CN104610415A - 肝靶向铂类抗癌药物及其合成方法 - Google Patents
肝靶向铂类抗癌药物及其合成方法 Download PDFInfo
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- CN104610415A CN104610415A CN201410636868.0A CN201410636868A CN104610415A CN 104610415 A CN104610415 A CN 104610415A CN 201410636868 A CN201410636868 A CN 201410636868A CN 104610415 A CN104610415 A CN 104610415A
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- Prior art keywords
- platinum
- acid
- anticancer drug
- liver
- cholic acid
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 108
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 53
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 27
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 27
- 238000010189 synthetic method Methods 0.000 title abstract description 6
- 210000004185 liver Anatomy 0.000 claims abstract description 38
- 230000008685 targeting Effects 0.000 claims abstract description 32
- 239000004380 Cholic acid Substances 0.000 claims abstract description 28
- 229960002471 cholic acid Drugs 0.000 claims abstract description 28
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims abstract description 26
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims abstract description 23
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims abstract description 23
- 235000019416 cholic acid Nutrition 0.000 claims abstract description 23
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- 238000001802 infusion Methods 0.000 claims abstract description 4
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims abstract description 4
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- 238000002360 preparation method Methods 0.000 claims description 7
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- DGABKXLVXPYZII-SIBKNCMHSA-N hyodeoxycholic acid Chemical compound C([C@H]1[C@@H](O)C2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 DGABKXLVXPYZII-SIBKNCMHSA-N 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims 1
- 230000008878 coupling Effects 0.000 abstract description 9
- 238000010168 coupling process Methods 0.000 abstract description 9
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- UYVVLXVBEQAATF-UHFFFAOYSA-N 4-(1,3,7,12-tetrahydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl)pentanoic acid Chemical compound OC1CC2CC(O)CC(O)C2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 UYVVLXVBEQAATF-UHFFFAOYSA-N 0.000 abstract description 2
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了肝靶向铂类抗癌药物及其合成方法,它是一类以胆酸及其衍生物为运载分子的肝靶向铂类抗癌药物及其合成方法,其氨/胺配体(A2)包括2NH3、1R,2R-二氨基环已烷、1,2-双(氨甲基)环丁烷、(4S,5S)-4,5-双(氨甲基)-2-异丙基-1,3-二氧环戊烷,胆酸、去氧胆酸、猪取氧胆酸、熊去氧胆酸鹅去氧胆酸(RCOOH)通过与酰胺键与1,1-环丁烷二羧酸根偶联,形成如下结构的化合物,它们具有抗癌活性高、肝靶向性强的特点,可作抗癌药物用于肝癌的肝动脉灌注或肝动脉介入栓塞治疗,其结构式为:
