CN115181134A - 一种含三氟甲基的铂类抗肿瘤化合物及其制备方法和应用 - Google Patents
一种含三氟甲基的铂类抗肿瘤化合物及其制备方法和应用 Download PDFInfo
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- CN115181134A CN115181134A CN202210871022.XA CN202210871022A CN115181134A CN 115181134 A CN115181134 A CN 115181134A CN 202210871022 A CN202210871022 A CN 202210871022A CN 115181134 A CN115181134 A CN 115181134A
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
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- Genetics & Genomics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
技术领域
本发明属于癌症治疗药物技术领域,具体涉及一种含三氟甲基的铂类抗肿瘤化合物及其制备方法和应用。
背景技术
目前超过50%的化疗治疗方案涉及铂类药物的使用,其中FDA批准的顺铂、卡铂和奥沙利铂是癌症临床化疗方案中的支柱药物,它们主要通过与肿瘤DNA作用引起肿瘤细胞凋亡。传统铂类药物缺少选择性,生物利用度低,毒副作用强,易导致肿瘤细胞产生耐药性,极大影响了其治疗效果。目前上市的铂类药物的水溶性依次为顺铂1mg/mL,奥沙利铂8mg/mL,卡铂16mg/mL。研究报道的铂类配合物3-羟基卡铂35mg/mL(Eur.J.Med.Chem.2013,69,842-847),3-羰基卡铂8mg/mL(Chem.Eur.J.2014,20,15216-15225)。3-羟基卡铂的水溶性优于卡铂,但其生物活性并未明显改变;3-羰基卡铂虽然水溶性小于卡铂和3-羟基卡铂,但是离去基团具有较好的动力学活性,其细胞毒活性与奥沙利铂相近。
三氟甲基官能团由于代谢稳定性,亲油性和自身有机功能分子的性质,可以有效提高化合物对生物膜和组织的渗透性。Natile课题组首次利用光学纯的三氟甲基丙氨酸作为离去基团,合成了铂类配合物(J.Med.Chem.2005,48(24),7821-7828)。Lippard课题组将三氟甲基引入β-二酮作为离去基团,合成了铂类配合物(J.Med.Chem.2012,55(11),5326-5336)。由于强吸电子基团三氟甲基的存在,化合物具有较好的动力学活性,从而使其细胞毒活性优于顺铂。化合物在HeLa肿瘤细胞中的铂含量是顺铂的10倍。含三氟甲基官能团的离去基团可以增加铂类配合物的动力学活性和脂溶性。因此,水溶性、动力学活性和脂溶性在铂类配合物的抗肿瘤活性研究中均发挥着重要作用。
发明内容
针对现有技术中存在的问题,本发明的目的在于提供一种含三氟甲基的铂类抗肿瘤化合物及其制备方法和应用,环丁二羧酸作为卡铂的离去基团具有较好的水溶性和稳定性,通过对其进行修饰,在环丁二羧酸的3-位上分别引入羟基、氨基、三氟甲基、酯基、酰胺基和糖基。引入不同类型的功能基团可以改善化合物溶解性和生物活性。三氟甲基官能团由于代谢稳定性,亲脂性和自身有机功能分子的性质,可以有效提高化合物对生物膜和组织的渗透性。
为达到上述目的,提出以下技术方案:
一种含三氟甲基的铂类抗肿瘤化合物,其结构式如式(Ⅰ)所示,
如式(Ⅰ)中的Am为氨基载体配体,取代基R1取代或不取代,
R1为羟基、氨基、三氟甲基、糖基、连接有生物活性化合物的酯键、连接有生物活性化合物的酰胺键或连接有生物活性化合物的醚键。
优选地,所述糖基为葡萄糖、半乳糖、甘露糖、阿洛糖、阿卓糖、古罗糖、艾杜糖、太洛糖、2-脱氧葡萄糖、核糖或脱氧核糖。
