CN112225779B - Arg(NO2)-Gly-Asp-Val-吉西他滨,其合成,抗肿瘤活性和应用 - Google Patents
Arg(NO2)-Gly-Asp-Val-吉西他滨,其合成,抗肿瘤活性和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及Arg(NO2)-Gly-Asp-Val-吉西他滨,涉及它的制备方法,涉及它与吉西他滨比 没有骨髓毒性,没有肝毒性,没有肾毒性及活性强等优点。因而本发明涉及它在制备没有 骨髓毒性,没有肝毒性,没有肾毒性及活性强的抗肿瘤药物中的应用。本发明属于生物医 药领域。
背景技术
吉西他滨是抗代谢类抗肿瘤药物的代表。广泛应用于各种实体肿瘤治疗,如用于非小细 胞肺癌,胰腺癌,乳腺癌和卵巢癌的治疗。目前,吉西他滨仍然是临床的重要一线化疗药 物之一。可是,半衰期短,骨髓毒性,肝毒性,肾毒性以及耐药性严重限制了吉西他滨的应 用及疗效。为克服吉西他滨的这些缺点,业内研究人员对吉西他滨进行了各种化学修饰。 不过,问题仍然没有解决。本案对吉西他滨进行了广泛的化学修饰及活性评价之后,发明 人发现下式的Arg(NO2)-Gly-Asp-Val-吉西他滨不仅没有吉西他滨那样的毒副作用,而且 抗肿瘤活性强。根据这些发现,发明人提出了本发明。
发明内容
本发明要解决的技术问题是提供一种制备下式的Arg(NO2)-Gly-Asp-Val-吉西他滨的方 法,以及由该方法制得的下式的Arg(NO2)-Gly-Asp-Val-吉西他滨。实验证明,由本发明制 备的下式的Arg(NO2)-Gly-Asp-Val-吉西他滨是没有骨髓毒性,没有肝毒性,没有肾毒性及 活性强的抗肿瘤药物。为了达到所述目的,本发明采用了五方面的技术手段。
第一方面的技术手段是提供了下式的Arg(NO2)-Gly-Asp-Val-吉西他滨,特征在于它与 下式的Arg-Gly-Asp-Val-吉西他滨一样在血液循环中可以稳定存在,不进入其它器官而是 靶向肿瘤组织,在肿瘤组织中转化为Arg-Gly-Asp-Val-吉西他滨并释放吉西他滨,发挥抗 肿瘤作用。
第二方面的技术手段是提出了一种所述Arg(NO2)-Gly-Asp-Val-吉西他滨的制备方法, 该方法的特征在于将Boc-Arg(NO2)-Gly-Asp(OtBu)与Val-吉西他滨缩合代替 Boc-Arg-Gly-Asp(OtBu)与Val-吉西他滨缩合,使肽部分的合成避免了脱NO2步骤,使缩合 收率提高从14%提高到32%。
第三方面的技术手段是提出Arg(NO2)-Gly-Asp-Val-吉西他滨的抗肿瘤活性比吉西他滨 强10倍。
第四方面的技术手段是提出Arg(NO2)-Gly-Asp-Val-吉西他滨没有肾毒性,肝毒性和骨 髓毒性。
第五方面的技术手段是提出了Arg(NO2)-Gly-Asp-Val-吉西他滨具有肿瘤靶向作用。
第六方面的技术手段是披露Arg(NO2)-Gly-Asp-Val-吉西他滨的所述内容适用于Arg(NO2)-Gly-Asp-Ser-吉西他滨和Arg(NO2)-Gly-Asp-Phe-吉西他滨。
附图说明
图1NG-NO2-Arg-Gly-Asp-Val-吉西他滨的合成路线.(i)二环己基碳二亚胺,N-羟基苯并三 氮唑,无水四氢呋喃;(ii)NaOH甲醇溶液(2M);(iii)氯化氢的乙酸乙酯溶液。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用 来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1制备Boc-Arg(NO2)-Gly-OBzl
将3.19g(10mmol)Boc-Arg(NO2)溶于100mL无水四氢呋喃(THF)。在冰浴与搅拌下向 得到的溶液中依次加入1.35g(10mmol)N-羟基苯并三氮唑(HOBt)和2.47g(12mmol) 二环己基碳二亚胺(DCC)。搅拌30min之后,再加3.53g(12mmol)Tos·Gly-OBzl。反应混 合物用N-甲基吗啉(NMM)调节pH 9。之后,室温搅拌10h,TLC(二氯甲烷/甲醇=15/1) 检测反应完。反应混合物过滤,除去二环己基尿(DCU)。滤液减压浓缩,得到的油状物用 石油醚洗。洗后的残留物用150mL乙酸乙酯溶解,溶液静置30min,再滤除二环己基尿。 