Description
技术领域
本发明涉及一类以胆酸及其衍生物为运载分子的肝靶向铂类癌药物及其合成方法,属于生物制药领域。
背景技术
据世界卫生组织2014年发布的《世界癌症报告》的统计,肝癌是中国最常见的恶性肿瘤之一,全球的80%肝癌患者在我国,导致的死亡人数每年达到13万,位居癌症死亡率的第二位,仅次于肺癌。手术是治疗早期肝癌的最有效方法,但对于无法接受手术治疗和晚期的患者,化疗是一种重要的选择,而铂类抗癌药物[1](主要是顺铂、卡铂、奥沙利铂,见结构式1)是少数几种对肝癌有效的药物之一,用于肝动脉灌注化疗和肝动脉介入栓塞化疗[2]。然而,目前临床应用铂类抗肿瘤药物还存在两大障碍[3]:毒副反应和耐药性。铂类药物属于细胞毒类化合物,对癌细胞缺乏足够的选择性,在杀伤癌细胞的同时,对正常的组织细胞也产生不同程度的损伤作用,通常导致骨髓抑制、肾损伤、神经毒性、恶心呕吐。在化疗过程中,癌细胞对既往使用过的铂类药物不敏感、产生耐药性,而耐药性的产生又导致药物剂量的增加,加重了药物的毒副反应,是化疗失败的重要原因,也是铂类药物化疗急需解决的难题。靶向给药因此被认为是降低低药物毒性和克服耐药性的最有效的方法之一[4,5]。
结构式1。
胆酸及其衍生物(RCOOH),包括胆酸、去氧胆酸、猪取氧胆酸、熊去氧胆酸鹅去氧胆酸,是胆汁酸的重要组成部分,体内主要被肝组织吸收利用,对肝组织有高达的亲合力,因为一直作为肝靶向药物的运转分子得到关注[6-8]。医药界正在研究胆酸与药物偶联,以期望达到肝靶向的目的。
1997年,西班牙科学家Criado J.J.等[9-11]首先报道了顺铂-胆汁酸的偶联物 Bamet-R(见结构式2和3),这种偶联是通过胆汁酸中的甘氨酸羧基直接与金属铂的配位来实现,但这种偶联方式很不稳定,胆汁酸会很快解离,失去运载铂类药物靶向肝的能力。同时,他们还设计和合成了另一种如结构式4所示的胆汁酸和铂的化合物Bamet-H2,然而,这种化合物不符合铂类药物所应有的经典构效关系,失去体内抗癌活性。
Bamet-R的化学结构式2
Bamet-H2的化学结构式3
ChAPt的化学结构式4。
2000年德国科学家Reinhard P等[12,13].合成了一类新型的含有胆酸基的铂类抗癌配合物ChAPt,如结构式5所示,胆酸通过酯键与二胺配体偶联,离去基团选择了2个氯离子或1,1-环丁烷二羧酸。目前已有很多的研究表明,在二胺配体上连接一个庞大的基团会给金属铂与DNA嘌呤上N7的配位增加空间位阻,影响抗癌活性。
最近,美国专利(US 7,348,320B2)公开了一组铂类抗癌配合物,结构如结构 式5所示,它合成是以去氢胆酸为起始原料,在去氢胆酸上3位酮基上引入带有二羧酸的基团,再通过二羧酸与铂配位,得到目标化合物。去氢胆酸上3位酮基引入一个较复杂的基团,会破坏胆酸原有的化学结构,影响肝组织对胆酸的识别,降低化合物的肝靶向性。
结构式5:US 7,348,320B2报道的结构式。
上述背景技术中所列出参考文献为:
[1]韩锐,孙燕主编.新世纪癌的化学预防与药物治疗.人民军医出版社,2005,北京.
[2]Kelland L.The resurgence of platinum-based cancer chemotherapy.Nature Rev Cancer,2007,7,573-584.
[3]Rabic C A,Dolan M E.Molecular mechanisms of resistance and toxicity associated with platinating agents.Cancer TreatRev,2007,33,9-13.
[4]Jakupec M A,Galanski M and Keppler B K.Tumour-inhibiting platinum complexes-state ofthe art and future perspectives.Rev Physiol Biochem Pharmacol,2003,146,1-53.
[5]Galanski M,Keppler B K.Searching for the magic bullet:anticancer platinum drugs which can be
accumulated or activated in the tumor tissue.Anti-Cancer Agents in Med Chem,2007,7,55-73.
[6]KramerW,Wess G,Schubert G,Bickel M,Girbig F,Gutjahr U.Liver-specific drug targeting by coupling to bile acids.JBiol Chem,1992,267,18598-804.
[7]KramerW,Wess G.Bile acid transport systems as pharmaceutical targets.Eur J Clin Invest,1996,26,715-32.
[8]Meijer D K E.Drug targeting to the liver with bile acids–the Trojan horse resurrected.Hepatology,1993,17,945-8.
[9]Criado J J,Macias R I R,Medarde M,Monte M J,Serrano M A,Marin J J G.Synthesis and characterization ofthe new cytostatic complex cis-diammineplatinum(I1)chloro cholylglycinate.Cytostatic activity.Bioconjugate Chem,1997,8:453-458.