一种含三氟甲基的铂类抗肿瘤化合物的制备方法,包括如下步骤:在避光通氮气的条件下,将如式(Ⅱ)所示的化合物悬浮于水中,加入如式(Ⅲ)所示的化合物,磁力搅拌,避光反应,反应完成后过滤浓缩至固体析出,最后进行过滤洗涤和干燥得到如式(Ⅰ)所示的化合物,
式(Ⅱ)中,
以氨/胺铂碘或胺铂氯为中间体,再与3-三氟甲基环丁烷-1,1-二羧酸银类衍生物的银盐化合物按照摩尔比为1:1投料,反应结束后将滤液过滤,除去AgI或者AgCl沉淀,浓缩至析出固体,最后过滤洗涤干燥得纯品。
进一步地,避光反应的温度为40-55℃,反应时间为10-25小时。
一种含三氟甲基的铂类抗肿瘤化合物在制备肿瘤抑制药物中的应用,肿瘤细胞为肺癌细胞A549、肝癌细胞HepG2、乳腺癌细胞MCF-7或结肠癌细胞HCT-116。
用含三氟甲基的铂类抗肿瘤化合物制备肿瘤抑制药物,可制备成水溶液或冻干粉剂,含三氟甲基的铂类抗肿瘤化合物在药学上可接收盐包括碳酸盐、磷酸盐、甲磺酸盐、对甲苯磺酸盐、硫酸盐、草酸盐、马来酸盐、酒石酸盐、乙酸盐、苹果酸盐、琥珀酸盐、乳酸盐、谷氨酸盐、天冬氨酸盐、硝酸盐、三氟甲磺酸盐、富马酸盐或枸橼酸盐。
本发明的有益效果在于:
本发明的化合物具有较好的稳定性和水溶性;化合物体外对肺癌细胞A549、肝癌细胞HepG2、乳腺癌细胞MCF-7和人结肠癌细胞HCT-116的生长均有明显的抑制作用,抗癌活性大于卡铂,其中个别化合物的抗肿瘤活性优于奥沙利铂,与顺铂相近,并且对于正常肺上皮细胞BEAS-2B的细胞毒活性较小,具有良好的临床应用前景。
附图说明
图1为不同实验组别对裸鼠移植瘤的移植瘤块体积影响的对比图;
图2为不同实验组别对裸鼠移植瘤的移植瘤块重量影响的对比图。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。
(一)配合物合成
实施例1:
在避光通氮气的条件下,将顺式-二碘二氨合铂(0.24g,0.5mmol)悬浮于100mL水中,加入3-羟基-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.22g,0.5mmol),开启磁力搅拌,于55℃避光反应16小时,过滤除去碘化银沉淀,将滤液浓缩至5mL,有白色固体析出,过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.136g,产率61%。
1H NMR(600MHz,d6-DMSO):δ4.18(s,6H,2×NH3),3.14-3.17(d,2H,CCH2C),2.90-2.94(d,2H,CCH2C);13C NMR(d6-DMSO/TMS,ppm):δ177.8,177.6,125.5,123.6,121.8,119.9,66.4,66.2,66.1,65.8,45.7,35.9.ESI-MS:m/z[M+H]+=456.
实施例2:
在避光通氮气的条件下,将1R,2R-环己二胺胺铂氯(0.19g,0.5mmol)悬浮于110mL水中,加入3-羟基-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.22,0.5mmol),开启磁力搅拌,于48℃避光反应20小时,过滤除去氯化银沉淀,将滤液浓缩至8mL,有白色固体析出,过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.168g,产率63%。
1H NMR(600MHz,d6-DMSO):δ6.30(s,1H,OH),5.96(s,2H,CHNH2),5.24(s,2H,CHNH2),3.15-3.22(m,2H,CCH2C),2.90-2.98(m,2H,CCH2C),2.07(m,2H,2×CHNH2),1.82-1.85(m,2H,CH2 of DACH),1.47-1.49(m,2H,CH2 of DACH),1.23-1.24(m,2H,CH2 ofDACH),1.03-1.05(m,2H,CH2 of DACH);ESI-MS:m/z[M+Na]+=558.
