CN106543234B - 以饱和链为桥的手性双核铂配合物及其制备方法和应用 - Google Patents
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Classifications
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- 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
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类结构式为式Ⅰ或式Ⅱ所示的饱和链为桥的新型手性双核铂配合物及其制备方法,该类化合物具有抗肿瘤活性,合成方法简单易行,适于产业化生产;其中R选自 n=4‑12,m=1‑5;D选自Z选自CH3COO‑、ClCH2COO‑、CH3(CH2)6COO‑、CH3(CH2)8COO‑、Cl‑。
Description
技术领域
本发明涉及有机化合物,尤其涉及一类以饱和链为桥的新型手性双核铂配合物及其制备方法及其抗肿瘤活性。
背景技术
恶性肿瘤是世界公认的对人类健康危害最严重的疾病之一,其危害性仅次于心血管疾病。因此,加强肿瘤治疗的研究,提高现有各种治疗手段的效果,降低癌症死亡率,减少复发率,改善癌症患者的生活质量,是医药作者的急迫职责。在肿瘤治疗中,化疗是当前肿瘤治疗的重要方法之一。在众多化疗药物中,铂类配合物是一类抗肿瘤作用较强、抗肿瘤谱较广的药物。自1967年Rosenberg等人发现顺铂有抗癌活性以来,顺铂作为一种高效的抗癌药物,被广泛地用于治疗多种癌症,例如睾丸癌、卵巢癌、子宫颈癌、膀胱癌、肺癌以及头颈癌等。奥沙利铂作为第三代铂药的典型代表,在临床上取得了显著突破。研究发现,它的手性配体1R,2R-环己二胺是其对中晚期大肠癌发挥疗效的核心组成部分。
上世纪90年代以来,基于对铂类配合物作用机理和耐药机制的不断深入研究,科学家们不再局限于Cleare等人提出的经典构效关系。已设计出不同于经典构效关系的多种铂抗肿瘤配合物,并取得了良好的效果。在各类非经典铂类抗肿瘤药物中,多核铂(II)配合物已经广泛地引起了人们的兴趣。大量研究表明,具有多胺桥链的双核及多核铂配合物显示了良好的细胞毒活性,桥联的双核铂配合物与DNA形成远程的链间交叉连接,能跨越四个甚至更多的碱基对与DNA发生多点键合,键合能力强,对DNA结构破坏更加严重,使癌细胞难以自我修复,因此与现有铂类药物不存在交叉耐药性。
因此,我们基于奥沙利铂的手性配体DACH,以柔性的饱和烷基链或含醚键的碳链连接2个手性环己二胺从而设计了如式(I)结构的化合物,我们期望该配合物在后续铂药研究中既能发挥奥沙利铂的抗肿瘤作用,又能发挥双核铂抗肿瘤药物的优势。
发明内容
本发明的目的是提供一种结构式为式Ⅰ或式Ⅱ所示的以饱和链为桥的手性双核铂配合物;
其中R选自n=4-12,m=1-5;
D选自
Z选自CH3COO-、ClCH2COO-、CH3(CH2)6COO-、CH3(CH2)8COO- Cl-。
本发明中以饱和链为桥的手性双核铂配合物合成路径如下:
1、1-N-Boc-1R,2R-环己二胺为市购产品或采用下述路径合成:
2、二卤代烷为其中n=4-12,X为Cl或Br,二卤代醚为其中m=1-5,X为Cl或Br,均为市购产品;
3、以1-N-Boc-1R,2R-环己二胺为原料,溶于无水DMF中并加入市售4A分子筛和氢氧化铯,然后滴入二卤代烷或二卤代醚,,常温下反应12-24小时,抽滤后旋干,使用二氯甲烷/石油醚体系重结晶得以饱和链为桥的含boc保护基的多胺配体纯品,其中1-N-Boc-1R,2R-环己二胺与二卤代烷或二卤代醚的摩尔比为2:1,氢氧化铯的添加量高于1-N-Boc-1R,2R-环己二胺的摩尔量;