[10]Marin J J G,Macias R I R,Criado J J,Bueno A,Monte M J,Serrano M A.DNA interaction and cytostatic activity ofthe new liver organotropic complex of cisplatin with glycocholic acid:Bamet-R2.IntJ Cancer,1998,78,346-352.
[11]Macias R I R,Monte M J,El-Mir M Y,Villanueva G R,Marin J J G.Transport and biotransformation of the new cytostatic complex cis-diammmineplatinum(II)-chlorocholylglycinate(Bamet-R2)by the rat liver.JLipid Res,1998,39,179228.
发明内容
综上所述,多年来利用胆酸作为运转分子的肝靶向铂类药物研制并不顺利,尚未获得肝靶向性高、抗癌作用强的铂类药物。为此,我们通过多年的研究和试验,提出了新的偶联方案,成功发展了一类以胆酸及其衍生物为运载分子的肝靶向铂类抗药物,其结构如结构式6所示。
其中,RCOOH代表胆酸及其衍生物(如去氧胆酸、猪去氧胆酸、熊去氧胆酸鹅去氧胆酸),R为胆酸及其衍生物的非羧基部分;A2为目前已上市铂类药物的氨/胺配体,包括括氨(顺铂、卡铂、奈达铂的氨配体)、1R,2R-二氨基环已烷(奥沙利铂的胺配体)、1,2-双(氨甲基)环丁烷(洛铂的胺配体)、(4S,5S)-4,5-双(氨甲基)-2-异丙基-1,3-二氧环戊烷(舒铂的胺配体)。
结构式6.本发明的肝靶向铂类抗癌药物。其中:
本发明的肝靶向铂类抗癌药物最优选具有如下结构的化合物:
本发明的肝靶向铂类抗癌药物是以已上市的铂类药物的氨/胺为配体,保留了铂类抗癌药物的药效基团[cis-A2Pt]2+。同时,肝靶向运转分子胆酸及其衍生物通过卡铂的离去基团1,1-环丁烷二羧根来与药效基团偶联,符合铂类药物的经典构效关系。以下为本发明的肝靶向铂类抗癌药物的组成部分:
本发明的肝靶向铂类抗癌药物的制备分成两个阶段:(1)按文献报道的方法合成3-羟基-1,1-环丁二羧酸乙酯,以此有机酯为起始原料,通过本发明的制备路线 和条件,用氨基置换羟基,形成3-氨基-1,1-环丁二羧酸乙酯,与胆酸及其衍生物RCOOH进行缩合脱水反应,可将胆酸及衍生物通过酰胺键与1,1-环丁二羧酸乙酯结合,酯键水解后,生成3-RCONH-1,1-环丁烷二羧酸;(2)3-RCONH-1,1-环丁烷二羧酸溶于NaOH中转化成钠盐后,与已上市铂类药物的水合物cis-[PtA2(H2O)2](NO3)2发生配位取代反应,沉淀出白色的目标化合物,过滤洗涤后,在50-60℃下真空干燥,得到本发明的肝靶向铂类抗癌药物。本发明的肝靶向铂类抗癌药物的制备路线和条件如下:
本发明肝靶向铂类抗癌药物有很高的抗癌活性,对人肝癌细胞株(HEPG2、SMMC-7721)和人肺癌细胞株(A549)的生长都有明显的抑制作用,活性与对应的母体化合物卡铂和奥沙利铂相当,说明肝靶向运转分子胆酸及其衍生物的偶联不影响铂类药物的活性。