实施例3
在避光通氮气的条件下,将顺式-二碘二氨合铂(0.24g,0.5mmol)悬浮于100mL水中,加入3-三氟甲基环丁烷-1,1-二羧酸银(0.22g,0.5mmol),开启磁力搅拌,于55℃避光反应12小时,过滤除去碘化银沉淀。将滤液浓缩至12mL,有白色固体析出。过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.136g,产率57%。
1H NMR(600MHz,d6-DMSO):δ4.17(s,6H,2×NH3),3.02-3.06(m,2H,CCH2CH),2.81-2.88(m,1H,CHCF3),2.71-2.75(m,2H,CCH2CH);ESI-MS:m/z[M+H]+=440.
实施例4
在避光通氮气的条件下,将1R,2R-环己二胺胺铂氯(0.19g,0.5mmol)悬浮于120mL水中,加入3-三氟甲基环丁烷-1,1-二羧酸银(0.22,0.5mmol),开启磁力搅拌,于55℃避光反应20小时,过滤除去氯化银沉淀。将滤液浓缩至15mL,有白色固体析出。过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.168g,产率66%。
1H NMR(600MHz,d6-DMSO):δ6.03(d,2H,CHNH2),5.30(d,2H,CHNH2),3.15-3.19(m,1H,CCH2CH),3.08-3.11(m,1H,CCH2CH),2.92-2.96(m,1H,CHCF3),2.80-2.84(m,2H,CCH2CH),2.13(s,2H,2×CHNH2),1.88-1.90(d,2H,CH2 of DACH),1.52-1.54(d,2H,CH2 ofDACH),1.28-1.29(m,2H,CH2 of DACH),1.05-1.10(m,2H,CH2 of DACH);ESI-MS:m/z[M+H]+=520.
实施例5
在避光通氮气的条件下,将cis-[Pt(II)(1,2-双(氨甲基)环丁烷)I2](0.28g,0.5mmol)悬浮于60mL水中,加入3-羟基-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.22g,0.5mmol),开启磁力搅拌,于52℃避光反应16小时,过滤除去碘化银沉淀,将滤液浓缩至4mL,有白色固体析出,过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.173g,产率65%。
1H NMR(600MHz,d6-DMSO):δ5.24-5.26(m,2H,CHNH2),5.03-5.07(m,2H,CHNH2),2.98-3.08(m,2H,CH2NH2),2.63-2.65(m,2H,CH2NH2),2.35-2.37(m,2H,CH2),2.22-2.24(m,2H,CH2),2.23-2.25(m,2H,CH of cyclobutane),1.86-1.88(m,2H,CH2 of cyclobutane),1.58-1.60(m,2H,CH2 of cyclobutane);ESI-MS:m/z[M+H]+=536.
实施例6
在避光通氮气的条件下,将cis-[Pt(II)(4R,5R)-4,5-双(氨甲基)-2-异丙基-1,3-二氧环戊烷)I2](0.311g,0.5mmol)悬浮于130mL水中,加入3-羟基-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.22g,0.5mmol),开启磁力搅拌,于50℃避光反应12小时,过滤除去碘化银沉淀,将滤液浓缩至10mL,有白色固体析出,过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.20g,产率68%。
1H NMR(600MHz,d6-DMSO):δ5.36(d,1H,OCHO),5.16(s,1H,OH),3.96(m,2H,CHNH2),3.84(m,2H,CHNH2),3.77(m,2×1H,OCHCH2),2.90-2.98(m,2H,CHCH2NH2),2.67(m,2H,CHCH2NH2),1.82-1.85(m,4H,2×CH2),2.01(m,1H,CH3CHCH3),0.88(d,3H,CH3CH),0.87(d,3H,CH3CH),ESI-MS:m/z[M+H]+=596.
