CN105693809B - 一种具有抗肿瘤活性的化合物及其应用 - Google Patents

一种具有抗肿瘤活性的化合物及其应用 Download PDF

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CN105693809B
CN105693809B CN201610023375.9A CN201610023375A CN105693809B CN 105693809 B CN105693809 B CN 105693809B CN 201610023375 A CN201610023375 A CN 201610023375A CN 105693809 B CN105693809 B CN 105693809B
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phenanthren
cyclopenta
ylidene
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CN105693809A (zh
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曹秀芳
汪小慧
陈长水
苏海欢
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Huazhong Agricultural University
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    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
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Abstract

本发明公开了一种具有抗肿瘤活性的以氨基酸为导向的甾体小肽化合物，其结构如通式Ⅰ所示。利用去氢表雄酮(DHEA)合成相应的腙和肟，再与氨基酸衍生物缩合得到该化合物，该化合物对肿瘤细胞尤其是人肝癌细胞、人肺癌细胞、人黑色素瘤细胞的生长具有显著的抑制作用，可作为抗肿瘤药物的活性成分应用与癌症的预防与治疗中。

Description

一种具有抗肿瘤活性的化合物及其应用
技术领域
本发明属于制药领域，具体涉及一种具有抗肿瘤活性的化合物及其在制备抗肿瘤药物中的应用。
背景技术
肿瘤是严重威胁人类健康的一种疾病，目前肿瘤的治疗手段仍是以药物治疗为主。因此，研究开发新的高效低毒的抗肿瘤药物具有重要意义。
氨基酸载体具有良好的生物相容性和亲和性，将氨基酸引入抗肿瘤药物分子中，可提高对肿瘤细胞的选择性，抑制肿瘤细胞的增殖，增加药物的溶解性，提高抗肿瘤活性，降低对正常细胞的毒性。此外，以氨基酸为导向的肽类化合物是全能型的生物活性分子之一，伪肽及其衍生物具有广泛的生物活性，例如抗菌，抗病毒及抗癌。
甾体化合物具有多种药理活性，在药物化学领域中应用非常广泛。在甾体环上引入含氮官能团、或在甾核上引入氮原子或对甾核进行结构改造，都能使生成的甾体化合物具有独特的甚至于超越母体化合物的活性。此外，去氢表雄酮(DHEA)是人体血液循环中最为丰富的甾体物质，在人体中具有构筑免疫系统、调节激素平衡、控制胰岛素分泌、维持正常的生理和代谢的作用。
发明内容
本发明目的在于提供一类具有抗肿瘤活性的以氨基酸为导向的甾体小肽化合物及其应用。
本发明提供的化合物，其结构如通式Ⅰ所示：
通式Ⅰ中：
R1选自下述基团之一：H、-CH3、-CH2CH(CH3)2、-CH(CH3)CH2CH3、-CH(CH3)2、-CH2CH2SCH3、-CH2OH、-CH2SH、-CH2COOH、-CH2CH2COOH、-CH2Ph、Ph、或者R1与式中的NH共同构成基团；
R2选自下述基团之一：-OCH2Ph、-OtBu、-OCH2CH3、-OCH3、-OCH2CH＝CH2、
X为NH或O。
本发明提供了上述化合物的一种制备方法，该方法包括以下步骤：
1)中间体的制备：将去氢表雄酮与水合肼缩合得到结构如式Ⅱ所示的中间体B或将去氢表雄酮与盐酸羟胺缩合得到结构如式Ⅲ所示的中间体C；
2)目标化合物的制备：将中间体B或中间体C与结构如式Ⅳ所示的氨基酸衍生物缩合。
反应式为：
式中：
R1选自下述基团之一：H、-CH3、-CH2CH(CH3)2、-CH(CH3)CH2CH3、-CH(CH3)2、-CH2CH2SCH3、-CH2OH、-CH2SH、-CH2COOH、-CH2CH2COOH、-CH2Ph、Ph、或者R1与式中的NH共同构成基团；
