液,加入100μLDMSO。酶标仪测定570nm波长下各孔的吸光度(OD值),计算IC50。结果见表1。
声动力活性:
同光活性评价操作的区别在于:将加入药液的96孔板置于底部发超声的装置上,加入脱气水,使悬浮于水面上,距超声发声探头2cm,超声激发(2MHz,2W)2min,再放入37℃培养箱(5%CO2)中孵育24h后,每孔加入浓度为5mg/mL的MTT溶液20μL,继续培养4h,吸走上清液,加入100μLDMSO。酶标仪测定570nm波长下各孔的吸光度(OD值),计算IC50。结果见表2。
暗毒性活性:
同光活性评价操作的区别在于:将加入药液的96孔板置于暗室中2min,再放入37℃培养箱(5%CO2)中孵育24h后,每孔加入浓度为5mg/mL的MTT溶液20μL,继续培养4h,吸走上清液,加入100μLDMSO。酶标仪测定570nm波长下各孔的吸光度(OD值),计算IC50。
表1目标化合物对Hela宫颈癌细胞的体外光活性与暗毒性
表2目标化合物对Hela宫颈癌细胞的体外超声活性与暗毒性
②化合物释放NO的量的检测
采用Griess法测化合物在水溶液中的NO释放量。10mM的化合物DMSO溶液,取10μL,加到990μL的5mM半胱氨酸的磷酸盐缓冲液(50mM,pH=7.40)中。(化合物最终浓度是100uM)。将化合物溶液在黑暗中于37℃孵育不同时间。加磺胺的8.5%磷酸溶液,N-萘乙二胺盐酸盐的8.5%磷酸溶液各125μL。在37℃下于黑暗中放置30分钟后,使用酶标仪在540nm处读取吸光度,设置空白组为含5mM半胱氨酸的PBS溶液。以标准亚硝酸钠溶液浓度与吸光度关系曲线为依据,测定结果见图1。
Claims (3)
2.如权利要求1所述的一种具有光、声敏活性的二氢卟吩硝酸酯类化合物的制备方法,其特征在于,步骤如下:
①以叶绿酸a为原料,在0℃下溶解于50wt.%甲醇钠甲醇溶液,浓度为0.1M,在室温下反应10h,得到131,152-二氢卟吩e6二甲酯;再将131,152-二氢卟吩e6二甲酯溶解于DMF,浓度为0.15M,依次加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、端基溴脂肪链状烷基伯胺盐和N,N-二异丙基乙胺,其中,131,152-二氢卟吩e6二甲酯:1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐:端基溴脂肪链状烷基伯胺盐:N,N-二异丙基乙胺的摩尔比为1:1~2:1~2:1~4,在室温下反应24h,得到化合物1;再将化合物1溶解于无水乙腈中,浓度为0.1M,加入硝酸银,其中化合物1:硝酸银的摩尔比为1:1~3,在60℃下反应4h,得到化合物2;所述的端基溴脂肪链状烷基伯胺盐的直链的碳的个数为2~10;反应式如下:
②以化合物2为原料,溶解于体积比3:1:1的THF、MeOH和H2O的混合液,浓度为0.1M,加入LiOH·H2O,化合物2:LiOH·H2O的摩尔比为1:2~5,在室温下反应24h,得到化合物2i;反应式如下:
③以二氢卟吩e6为原料,溶解于DMF,浓度为0.1M,依次加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、端基溴脂肪链状烷基伯胺盐和N,N-二异丙基乙胺,其中,二氢卟吩e6:1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐:端基溴脂肪链状烷基伯胺盐:N,N-二异丙基乙胺的摩尔比为1:1~2:1~2:1~4,在室温下反应20h,得到化合物3;再将化合物3溶解于无水乙腈中,浓度为0.1M,加入硝酸银,其中化合物3:硝酸银的摩尔比为1:1~3,在60℃下反应6h,得到化合物4;反应式如下:
④以化合物4为原料,在0℃下溶解于DMF,浓度为0.1M,依次加入碳酸钾、碘甲烷,其中化合物4:碳酸钾:碘甲烷的摩尔比为1:6:6,室温下反应5h,得到化合物5,反应式如下:
⑤以甲基叶绿酸a为原料,溶解于DMF,浓度为0.1M,依次加入端基溴脂肪链状烷基伯胺盐和N,N-二异丙基乙胺,其中,甲基叶绿酸a:端基溴脂肪链状烷基伯胺盐:N,N-二异丙基乙胺的摩尔比为1:1~2:1~4,在室温下反应24h,得到化合物6;再将化合物6溶解于无水乙腈中,浓度为0.1M,加入硝酸银,其中化合物6:硝酸银的摩尔比为1:1~2,在60℃下反应6h,得到化合物7;反应式如下:
⑥以化合物7为原料,溶解于体积比3:1:1的THF、MeOH和H2O的混合液,浓度为0.1M,加入LiOH·H2O,化合物7:LiOH·H2O的摩尔比为1:2~5,在室温下反应24h,得到化合物7i;反应式如下:
⑦以二氢卟吩e6为原料,溶解于DMF,浓度为0.1M,依次加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺和3-氨基-1-丙醇硝酸酯,其中,二氢卟吩e6:苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯:N,N-二异丙基乙胺:3-氨基-1-丙醇硝酸酯的摩尔比为1:3~6:3~6:6~10,在室温下反应96h,得到化合物8;反应式如下:
3.如权利要求1所述的具有光、声敏活性的二氢卟吩硝酸酯类化合物用于制备抗肿瘤药物或作为活性组份制备用于肿瘤的治疗药物复合物。
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