实施例7
在避光通氮气的条件下,将顺式-二碘二氨合铂(0.24g,0.5mmol)悬浮于80mL水中,加入3-氨基-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.22g,0.5mmol),开启磁力搅拌,于52℃避光反应14小时,过滤除去碘化银沉淀,将滤液浓缩至4mL,有白色固体析出,过滤,冷水洗涤,40℃真空干燥16小时,得白色固体0.058g,产率25%。
1H NMR(600MHz,d6-DMSO):δ8.52(s,2H,NH2),4.18(s,6H,2×NH3),3.14-3.17(d,2H,CCH2C),2.90-2.94(d,2H,CCH2C);ESI-MS:m/z[M+H]+=455.
实施例8
在避光通氮气的条件下,将1R,2R-环己二胺胺铂氯(0.19g,0.5mmol)悬浮于55mL水中,加入3-氨基-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.22g,0.5mmol),开启磁力搅拌,于50℃避光反应18小时,过滤除去氯化银沉淀,将滤液浓缩至5mL,有白色固体析出,过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.063g,产率25%。
1H NMR(600MHz,d6-DMSO):δ8.53(s,2H,NH2),5.96(s,2H,CHNH2),5.24(s,2H,CHNH2),3.15-3.22(m,2H,CCH2C),2.90-2.98(m,2H,CCH2C),2.07(m,2H,2×CHNH2),1.82-1.85(m,2H,CH2 of DACH),1.47-1.49(m,2H,CH2 of DACH),1.23-1.24(m,2H,CH2 ofDACH),1.03-1.05(m,2H,CH2 of DACH);ESI-MS:m/z[M+H]+=535.
实施例9
在避光通氮气的条件下,将cis-[Pt(II)(1,2-双(氨甲基)环丁烷)I2](0.28g,0.5mmol)悬浮于120mL水中,加入3-二氯乙酸酯-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.276g,0.5mmol),开启磁力搅拌,于48℃避光反应24小时,过滤除去碘化银沉淀。将滤液浓缩至13mL,有白色固体析出。过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.20g,产率65%。
1H NMR(600MHz,d6-DMSO):δ6.87(s,1H,CHCl2),5.29-5.30(m,2H,CHNH2),5.00-5.02(m,2H,CHNH2),4.55-4.57(m,2H,CH2NH2),4.28-4.31(m,2H,CH2NH2),2.66-2.68(m,2H,CH2 of cyclobutane),2.59-2.51(m,2H,CH2 of cyclobutane),2.28-2.29(m,2H,CH2CHCH2),1.84-1.86(m,2H,CH2CH2CH),1.60-1.62(m,2H,CH2CH2CH);ESI-MS:m/z[M+H]+=647.
实施例10
在避光通氮气的条件下,将顺式-二碘二氨合铂(0.24g,0.5mmol)悬浮于130mL水中,加入3-二氯酰胺-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.276g,0.5mmol),开启磁力搅拌,于48℃避光反应17小时,过滤除去碘化银沉淀。将滤液浓缩至14mL,有白色固体析出,过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.19g,产率68%。
1H NMR(600MHz,d6-DMSO):δ6.76(s,1H,NH),5.98(s,1H,CHCl2),5.57(s,6H,2×NH3),2.18-2.22(m,2H,CCH2C),2.10-2.11(m,2H,CCH2C);ESI-MS:m/z[M+H]+=564.
实施例11
在避光通氮气的条件下,将顺式-二碘-氨-环戊胺合铂(0.24g,0.5mmol)悬浮于60mL水中,加入3-氨基-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.22g,0.5mmol),开启磁力搅拌,于54℃避光反应18小时,过滤除去碘化银沉淀。将滤液浓缩至6mL,有白色固体析出。过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.052g,产率20%。
1H NMR(600MHz,D2O):δ5.52(m,2H,NH2),4.92(m,2H,NH2),4.11(m,3H,NH3),3.03(m,2H,CH2 of cyclobuty),2.30(m,1H,CH of cyclopentyl),2.28(m,2H,CH2 ofcyclobuty),1.94(m,2H,CH2 of cyclopentyl),1.62(m,2H,CH2 of cyclopentyl),1.47(m,4H,2×CH2 of cyclopentyl);ESI-MS:m/z[M+H]+=522.