本发明靶向铂类抗癌药物腹腔注射给药后,在不同的时间小鼠肝组织的药物浓度明显高于对应的药物(如卡铂、奥沙利铂),说明具有肝靶向的特性,运转分子胆酸及其衍生物可以把药物的定向运载到肝组织。
同时,发明肝靶向铂类抗癌药物,具有好的稳定性和一定的脂溶性,在甘油和聚乙二醇-400有一定的溶解度,满足肝动脉灌注化疗和肝动脉介入栓塞化疗的给药要求。
因此,本发明的肝靶向铂类抗癌药物具有抗癌活性高、肝靶向性好、稳定和脂溶的 特点,显示出重大的临床应用前景。
附图说明
图1为LLC-202和奥沙利铂等摩尔剂量腹腔给药后ICR小鼠肝铂的含量变化(μg/g)(n=10,*P<0.05,**P<0.01)。
具体实施方式
(1)本发明的肝靶向铂类抗癌药物的合成方法
a)3-TsO-1,1-环丁烷二羧酸二乙酯(2)的制备
氮气保护下,取5.1g(0.024mol)3-羟基-1,1-环丁烷二羧酸二乙酯,9.6g(0.094mol,4eq.)三乙胺(Et3N),0.58g(0.0047mol,20%eq.)4-二甲氨基吡啶(DMAP)加入10mL二氯甲烷中,搅拌后溶解,将9.0g(0.047mol,2eq.)对甲苯磺酰氯(TsCl)和10mL二氯甲烷混合后在冰浴中滴入,加毕,室温搅拌过夜,TLC监控反应完全。展开剂:石油醚:乙酸乙酯=4:1,Rf=0.4,柱色谱分离(石油醚:乙酸乙酯=6:1)得产物8.2g,产率94%。
b)3-叠氮-1,1-环丁烷二羧酸二乙酯(3)的制备
氮气保护下,取8.0g(0.022mol)3,4.2g(0.065mol,3eq.)叠氮钠(NaN3),7.3g(0.022mol,1eq.)Bu4NHSO4溶于10mLDMF中,80℃搅拌过夜,TLC监控反应完全。冷却至室温,转入1L分液漏斗中,加入大量水,用2×100mL乙酸乙酯萃取,合并乙酸乙酯层,用3×100mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,展开剂:石油醚:乙酸乙酯=10:1,Rf=0.5,柱色谱分离(石油醚:乙酸乙酯=10:1)得产物3.3g,产率64%。
c)3-氨基-1,1-环丁烷二羧酸二乙酯(3)的制备
取5.0g4,溶于150mL乙酸乙酯,加1.0g(20%eq.)10%Pd/C,在室温常压H2反应过夜,直接过滤浓缩得产物3-氨基-1,1-环丁烷二羧酸二乙酯4.4g,产率96%。
d)3-胆酸酰胺-1,1-环丁烷二羧酸二乙酯(2)的制备
称取1.1g(5.25mmol,1.05eq.)二环己基碳二亚胺(DCC)溶于5mL四氢呋喃中,放于冰箱中冷却待用。称取2.0g(5mmol,1eq.)胆酸溶于10mL四氢呋喃,搅拌使之溶解,冰盐浴冷却,-15℃左右加入0.77g(5mmol,1eq.)1-羟基苯并三唑(HOBt),1.1g3(5mmol),0.55mLN-甲基吗啡啉(NMM),搅拌,1~2min后倾入冷却的DCC的四氢呋喃溶液,-15℃以下搅拌2h,自然恢复室温,搅拌过夜,滤去白色不溶固体,减压旋除四氢呋喃,得黄色粘稠状液体,用二氯甲烷溶解,依次用饱和NaHCO3水溶液、10%柠檬酸溶液、饱和NaHCO3水溶液及饱和NaCl水溶液洗涤三次,收集有机层,无水Na2SO4干燥。过滤除去干燥剂,浓缩,以石油醚研磨固化,过滤,得白色固体。展开剂: 石油醚:乙酸乙酯:乙醇=4:4:1,Rf=0.5,柱色谱分离(石油醚:乙酸乙酯:乙醇=4:4:1)得产物2.0g,产率66%。