R2选自下述基团之一：-OCH2Ph、-OtBu、-OCH2CH3、-OCH3、-OCH2CH＝CH2、
本发明所提供的化合物对肿瘤细胞尤其是人肝癌细胞、人肺癌细胞、人黑色素瘤细胞的生长具有显著的抑制作用，特别是当R1为-CH2Ph，R2为-OtBu，X为NH时抑制作用最强，因此可作为抗肿瘤药物的活性成分应用与癌症的预防与治疗中，并且该类化合物的制备过程简单易行，原料易得，具有较大的应用前景。
具体实施方式
下面通过具体实施例对本发明进行详细地说明，但本发明并不限于以下实施例。
实施例1化合物的制备
本发明的部分化合物结构如表1所示。
表1代表性化合物的结构列表及物理性质
1)中间体氨基酸衍生物的制备，以N-苄氧羰基甘氨酸为例，如下式所示：
于100mL三口瓶中加入甘氨酸(20mmol)，将装置置于冰浴中，然后加入氢氧化钠水溶液(21mmol)约20mL，搅拌均匀，同时向三口瓶中逐滴滴加氯甲酸苄酯(11mmol)的二氯甲烷溶液20mL和氢氧化钠水溶液(21mmol)约20mL，待氢氧化钠滴加完毕后，自然升至室温反应约8h。反应完毕后，先用二氯甲烷洗去过量有机物，然后搅拌条件下调pH至1-2， 乙酸乙酯萃取，有机相经5％食盐水洗、水洗，无水硫酸钠干燥，过滤，减压浓缩滤液得粗产物，直接用于下步反应。
2)中间体B的制备，如下式所示：
于100mL两口瓶中加入水合肼(22mmol)，向两口瓶中逐滴滴加DHEA(20mmol)的乙醇溶液20mL，78℃冷凝回流反应约6h，减压浓缩，加入约15mL氯仿溶解，用蒸馏水水洗两次，无水硫酸钠干燥，过滤，滤液浓缩得到白色粗品，直接用于下步反应。
3)中间体C的制备，如下式所示：
于100mL两口瓶中加入DHEA(20mmol)，盐酸羟胺(22mmol)，20mL乙醇溶液和10mL蒸馏水，搅拌均匀至一相，常温下滴加醋酸钠(20mmol)水溶液20mL，滴加完毕后，升至78℃继续反应6h。反应完毕后，抽滤，滤渣用蒸馏水洗涤数次，所得粗品再用无水乙醇重结晶得到白色固体，直接用于下步反应。
4)氨基酸导向的甾体小肽化合物的制备：
于100mL单口瓶中加入N-苄氧羰基甘氨酸(1mmol)，CDI(N,N'-羰基二咪唑)(1.2mmol)，乙腈(20mL)，室温搅拌反应约2h，加入中间体B或中间体C(1.1mmol)，室温反应，TLC跟踪至反应完全。先将反应液减压浓缩并用二氯甲烷溶解，有机相用碳酸氢钠溶液(30mL×3)水洗、5％食盐 水水洗、蒸馏水水洗，无水硫酸钠干燥，过滤，减压浓缩得到产物。
参照上述的基本合成方法，并结合目标化合物的结构特征选用不同的常规化工原料，便可制备得到表1中的其它化合物，代表性化合物的理化数据如下：
化合物1Benzyl(2-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-2-oxoethyl)carbamate：white solid,mp:108-110℃.1H NMR(400MHz,CDCl3):δ＝9.39(s,1H),7.38-7.30(m,6H),5.38(d,J＝8Hz,1H),3.69(s,2H),3.57-3.50(s,1H),3.27(s,2H),2.42-2.14(m,5H),1.99-1.86(m,3H),1.68-1.61(m,5H),1.59-1.52(m,3H),1.50-1.38(m,2H),1.22-1.12(m,2H),1.05(s,3H),0.94(s,3H)；ESI-MS:calcd for C29H39N3O4([M+Na+]+),515.3；found,515.2.
化合物2tert-Butyl(2-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-ecahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-2-oxoethyl)carbamate：white solid,mp:138-140℃.1H NMR(400MHz,CDCl3):δ＝8.05(s,1H),5.37(d,J＝4Hz,1H),4.28(t,J＝4Hz,8Hz,1H),3.58-3.50(m,1H),2.37-2.28(m,2H),2.25-2.01(m,3H),1.97-1.87(m,4H),1.64-1.53(m,8H),1.47(s,9H),1.36-1.11(m,5H),1.05(s,3H),0.88(s,3H)；ESI-MS:calcd for C26H41N3O4([M+H]+),460.3；found,460.5.