实施例12
在避光通氮气的条件下,将顺式-二碘-氨-环己胺合铂(0.24g,0.5mmol)悬浮于75mL水中,加入3-羟基-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.22g,0.5mmol),开启磁力搅拌,于54℃避光反应22小时,过滤除去碘化银沉淀,将滤液浓缩至8mL,有白色固体析出。过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.187g,产率70%。
1H NMR(600MHz,d6-DMSO):δ4.98(m,2H,NH2),4.10(m,3H,NH3),3.02(m,2H,CCH2C),2.36(m,2H,CCH2C),2.31(m,1H,CH of cyclohexyl),2.23(m,2H,CH2 of cyclohexyl),1.66(m,2H,CH2 of cyclohexyl),1.52(m,2H,CH2 of cyclohexyl),1.21(m,2H,CH2 ofcyclohexyl),1.07(m,2H,CH2 of cyclohexyl);ESI-MS:m/z[M+H]+=537.
实施例13
在避光通氮气的条件下,将顺式-二碘二氨合铂(0.24g,0.5mmol)悬浮于150mL水中,加入3-己酸酯-3-(三氟甲基)环丁烷-1,1-二羧酸银(0.27g,0.5mmol),开启磁力搅拌,于50℃避光反应18小时,过滤除去碘化银沉淀,将滤液浓缩至20mL,有白色固体析出。过滤,冷水洗涤,40℃真空干燥12小时,得白色固体0.20g,产率73%。
1H NMR(600MHz,d6-DMSO):δ4.18(s,6H,2×NH3),3.14-3.17(d,2H,CCH2C),2.90-2.94(d,2H,CCH2C),2.32(t,2H,COCH2CH2),1.67(m,2H,CH2CH2CH2),1.29(m,2H,CH2CH2CH2),1.28(m,2H,CH2CH3),0.88(t,3H,CH3);ESI-MS:m/z[M+H]+=554.1.
实施例14
将3-糖苷-3-(三氟甲基)环丁烷-1,1-二羧酸(1.0g)溶于15mL水中,用饱和氢氧化钡溶液调节溶液的pH至8,该混合液在室温下搅拌20分钟。在氮气保护下将含有二胺硫酸铂(0.70g)的水溶液(7mL)加入到上述所得反应液中,室温避光搅拌反应14小时。待反应完成后,使得离心机除去沉淀,收集上清液,使用冷冻干燥机干燥,用半制备高压液相色谱分离得到0.39g最终产品。
1H NMR(600MHz,D2O):δ5.20-5.28(m,1H),3.72(s,3H),3.64(t,J=9.4Hz,1H),3.44-3.51(m,1H),3.35-3.43(m,1H),3.14-3.23(m,1H),2.98-3.11(m,3H).