e)3-胆酸酰胺-1,1-环丁烷二羧酸(1)的制备
在250mL反应瓶中加入0.6g(0.015mol,2.6eq.)NaOH和50mL水,搅拌溶解,将3.5g(0.0058mol)2和100mL甲醇混合后滴入,加毕,50℃搅拌8h,TLC监控反应完全。加入2g活性炭,搅拌30min,过滤,减压回收甲醇,水层用2×50mL乙酸乙酯提取除去有机杂质。分出水层,加入稀盐酸调pH至1,用3×60mL乙酸乙酯提取,合并有机层,用3×60mL饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得白色产物,展开剂:石油醚:乙酸乙酯:甲酸=10:15:2,Rf=0.3,即得3-胆酸酰胺-1,1-环丁烷二羧酸2.4g,产率76%。
f)肝靶向铂类抗癌药物的合成举例
LLC-201:
按文献的方法制备cis-[Pt(NH3)2(H2O)2](NO3)2水溶液。取3-胆酸酰胺-1,1-环丁烷二羧酸2.4g(4.4mmol),溶于88ml的0.1mol/LNaOH溶液中,在避光和搅拌条件下滴加cis-[Pt(NH3)2(H2O)2](NO3)2水溶液(4.8mmol,过量10%),滴加完毕后,继续搅拌反应12小时,析出白色沉淀产物,过量收集,用水洗涤3次后,在50-60℃下真空干燥8小时,得到产物2.2克,产率65%。
结构参数:
1)元素分析测定值:C46.4%,H6.57%,N5.41%,Pt25.2%;
计算值:C46.1%,H6.61%,N5.36%,Pt25.0%.
2)分子量HRESI+-MS:799.3223([MNa]+);
计算值:799.3222([MNa]+).
3)谱图解析IR(KBr,cm-1):3441(s,vO-H),3210(s,vN-H),1720(m,vC=0,酰胺),1631(vs,vas(COO)),1383(s,va(COO)).
以上测定数据符合结构式6所示的LLC-1201的组成和结构式。
LLC-202:
按文献的方法制备cis-[Pt(1R,2R-diaminocyclohexane)(H2O)2](NO3)2水溶液。取3-胆酸酰胺-1,1-环丁烷二羧酸2.4g(4.4mmol),溶于88ml的0.1mol/LNaOH溶液中,在避光和搅拌条件下滴加cis-[Pt(1R,2R-diaminocyclohexane)(H2O)2](NO3)2水溶液(4.8mmol,过 量10%),滴加完毕后,继续搅拌反应12小时,析出白色沉淀产物,过量收集,用水洗涤3次后,在50-60℃下真空干燥8小时,得到产物2.7克,产率71%。
结构参数:
1)元素分析测定值:C50.2%,H6.91%,N4.90%,Pt22.6%;
计算值:C50.5%,H6.89%,N4.91%,Pt22.8%.
2)分子量HRESI+-MS:879.3841([MNa]+);
计算值:879.3848([MNa]+).