化合物3Benzyl(1-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate：white solid,mp:120-122℃.1H NMR(400MHz,CDCl3):δ＝8.18(s,1H,N-H),7.37-7.29(m,5H,Ar-H),5.6(d,J＝6Hz,1H,N-H),5.37(d,J＝4Hz,1H),5.13-5.06(m,2H),3.56-3.50(m,1H),2.38-2.25(m,2H),2.23-1.99(m,4H),1.93-1.85(m,3H),1.69-1.57(m,5H),1.52-1.45(m,3H),1.42-1.25(m,2H),1.18-1.07(m,3H),1.05-0.97(m,6H),0.90(s,3H),0.86(s,3H)；E SI-MS:calcd forC32H45N3O4([M+H]+),536.3；found,536.7.
化合物4tert-Butyl(1-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate:shell solid,mp:118-120℃.1H NMR(400MHz,CDCl3):δ＝8.14(s,1H,N-H),5.37(d,J＝8Hz,1H),5.31(d,J＝4Hz,1H,N-H),5.03(dd,J＝4Hz,1H),3.58-3.51(m,1H),2.43-2.25(m,3H),2.18-1.99(m,4H),1.95-1.86(m,3H),1.70-1.63(m,3H),1.58-1.49(m,3H),1.45(s,9H),1.37-1.29(m,2H),1.0-1.10(m,3H),1.04-0.85(m,12H)；ESI-MS:calcd for C29H47N3O4([M+H]+),502.4；found,502.5.
化合物5Benzyl(1-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-4-methyl-1-oxopentan-2-yl)carbamate:white solid,mp:125-127℃.1H NMR(400MHz,CDCl3):δ＝7.99(s,1H,N-H),7.36-7.28(m,5H,Ar-H),5.45(d,J＝8Hz,1H),5.37(d,J＝4Hz,1H),5.21-5.11(m,2H),3.57-3.51(m,1H),2.38-2.25(m,3H),2.22-1.99(m,3H),1.94-1.85(m,3H),1.77-1.66(m,3H),1.63-1.50(m,6H),1.47-1.36(m,3H),1.34-1.10(m,3H),1.07-1.01(m,6H),0.95-0.90(m,6H)；ESI-MS:calcd for C33H47N3O4([M+H]+),550.4；found,550.7.
化合物8tert-Butyl(1-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-4-(methylthio)-1-oxobutan-2-yl)carbamate:white solid,mp:115-117℃.1H NMR(400MHz,CDCl3):δ＝8.16(s,1H,N-H),5.44(d,J＝16Hz,1H,N-H),5.37(d,J＝4Hz,1H),5.11(s,1H),3.57-3.51(m,1H),2.64-2.56(m,2H),2.40-2.20(m,4H),2.20-2.15(m,2H),2.10(s,3H),2.03-1.95(m,3H),1.91-1.83(m,4H),1.71-1.58(m,4H),1.54-1.51(m,3H),1.46(s,9H),1.20-1.11(m,2H),1.05(s,3H),0.91(s,3H)；ESI-MS:calcdfor C29H47N3O4S([M+H]+),534.3；found,534.5.
化合物9Benzyl 2-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinecarbonyl)pyrrolidine-1-carboxylate:white solid,mp:84-86℃.1HNMR(400MHz,CDCl3):δ＝9.73(s,1H,N-H),7.35-7.26(m,5H,Ar-H),5.35(d,J＝4Hz,1H),5.20-5.06(m,2H),4.39(d,J＝8Hz,1H),3.67-3.57(m,1H),3.52-3.38(m,2H),2.36-2.21(m,4H),2.15-2.05(m,2H),1.98-1.91(m,3H),1.88-1.76(m,4H),1.66-1.57(m,5H),1.52-1.35(m,3H),1.16-1.08(m,3H),1.05(s,3H),0.89(s,3H)；ESI-MS:calcd for C32H43N3O4([M+H]+),534.3；found,534.4.