(二)化合物稳定性测试
采用HPLC和1HNMR方法测定,分别对通过实施例1-实施例14制备得到的化合物取样3mg,溶于0.5mL D2O中,室温放置,比较不同时间段测得HPLC和1H NMR纯度,结果显示化合物在4天内HPLC和1H NMR无明显变化,说明化合物具有较好的稳定性。
(三)配合物的体外细胞毒活性测试
取对数生长期的A549肺癌、HepG-2肝癌、MCF-7乳腺癌、HCT-116结肠癌等4种人癌细胞株和BASE-2B人正常肺上皮细胞,接种于96孔培养板中,每个孔约5000个细胞,过夜培养(16h),待细胞贴壁后进行给药,分别设置阳性对照组(顺铂、卡铂和奥沙利铂)、阴性对照组合(不加铂药)和给药组(化合物1-14),待测试的配合物用DMF配制成贮液,临用前使用细胞培养基稀释成梯度浓度,其中DMF的终浓度不超过0.4%。每个浓度设置3个复孔,加药后继续培养72h,加20μL浓度为5mg/mL的3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H-溴代四唑(MTT),在37℃条件下孵育4h,去除上清液,加入150μL的DMSO溶解甲瓒,30min内用酶标仪490nm波长测定每个孔的OD值,并且计算抑制率,做浓度-抑制率曲线计算IC50值,得到表1的结果。
抑制率=(OD值对照孔-OD值给药孔)/OD值对照孔×100%
表1不同配合物的体外细胞毒活性测试结果
如表1所示,本发明的化合物1-14对肿瘤细胞为肺癌细胞A549、肝癌细胞HepG2、乳腺癌细胞MCF-7或结肠癌细胞HCT-116均有明显的抑制作用,抗癌活性优于卡铂,对并且对于正常肺上皮细胞BEAS-2B的细胞毒活性较小,具有良好的临床应用前景。当铂类化合物的离去基团环丁二羧酸3-位同时含有三氟甲基和羟基或者氨基的时候,如化合物3和4,化合物7和8即具有较好的水溶性并且具有较好的抗肿瘤活性。特别是化合物14的R1为糖基,具有最优的抗肿瘤活性。
(四)配合物的体内抑瘤作用
本试验例采用小鼠移植性肿瘤动物模型方法测试了本发明的化合物对动物移植性肿瘤A549的抑制作用,小鼠接种A549肿瘤细胞后,待肿瘤长到80-100mm3大小左右时,可进行给药,将裸鼠随机分为PBS、顺铂、奥沙利铂、化合物3、化合物4共5组,每组5只,通过尾静脉注射,提前将本次实验所用药物用无菌PBS分别配置成为6μMol/kg的浓度,分别于第8天,第10天,第12天尾静脉注射顺铂6μM/kg,奥沙利铂6μM/kg,化合物3为6μM/kg和化合物4为6μM/kg,给药前称量裸鼠体重,根据每只裸鼠的重量来确定给药体积。
测量所有小鼠肿瘤的体积大小和肿瘤重量大小,测试结果如图1和图2所示,在同等给药浓度下,化合物4的抑制作用要明显优于奥沙利铂;而化合物3的抑制作用同奥沙利铂相当,其水溶性要比所有阳性对照药好,体内药效也相对突出。化合物3和化合物4毒性比较弱,要优于顺铂的毒性。
Claims (7)
2.如权利要求1所述的一种含三氟甲基的铂类抗肿瘤化合物,其特征在于所述糖基为葡萄糖、半乳糖、甘露糖、阿洛糖、阿卓糖、古罗糖、艾杜糖、太洛糖、2-脱氧葡萄糖、核糖或脱氧核糖。
4.如权利要求3所述的一种含三氟甲基的铂类抗肿瘤化合物,其特征在于其在药学上可接受盐包括碳酸盐、磷酸盐、甲磺酸盐、包括碳酸盐、磷酸盐、甲磺酸盐、对甲苯磺酸盐、硫酸盐、草酸盐、马来酸盐、酒石酸盐、乙酸盐、苹果酸盐、琥珀酸盐、乳酸盐、谷氨酸盐、天冬氨酸盐、硝酸盐、三氟甲磺酸盐、富马酸盐或枸橼酸盐。
6.如权利要求4所述的制备方法,其特征在于避光反应的温度为40-55℃,反应时间为10-25小时。
7.一种如权利要求1所述的含三氟甲基的铂类抗肿瘤化合物在制备肿瘤抑制药物中的应用,其特征在于肿瘤细胞为肺癌细胞A549、肝癌细胞HepG2、乳腺癌细胞MCF-7或结肠癌细胞HCT-116。
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