滤液依次用5%碳酸氢钠水溶液洗(50mL×3),饱和氯化钠水溶液洗(50mL×3),5%硫酸氢 钾水溶液洗(50mL×3)。乙酸乙酯层用无水硫酸钠干燥12h,过滤,滤液减压浓缩。得到的 黄色油状物用50mL二氯甲烷溶解,静置,让固体充分析出。过滤,收集无色粉末。滤液 减压浓缩,残留物经柱层析纯化(二氯甲烷/甲醇=35/1)。柱层析纯化得到的产物与过滤收 集无色粉末合并,共得4.0g(86%)标题化合物。ESI-MS(m/z):467.2[M+H]+1;H-NMR(300 MHz,DMSO-d6)δ/ppm=8.484(s,1H),8.288(t,J=5.4Hz,1H),7.902(s,2H),7.365(m,5H), 6.915(d,J=7.8Hz,1H),5.123(s,2H),3.973(m,1H),3.898(m,2H),3.117(m,2H),1.638 (m,1H),1.501(m,3H),1.379(s,9H)。
实施例2制备Boc-Arg(NO2)-Gly
将4.0g(8.58mmol)Boc-Arg(NO2)-Gly-OBzl用30mL甲醇溶解。之后,在冰浴与搅拌下 用2M NaOH水溶液调pH 12并搅拌。4h之后TLC(二氯甲烷/甲醇=15/1)检测反应完成。反应混合物用饱和KHSO4水溶液调pH 7并过滤。滤液减压浓缩,残留物用饱和KHSO4水溶液调pH 2。之后,用乙酸乙酯萃取(100mL×3)。乙酸乙酯相减压浓缩至150mL。之后, 用饱和氯化钠水溶液洗(60mL×3),用无水硫酸钠干燥12h。过滤,滤液减压浓缩,得到2.81 g(88%)标题化合物,为无色粉末。ESI-MS(m/z):375.1[M-H]-;1H-NMR(300MHz, DMSO-d6)δ/ppm=8.486(s,1H),8.081(t,J=5.4Hz,1H),7.928(s,1H),7.039(s,1H),6.900 (d,J=2.7Hz,1H),3.957(m,1H),3.748(m,2H),3.128(m,2H),1.651(m,1H),1.502(m,3H), 1.381(s,9H)。
实施例3制备Boc-Arg(NO2)-Gly-Asp(OtBu)-OMe
采用实施例1的方法从2.81g(7.47mmol)Boc-Arg(NO2)-Gly和2.15g(8.96mmol)Asp(OtBu)-OMe得到3.15g(75%)标题化合物,为无色粉末。ESI-MS(m/z):562.2[M+H]+; 1H-NMR(300MHz,DMSO-d6)δ/ppm=8.481(s,1H),8.269(d,J=7.8Hz,1H),8.075(s,1H), 6.968(d,J=7.8Hz,1H),4.650(q,J1=6.6Hz,J2=14.1Hz,1H),3.929(m,1H),3.734(m, 2H),3.627(s,3H),3.122(m,2H),2.704(dd,J1=6.3Hz,J2=16.2Hz,1H),2.586(dd,J1=6.3 Hz,J2=16.2Hz,1H),1.639(m,1H),1.494(m,3H),1.384(s,18H)。
实施例4制备Boc-Arg(NO2)-Gly-Asp(OtBu)
采用实施例2的方法从3.15g(5.6mmol)Boc-Arg(NO2)-Gly-Asp(OtBu)-OMe得到2.55g (83%)标题化合物,为无色粉末。ESI-MS(m/z):546.2[M-H]-;1H-NMR(300MHz,DMSO-d6) δ/ppm=12.681(s,1H),8.164(s,1H),8.146(s,1H),8.052(s,1H),6.949(d,J=6.6Hz,1H), 4.553(m,1H),3.929(m,1H),3.734(m,2H),3.129(m,2H),2.669(m,2H),1.650(m,1H),1.498(m,3H),1.382(s,18H)。
实施例5制备Boc-Arg-Gly-Asp(OtBu)