化合物11Benzyl(1-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethy l-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-1-oxo-3-phenylpropan-2-yl)carbamate:white solid,mp:109-110℃.1H NMR(400MHz,CDCl3):δ＝8.50(s,1H,N-H),7.35-7.30(m,5H,Ar-H),7.25-7.15(m,5H,Ar-H),5.37(d,J＝8Hz,1H),5.39(d,J＝4Hz,2H),5.10(d,J＝4Hz,1H),5.07(d,J＝4Hz,1H),5.37-5.32(m,1H),3.23-3.11(m,1H),2.99-2.94(m,1H),2.35-2.26(m,3H),1.91-1.85(m,4H),1.73-1.61(m,5H),1.59-1.35(m,5H),1.18-1.09(m,3H),1.07-1.87(m,6H)；ESI-MS:calcd for C36H45N3O4([M+H]+),584.3；found,584.5.
化合物13Benzyl(1-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)carbamate:white solid,mp:131-133℃.1H NMR(400MHz,CDCl3):δ＝8.15(s,1H,N-H),8.02(s,1H,N-H),7.60(d,J＝8Hz,1H,Ar-H),7.35-7.30(m,6H,Ar-H),7.21-7.02(m,3H,Ar-H),5.66(d,J＝8Hz,1H,N-H),5.47-5.42(q,J＝8Hz,1H),5.39-5.32(m,1H),5.14-5.08(m,2H),3.58-3.51(m,1H),3.37-3.21(m,2H),2.36-2.24(m,3H),2.02-1.95(m,2H),1.91-1.84(m,4H),1.68-1.59(m,5H),1.54-1.41(m,4H),1.19-1.08(m,2H),1.06-0.80(m,6H)； ESI-MS:calcd for C38H46N4O4([M+H]+),624.4；found,624.6.
化合物14tert-Butyl(1-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)carbamate:white solid,mp:165-167℃.1H NMR(400MHz,CDCl3):δ＝8.36(s,1H),8.19(d,J＝12Hz,1H),7.65(q,1H),7.35(dd,J＝8Hz,1H),7.21-7.05(m,3H),5.39-5.33(m,3H),3.58-3.51(m,1H),3.37-3.16(m,2H),2.36-2.23(m,4H),2.01-1.94(m,2H),1.90-1.83(m,5H),1.71-1.61(m,4H),1.56-1.48(m,5H),1.43(s,9H),1.05-0.79(m,6H))；ESI-MS:calcd for C 35H48N4O4([M+H]+),589.4；found,589.5.
化合物16tert-Butyl(2-(((E)-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)amino)oxy)-2-oxoethyl)carbamate:white solid,mp:167-169℃.1H NMR(400MHz,CDCl3):δ＝5.37(d,J＝4Hz,1H),5.12(s,1H,N-H),4.07(d,J＝8Hz,2H),3.56-3.51(m,1H),2.70-2.52(m,1H),2.32-2.22(m,2H),2.10-2.05(m,2H),1.88-1.81(m,3H),1.68-1.48(m,6H),1.46(s,9H),1.42-1.06(m,6H),1.02(d,J＝8Hz,6H).ESI-MS:calcd forC26H40N2O5([M+Na]+),483.3；found,483.5.
化合物18tert-Butyl(1-(((E)-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)amino)oxy)-3-methyl-1-oxobutan-2-yl)carbamate:white solid,mp:102-104℃.1H NMR(400MHz,CDCl3):δ＝5.36(d,J＝4Hz,1H),5.11(d,J＝8Hz,1H),4.31-4.26(m,1H),3.56-3.49(m,1H),2.62-2.50(m,1H),2.33-2.14(m,2H),2.11-1.95(m,2H),1.91-1.84(m,3H),1.68-1.58(m,3H),1.54-1.45(m,5H),1.41(s,9H),1.29-1.21(m,3H),1.14-1.05(m,2H),1.03-0.94(m,12H)；ESI-MS:calcd for C29H46N2O5([M+Na]+),525.3；found,525.5.
化合物19Benzyl(1-((E)-2-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)hydrazinyl)-4-methyl-1-oxopentan-2-yl)carbamate:white solid,mp:94-96℃.1H NMR(400MHz,CDCl3):δ＝7.35-7.39(m,5H),5.36(d,J＝8Hz,1H),5.21(d,J＝8Hz,1H,N-H),5.10(s,2H),4.51-4.50(m,1H),3.56-3.50(m,1H),2.63-2.49(m,2H),2.34-2.21(m,2H),2.17-1.93(m,3H),1.88-1.74(m,4H),1.69-1.56(m,6H),1.54-1.44(m,4H),1.42-1.33(m,2H),1.27-1.13(m,2H),1.03-0.94(m,12H)；ESI-MS:calcd for C 30H48N2O5([M+Na+H]+),573.4；found,573.6.