其中R选自n=4-12,m=1-5;
4、将步骤3以饱和链为桥的含boc保护基的多胺配体加入1-1.5mol/L的盐酸乙酸乙酯中脱去boc保护基制得多胺配体的盐酸盐,将多胺配体盐酸盐溶于水,加入饱和碳酸钠溶液后使用乙酸乙酯萃取,取有机相干燥后得到以饱和链为桥的多胺配体;
其中R选自n=4-12,m=1-5;
5、将步骤4制得的以饱和链为桥的多胺配体溶于水后,滴加到K2PtI4水溶液中,40-50℃反应24h,过滤,依次用冰水、乙醚和乙醇洗涤固体,真空干燥后制得胺铂碘,其中以饱和链为桥的多胺配体与K2PtI4的摩尔比为1:2;
K2PtCl4+4Kl→K2Ptl4,
其中R选自n=4-12,m=1-5;
6、将胺铂碘溶于纯净水中,加热至50-60℃,称取AgZ或D(OAg)2加入溶液中,50-60℃搅拌反应2h,过滤洗涤,制得以饱和链为桥的手性双核铂配合物,其中胺铂碘与D(OAg)2摩尔比为1:2,胺铂碘与AgZ摩尔比为1:4;或在胺铂碘溶液中加入硝酸银后除去碘化银沉淀再加入氯化钠,过滤洗涤得以饱和链为桥的手性双核铂配合物,其中胺铂碘与AgNO3、NaCl的摩尔比为1:4:4;
其中R选自n=4-12,m=1-5;
D选自
Z选自CH3COO-、ClCH2COO-、CH3(CH2)6COO-、CH3(CH2)8COO-、Cl-。
本发明另一目是将上述含不饱和键的手性双核铂配合物应用在制备抗肿瘤药物中,如结构式Ⅰ或式Ⅱ所示的化合物由于具有两个手性环己二胺,它是抗肿瘤药物奥沙利铂的重要组成部分,且中间的桥链使环己二胺与两个铂进行配合,与DNA可结合的更加紧密。我们期望该类配合物在后续铂药研究中既能发挥奥沙利铂的抗肿瘤作用,同时又能发挥双核铂抗肿瘤药物的优势。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
本发明的主要优点在于:
1、本发明提供的结构式如Ⅰ或式Ⅱ所示的配合物,其具备奥沙利铂的药理活性部分手性环己二胺,同时又以饱和链连接2个铂核心,从而具有与DNA形成多点交联的能力,并且饱和链具有良好柔性,可以与DNA更紧密结合,在实施例中部分化合物已经初步显现出优于现有药物奥沙利铂、卡铂的细胞毒性,因此有望成为未来新型双核铂抗肿瘤药物。
2、本方法合成过程虽然步骤多,但后处理都是通过萃取或重结晶,相对简便,并且反应过程中没有高温高压,安全环保,有利于工业化生产。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不限制本发明的范围。下列实施例中未注明具体条件的试验方法,通常按照常规条件或按照制造厂商所建议的条件,除非另外说明,否则所有的百分数和比率都按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅做示范之用。
实施例1:制备如式Ⅰ所示化合物,即:
1、制备1-N-Boc-1R,2R-环己二胺
将22.4g(0.1mol)1R,2R-环己二胺溶于200ml的甲醇溶液,常温条件下置于500mL的单颈瓶并不断搅拌;量筒量取5.17mol/L的盐酸甲醇19.4mL置于恒压漏斗内;冰浴条件下盐酸甲醇缓慢滴加到单颈瓶中;滴毕,撤去冰浴,常温反应30分钟。称取38.28g(0.176mol)(Boc)2O溶于100mL甲醇,置于恒压漏斗,缓慢滴加至单颈瓶,滴毕,常温反应1小时,旋干,得白色固体;将该白色固体溶于水,乙醚萃取,取水相;调pH至10,CH2Cl2萃取,取有机相,旋干,CH2Cl2/PE重结晶,得白色晶体,产率78%。1H NMR(500MHz,CDCl3):δ7.28(s,1H,NH-Boc),4.52(s,2H,NH2),2.33(m,1H),1.98(m,1H),1.69(m,4H),1.46(s,9H,NH-Boc),1.19~1.32(m,2H),1.06~1.17(m,2H)。HR-MS(m/z):[C11H22N2O2+H]+=215.1689。