将2.55g(4.65mmol)Boc-Arg(NO2)-Gly-Asp(OtBu)溶于30mL甲醇,搅拌下加入500mg Pd/C。室温通入氢气,12h之后TLC(二氯甲烷/甲醇=15/1)监测反应完成。过滤除去Pd/C,无 色透明滤液减压浓缩,得到2.15g(92%)标题化合物,为无色粉末。ESI-MS(m/z):503.2 [M+H]+;1H-NMR(300MHz,DMSO-d6)δ/ppm=9.312(s,1H),8.530(s,1H),7.462(d,J=5.4Hz,1H),7.202(s,2H),6.947(d,J=7.2Hz,1H),3.978(m,1H),3.844(m,2H),3.443(m,1H),3.135(m,1H),2.972(m,1H),1.897(m,1H),1.560(m,3H),1.364(s,18H)。
实施例6制备Boc-Val-吉西他滨(1)
采用实施例1的方法从2.34g(20mmol)Boc-Val和2.63g(10mmol)吉西他滨得到3.15g (68%)标题化合物,为无色粉末。ESI-MS(m/z):463.2[M+H]+;1H-NMR(300MHz, DMSO-d6)δ/ppm=11.035(s,1H),8.276(d,J=7.5Hz,1H),7.277(d,J=7.5Hz,1H),7.020 (d,J=7.8Hz,1H),6.325(d,J=6.6Hz,1H),6.180(t,J=7.2Hz,1H),5.305(t,J=5.1Hz, 1H),4.256(m,1H),4.127(m,1H),3.911(m,1H),3.810(m,1H),3.659(m,1H),1.987(m, 1H),1.380(m,9H),0.882(t,J=6.6Hz,6H)。
实施例7制备Val-吉西他滨(2)
将3.15g(6.8mmol)Boc-Val-吉西他滨(1)用10mL无水乙酸乙酯溶液溶解。冰浴与搅拌下 向溶液中加30mL氯化氢的乙酸乙酯溶液(4M),室温搅拌。4h之后TLC(二氯甲烷/甲醇 =10/1)监测1消失。反应混合物减压浓缩,残留物用无水乙酸乙酯复溶后再减压浓缩,再用 干燥乙酸乙酯复溶。该操作重复3次,使不再有氯化氢残留。残留物用无水乙醚磨洗,得到 2.61g(92%)标题化合物,为无色粉末。ESI-MS(m/z):363.1[M+H]+;1H-NMR(300MHz,DMSO-d6)δ/ppm=11.568(s,1H),8.550(s,2H),8.383(d,J=7.5Hz,1H),7.240(d,J=7.5Hz,1H),6.177(t,J=7.2Hz,1H),5.500(s,1H),4.210(m,1H),3.925(m,2H),3.791(m,1H),3.643(m,1H),2.207(m,1H),0.975(t,J=7.5Hz,6H)。
实施例8制备Boc-Arg(NO2)-Gly-Asp(OtBu)-Val-吉西他滨(3)
采用实施例1的方法从547mg(1mmol)Boc-Arg(NO2)-Gly-Asp(OtBu)和478mg(1.2mmol)Val-吉西他滨(2)得到黄色油状物。该黄色油状物用甲醇和水溶解,用C18纯化(甲醇/水=40/60),得到270mg(32%)标题化合物,为无色粉末。ESI-MS(m/z):847.6[M+H]+; 1H-NMR(300MHz,DMSO-d6)δ/ppm=11.148(s,1H),8.278(m,2H),8.184(s,1H),7.920(m, 2H),7.571(d,J=6.6Hz,1H),7.462(d,J=6.6Hz,1H),7.248(d,J=7.8Hz,1H),7.060(m, 3H),6.534(s,1H),6.173(t,J=7.2Hz,1H),5.444(m,1H),4.676(q,J1=8.4Hz,J2=15.0Hz,1H),4.354(t,J=7.2Hz,1H),4.219(m,2H),3.946(m,2H),3.888(m,1H),3.735(m,4H),3.169(m,2H),3.094(m,2H),2.680(dd,J1=12.8Hz,J2=6.0Hz,1H),2.444(dd,J1=12.8Hz,J2=6.0Hz,1H),2.041(m,1H),1.670(m,1H),1.513(m,3H),1.372(s,9H),1.339(s,9H),0.867(t,J=6.3Hz,6H)。
实施例9制备Arg(NO2)-Gly-Asp-Val-吉西他滨(4)
采用实施例7的方法从100mg(0.118mmol)Boc-Arg(NO2)-Gly-Asp(OtBu)-Val-吉西他滨 (3)得到63.7mg(76%)标题化合物,为无色粉末。FT-(ESI+)-MS(m/z):736.28302[M+H]+; 1H-NMR(300MHz,DMSO-d6)δ/ppm=11.124(s,1H),8.859(s,1H),8.450(d,J=4.8Hz,