化合物21Benzyl 2-((((E)-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)amino)oxy)carbonyl)pyrrolidine-1-carboxylate:white solid,mp:191-193℃.1H NMR(400MHz,CDCl3):δ＝7.36-7.39(m,5H),5.35(d,J＝8Hz,1H),5.21-5.09(m,3H),4.44(s,1H),3.62-3.45(m,3H),2.62-2.45(m,1H),2.30-2.09(m,7H),2.01-1.83(m,7H),1.67-1.60(m,4H),1.54-1.40(m,4H),1.02-0.92(m,6H)；ESI-MS:calcd for C32H42N2O5([M+Na] +),557.3；found,556.8.
化合物23Benzyl(1-(((E)-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)amino)oxy)-1-oxo-3-phenylpropan-2-yl)carbamate:shell solid,mp:81-83℃.1H NMR(400MHz,CDCl3):δ＝7.35-7.14(m,10H),5.36(d,J＝8Hz,1H),5.21(d,J＝8Hz,1H,)5.13-5.08(m,2H),4.68(s,1H),3.56-3.50(m,1H),3.24-3.09(m,2H),2.61-2.46(m,3H),2.34-2.21(m,3H),2.11-2.04(m,1H),1.94-1.85(m,4H),1.70-1.57(m,4H),1.50-1.35(m,3H),1.25-1.10(m,2H),1.04-0.94(m,6H)；ESI-MS:calcd for C36H44N2O 5([M+Na]+),607.3；found,607.4.
化合物24tert-Butyl(1-(((E)-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)amino)oxy)-1-oxo-3-phenylpropan-2-yl)carbamate:white solid,m p:113-115℃.1H NMR(400MHz,CDCl3):δ＝7.31-7.28(m,2H),7.24-7.17(m,3H),5.36(s,1H),5.08(d,J＝12Hz,1H),4.66(d,J＝8Hz,1H),3.57-3.49(m,1H),3.08(d,J＝8Hz,2H),2.60-2.39(m,2H),2.36-2.21(m,4H),1.95-1.76(m,4H),1.69-1.55(m,4H),1.53-1.45(m,3H),1.41(s,9H),1.21-1.06(m,3H),1.03-0.94(m,6H)；ESI-MS:calcd for C33H46N2O5([M+Na]+),573.3；found,573.3.
化合物26tert-Butyl(1-(((E)-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-3,4,7,8,9,11,12,13,15,16-decahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)amino)oxy)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)carbamate:white solid,mp:125-127℃.1H NMR(400MHz,CDCl3):δ＝8.08(s,1H,N-H),7.55(d,J＝8Hz,1H,Ar-H),7.32-7.26(m,1H,Ar-H),7.17-7.03(m,3H,Ar-H),5.33(d,J＝4Hz,1H),5.12(d,J＝8Hz,1H,N-H),4.76-4.71(m,1H),3.54-3.48(m,1H),3.28(d,J＝4Hz,2H),2.32-2.16(m,3H),2.08-2.00(m,2H),1.85(d,J＝12Hz,2H),1.70-1.55(m,7H),1.51-1.46(m,3H),1.43(s,9H),1.26-1.09(m,3H),1.03-0.95(m,6H)；ESI-MS:calcd for C35H47N3O5([M+Na]+),612.4；found,612.5.
实施例2化合物对不同肿瘤细胞的体外生长抑制作用
为了证明本发明的有效性，申请人以5-氟尿嘧啶为阳性对照物，采用体外MTT法测定了不同化合物对人肝癌细胞(HepG2)、人肺癌细胞(A549)、人黑色素瘤细胞(A875)的生长抑制作用。
表2本发明部分化合物对不同肿瘤细胞的细胞活力影响

Claims (1)

1.结构如通式Ⅰ所示的化合物在制备抗肿瘤药物中的应用：
通式Ⅰ中：R1为-CH2Ph，R2为-OtBu，X为NH，
所述的肿瘤为肝癌或肺癌或黑色素瘤。
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