3)谱图解析IR(KBr,cm-1):3440(s,vO-H),3256(s,vN-H),1721(m,vC=0,酰胺),1633(vs,vas(COO)),1385(s,va(COO))
以上测定数据符合结构式6所示的LLC-1202的组成和结构。
符合本发明结构式6的其它肝靶向铂类抗癌药物:
在d)反应步骤后以不同的胆酸衍生物作为起始原料,采用如LLC-201和LLC-202同样的合成路线和条件,可以合成出本发明的其他肝靶向铂类抗癌药物。
(2)本发明的肝靶向铂类抗癌药物的抗癌活性
以LLC-201和LLC-202为例
本发明的化合物溶于20%的聚乙二醇-400水溶液中,对照药品卡铂、奥沙利铂溶于水中。用不含血清的培养液将测试的化合物配成所需浓度,应用SRB法(磺酰罗丹明B蛋白染色法)检测目标化合物对人肝癌细胞株(HEPG2、SMMC-7721)和人肺癌细胞株(A549)增殖生长的抑制作用。
SRB法:接种对数生长期细胞于96孔培养板,加入不同浓度的药物,每个浓度设3个复孔,同时设相应浓度的溶媒对照。癌细胞在37℃、5%CO2条件下培养72小时。细胞用SRB室温中染色,最后加入Tris溶液溶解,酶标仪(BioTek)510nm波长下测定OD值,以下列公式计算细胞生长抑制率,根据各浓度抑制率,根据非线性回归方法计算半数抑制浓度IC50。抑制率=(OD值对照孔-OD值给药孔)/OD值对照孔×100%
表1.目标化合物对癌细胞生长的半数抑制浓度IC50(t=72h)
如表1结果所示,本发明的其中2个化合物体外对人肝癌细胞株(HEPG2、SMMC-7721)和人肺癌细胞株(A549)的生长都有明显的抑制作用。其中,LLC-201与其对应的母体化合物卡铂相当,LLC-202与其对应的母体化合物奥沙利铂相当,说明肝靶向运转分子胆酸及其衍生物的偶联不影响铂类药物的抗癌活性。
(3)本发明的铂类抗癌药物的肝靶向特性测试
以LLC-202为例
1)测试样品
奥沙利铂,用5%葡萄糖溶液配置成每0.4ml含0.18mg奥沙利铂的溶液;LLC-202,用20%聚乙二醇-400配置成每0.4ml含0.4mg LLC-1202水溶液。
2)动物和分组
60只健康的ICR雄性小鼠,20克左右,随机分成LLC-202和奥沙利铂,每组30只,正常饲养。
3)方法
每只小鼠一次性腹腔给予0.4ml的体积的LLC-202或奥沙利铂溶液,剂量均为0.023mmol/kg。1小时后,每组取10只小鼠,麻醉取肝组织约0.5克,用AAS法测定铂含量;3小时后,每组另取10只小鼠,麻醉肝组织约0.5克,用AAS法测定铂含量;6小时后,每组剩余10只小鼠,麻醉取肝组织约0.5克,用AAS法测定铂含量。
4)测定结果
如图1所示,给药后的1,3,6小时,LLC-202组的小鼠肝铂含量明显高于对照组奥沙利铂,特别是第6小时,奥沙利铂组小鼠的铂含量开始下降而LLC-202组的小鼠肝铂还在增加,接近奥沙利铂组小鼠的两倍,说明随着药物在体内的循环,LLC-202在肝脏中的量不断积累,与奥沙利铂比较显示出明显的肝靶向特性。
Claims (4)
1.一种肝靶向铂类抗癌药物,其特征在于:为结构式如下的铂(II)化合物,其中,RCOOH代表胆酸及其衍生物,包括:胆酸、去氧胆酸、猪去氧胆酸、熊去氧胆酸鹅去氧胆酸,R为胆酸及其衍生物的非羧基部分;A2为目前已上市铂类抗癌药物的氨/胺配体,包括2NH3、1R,2R-二氨基环已烷、1,2-双(氨甲基)环丁烷、(4S,5S)-4,5-双(氨甲基)-2-异丙基-1,3-二氧环戊烷,
其中
2.一种肝靶向铂类抗癌药物,其特征在于:其结构式如下的两个化合物:
3.权利要求1或2的所述的铂(II)化合物在制备抗肝癌的肝动脉灌注和肝动脉介入栓塞治疗药物中的应用。
4.权利要求1或2的所述铂(II)化合物,其特征在于:采用如下路线和条件合成:
其中,a)TsCl,Et3N,DMAP,DCM,0℃~室温;
b)NaN3,Bu4NHSO4,DMF,80℃;
c)Pd/C,H2;d)DCC,HOBt,NMM;e)NaOH,MeOH,50℃;
f)室温,12小时。
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