1H),8.359(s,3H),8.302(d,J=8.4Hz,1H),8.092(d,J=7.8Hz,1H),7.971(s,1H),7.250(d, J=7.8Hz,1H),6.182(t,J=5.4Hz,1H),4.670(q,J1=8.4Hz,J2=15.0Hz,1H),4.345(t,J= 7.2Hz,1H),4.182(m,2H),3.885(m,6H),3.654(m,2H),3.143(m,2H),2.691(dd,J1=12.8 Hz,J2=6.0Hz,1H),2.502(dd,J1=12.8Hz,J2=6.0Hz,1H),2.061(m,1H),1.751(m,2H), 1.557(m,2H),0.883(t,J=6.3Hz,6H)。
实验例1测定Arg(NO2)-Gly-Asp-Val-吉西他滨(4)抑制肿瘤细胞增殖活性
1)本发明的化合物4用含0.1%DMSO的培养基配制成所需浓度。
2)实验用的肿瘤细胞为MCF-7(人乳腺癌细胞),HCT-8(人结肠癌细胞),HepG2(人肝癌细 胞),A549(人非小细胞肺癌细胞)和95D(人高转移肺癌细胞)。
3)MCF-7,HCT-8,95D和A549细胞选用RPMI-1640培养基,培养基中含10%经灭活的胎牛 血清和1×105U/L青霉素和100mg/L链霉素。HepG2细胞选用RPMI-DMEM培养基,培养基中含10%经灭活的胎牛血清和1×105U/L青霉素和100mg/L链霉素。将生长状态良好处于对数生长期的细胞以3×104个/mL的密度接种于96孔板,每孔100μL,置于37℃和5% CO2的细胞孵育箱中培养4小时,然后按预设的浓度梯度加入经灭菌处理的化合物4与含 0.1%DMSO的培养基配制成的溶液,每孔25μL,对照组加入等体积溶媒。继续培养48小 时后,每孔加25μL浓度为5mg/mL的MTT溶液,置于37℃和5%CO2的细胞孵育箱中培养4 小时。小心除去上清液后每孔加入100μL的DMSO,振荡约10min溶解紫色残留物(甲瓒), 立即于酶标仪上检测O.D.值(吸光度),检测波长为570nm。
4)按下式求出各个浓度下化合物抑制肿瘤细胞增殖的活性:
细胞增殖(%)=化合物4组平均O.D.值/对照组平均O.D.值)×100%,实验重复3次, 以细胞增殖对化合物4浓度作图,按作图法求出IC50(半数有效抑制浓度)。
5)表1表明化合物4抗肿瘤细胞增殖活性与吉西他滨处在同一水平。
表1化合物4抗肿瘤细胞增殖的IC50(均值±SDμM,n=3)
实验例2化合物4的抗肿瘤活性评价
测定前将本发明的化合物4溶于生理盐水。无菌条件下取接种于ICR小鼠10天的S180肉 瘤,加入适量生理盐水配制成瘤细胞悬液,细胞数为2×107/mL,接种于健康雄性ICR小鼠 (20±2g)前肢腋皮下,每只小鼠注射0.2mL。肿瘤接种5天后,化合物4组小鼠每3天腹腔注 射一次化合物4,分别在第1,4,7和11天注射,剂量为8.4μmol/kg/天,0.84μmol/kg/天及 0.084μmol/kg/天。阳性对照吉西他滨组小鼠每3天腹腔注射一次吉西他滨,分别在第1,4,7 和11天注射,剂量为84μmol/kg/天。生理盐水组小鼠每3天腹腔注射一次生理盐水,分别在 第1,4,7和11天注射,剂量为0.2mL/只/天。给药的第11天,称小鼠体重,乙醚麻醉,剖取各 组小鼠的肿瘤称重,数据列入表2。数据表明在8.4μmol/kg/天剂量下化合物4的抗肿瘤活性 与84μmol/kg/天剂量下吉西他滨的抗肿瘤活性无显著性差异。可见,化合物4的抗肿瘤活 性是吉西他滨的抗肿瘤活性的10倍。在0.84μmol/kg/天的剂量下化合物4仍然具有抗肿瘤 活性。可见,化合物4抗肿瘤的最低有效剂量是0.84μmol/kg/天。抗肿瘤活性比吉西他滨强 10倍以及最低有效剂量低至0.84μmol/kg/天都显示本发明有突出的技术效果。
表2化合物4抑制S180荷瘤小鼠肿瘤生长活性
a)与生理盐水比P<0.01,与吉西他滨比P>0.05;b)与生理盐水及8.4μmol/kg/天剂量组
比P<0.05;c)与生理盐水比P>0.05,与0.84μmol/kg/天剂量组比P<0.05;n=12.
实验例3化合物4对小鼠肝功能的影响
谷丙转氨酶和谷草转氨酶是反映肝损伤的重要生化指标。为了考察化合物4对肿瘤小鼠 肝功能的潜在影响,本发明按照试剂盒说明书规定的标准操作测定了谷丙转氨酶与谷草 转氨酶在S180小鼠血清中的浓度。结果见表3。数据表明在8.4μmol/kg/天剂量下化合物4 治疗的S180小鼠血清谷丙转氨酶和谷草转氨酶的浓度与生理盐水治疗的S180小鼠血清谷 丙转氨酶和谷草转氨酶的浓度没有差异。可见,化合物4治疗不损伤S180小鼠的肝功能。 相反,在84μmol/kg/天剂量下吉西他滨治疗的S180小鼠血清谷丙转氨酶和谷草转氨酶浓 度与生理盐水治疗的S180小鼠血清谷丙转氨酶和谷草转氨酶的浓度有显著性差异。可见, 吉西他滨治疗损伤S180小鼠的肝功能。在抗肿瘤活性与吉西他滨相同的前提下化合物4治 疗不损伤S180小鼠的肝功能,体现了本发明的突出技术效果。
表3化合物4对S180小鼠血清谷丙转氨酶和谷草转氨酶浓度的影响
a)与生理盐水比p<0.05;b)与生理盐水比p>0.05;n=4.
实验例4化合物4对小鼠肾功能的影响
肌酐和尿素氮是反映肾损伤的重要生化指标。为了考察化合物4对肿瘤小鼠肾功能的潜 在影响,本发明按照试剂盒说明书规定的标准操作测定了肌酐和尿素氮在S180小鼠血清 中的浓度。数据见表4。数据表明在8.4μmol/kg/天剂量下化合物4治疗的S180小鼠血清肌 酐和尿素氮浓度与生理盐水治疗的S180小鼠血清肌酐和尿素氮浓度没有差异。可见,化合 物4治疗不损伤S180小鼠的肾功能。相反,在84μmol/kg/天剂量下吉西他滨治疗的S180小 鼠血清肌酐和尿素氮浓度与生理盐水治疗的S180小鼠血清肌酐和尿素氮浓度有显著性差 异。可见,吉西他滨治疗损伤S180小鼠的肾功能。在抗肿瘤活性与吉西他滨相同的前提下 化合物4治疗不损伤S180小鼠的肾功能,体现了本发明的突出技术效果。
表4化合物4对小鼠血清肌酐和尿素氮浓度的影响
a)与生理盐水比p<0.01;b)与生理盐水比p>0.05;n=4.
实验例5化合物4对S180小鼠的骨髓毒性
骨髓抑制毒性主要表现在降低血液中红细胞,白细胞,血小板及中性粒细胞计数。不降 低淋巴细胞计数。为了考察化合物4治疗的潜在骨髓毒性,本发明采用迈瑞全自动三分类 血球分析仪BC3000测定了化合物4治疗的S180小鼠血液中红细胞,白细胞及血小板计数。结果见表5。数据表明在8.4μmol/kg/天剂量下化合物4治疗的S180小鼠血液中红细 胞,白细胞及血小板计数与生理盐水治疗的S180小鼠血液中红细胞,白细胞及血小板计 数没有显著性差异。可见,化合物4治疗对S180小鼠没有骨髓毒性。相反,在84μmol/kg/ 天剂量下吉西他滨治疗的S180小鼠血液中红细胞,白细胞及血小板计数与生理盐水治疗 的S180小鼠血液中红细胞,白细胞及血小板计数有显著性差异。可见,吉西他滨对S180 小鼠有骨髓毒性。在抗肿瘤活性与吉西他滨相同的前提下化合物4没有骨髓毒性,体现了 本发明的突出技术效果。
表5化合物4对小鼠红细胞,白细胞和血小板计数的影响
a)与生理盐水比p<0.01;b)与生理盐水比p>0.05;n=8.
实验例6化合物4的肿瘤靶向性
为考察化合物4的肿瘤靶向性,本发明将实验例2获得的生理盐水及化合物4治疗的 S180小鼠的肿瘤组织,肝脏,脾脏,肾脏,脑,心脏和血制备匀浆。制备肿瘤组织,肝脏,脾脏,肾脏,脑,心脏的匀浆时按1g/9mL(w/v)将它们分别与生理盐水混合,用组织匀浆 机将打匀浆,定量吸取匀浆液,按1mL匀浆液/3mL色谱纯甲醇(v/v)将匀浆液与色谱纯甲 醇混合,室温超声30min,12000rmp/分钟离心10min,吸取上清液测傅里叶变换电喷雾(+) 串联质谱,即FT-(ESI+)/MS。测定表明,在肝脏,脾脏,肾脏,脑和心脏的匀浆中均未发 现任何与化合物4相关的峰。在血液匀浆中发现了质量数为736.28332的峰,这是化合物 4的[M+H]+,理论值为736.28260。不过没有发现化合物4的任何代谢产物峰。结果见图1。 在血浆中能够检测到化合物4的精确分子量,而没有检测到吉西他滨的精确分子量,说明 化合物4在血浆中可以稳定存在。这为化合物4靶向运送到肿瘤部位奠定了基础。
在化合物4治疗的小鼠肿瘤匀浆的FT-MS(ESI+)谱中测到质量数为736.28302的离子(化 合物4的离子峰,精确[M+H]+为736.28260);测到质量数为691.30136的离子(化合物4减 NO2的离子峰,也就是RGDV-吉西他滨的离子峰,精确[M+H]+为691.29697);测到质量数为557.17313的离子(GDV-吉西他滨的离子峰,精确[M+Na]+为557.17780);测到质量数为478.16946的离子(DV-吉西他滨的离子峰,精确[M+H]+为478.16439);测到质量数为363.20608的离子(V-吉西他滨的离子峰,精确[M+H]+为363.20939);测到质量数为264.07717的离子(吉西他滨的离子峰,精确[M+H]+为264.07903);测到质量数为468.21153的离子(RGDV的离子峰,精确[M+Na]+为468.21771。测定到的这些离子说明,化合物4 从血液循环进入肿瘤组织之后,先丢失NO2生成Arg-Gly-Asp-Val-吉西他滨,然后释放吉 西他滨发挥抗肿瘤作用。
Claims (5)
2.权利要求1所述的Arg(NO2)-Gly-Asp-Val-吉西他滨,其特征在于它既没有骨髓毒性也没有肝及肾毒性。
3.权利要求1所述的Arg(NO2)-Gly-Asp-Val-吉西他滨,其特征在于它的抗肿瘤活性比吉西他滨强10倍,最低有效剂量比吉西他滨低100倍。
4.权利要求1所述的Arg(NO2)-Gly-Asp-Val-吉西他滨的制备方法,该方法使它可以这样制得:制备Val-吉西他滨,用液相法制备Boc-Arg(NO2)-Gly-Asp(OtBu),将Boc-Arg(NO2)-Gly-Asp(OtBu)与Val-吉西他滨缩合为Boc-Arg(NO2)-Gly-Asp(OtBu)-Val-吉西他滨,将Boc-Arg(NO2)-Gly-Asp(OtBu)-Val-吉西他滨脱保护基制备Arg(NO2)-Gly-Asp-Val-吉西他滨。
5.权利要求1所述的Arg(NO2)-Gly-Asp-Val-吉西他滨在制备没有骨髓毒性、没有肝毒性、没有肾毒性的抗S180肉瘤药物中的应用。
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