2、制备化合物
将4.28g(20mmol)1-N-Boc-1R,2R-环己二胺溶于40mLDMF中,加入6g(40mmol)氢氧化铯和4g 4A分子筛,搅拌,称取2.44g(10mmol)1,6-二溴己烷,缓慢滴入DMF溶液中,搅拌反应12h,抽滤后旋干DMF,将所得白色固体加入二氯甲烷至刚好溶解,再加入石油醚至有絮状物产生,置于冰箱冷冻24h,过滤得白色固体,产率79%。1H NMR(500MHz,DMSO):δ7.28(s,2H,NH-Boc),3.64(m,2H,CH-NHBoc),3.45(s,2H,NH-CH2),3.33(m,2H,CH-NHCH2),2.51(t,4H,CH2-NH),1.72(m,8H),1.52(s,18H,NH-Boc),1.31~1.39(m,8H)1.20~1.33(m,4H),1.08~1.19(m,4H)。HR-MS(m/z):[C28H55N4O4+H]+=511.4231。
3、制备化合物
称取化合物2.56g(5mmol)溶于50mL乙酸乙酯,置于茄形瓶,滴加1mol/L盐酸乙酸乙酯,使反应液呈强酸性(pH=1-2),室温反应12小时后,抽滤,得白色固体,产率96%。将该固体溶于蒸馏水,饱和Na2CO3中和盐酸盐,萃取,得白色晶体,产率87%。1H NMR(500MHz,DMSO):δ7.21(s,2H,NH-Boc),3.58(m,2H,CH-NHBoc),3.44(s,2H,NH-CH2),3.22(m,2H,CH-NHCH2),2.46(t,4H,CH2-NH),1.71(m,8H),1.30~1.39(m,8H),1.17~1.29(m,4H),1.05~1.16(m,4H)。HR-MS(m/z):[C18H36N4+H]+=311.3181。
4、制备胺铂碘(R=R1,n=6)
准备温度为120℃油浴锅和0℃冰浴锅;称取0.775g(2.5mmol)溶于5mL纯净水,将20mL纯净水置于双颈瓶,在油浴锅中预热至80℃;称取K2PtCl42.08g(5mmol),直接加入双颈瓶中,搅拌使其溶解;称取KI 8.3g(50mmol),加入少量纯净水避光溶解且预热至80℃后,将其迅速加入双颈瓶并不断搅拌2.5min。迅速将双颈瓶取出,置于冰浴锅,并不断搅拌,使温度迅速下降至25℃。再将化合物的溶液缓慢滴加至双颈瓶,滴毕,将该反应置于45℃避光反应24h,抽滤,分别用纯净水、乙醚和乙醇洗涤数次,得滤饼,即得R为R1的胺铂碘,产率为91.44%。1H NMR(500MHz,DMSO):δ4.01(m,2H,CH-NHBoc),3.67(m,2H,CH-NHCH2),2.84(t,4H,CH2-NH),1.89(m,8H),1.48~1.56(m,8H),1.29~1.41(m,4H),1.11~1.24(m,4H)。HR-MS(m/z):[C18H35N4I4Pt2+H]+=1203.8320(100%,1204..8319(70%),1205.8322(65%))。
5、制备铂配合物(R=R1)
a、制备铂配合物(A-1)(R=R1,D=D1):
称取步骤4中制备的胺铂碘0.662g(0.55mmol)置于圆底烧瓶,加入80mL纯净水溶解。将其温度为55℃,避光搅拌1h,得悬浊液。称取草酸银0.332g(1.1mmol)加入反应瓶,并于55℃避光反应24h。抽滤,除去AgI沉淀,得黄色澄清透明溶液,减压浓缩至5mL,至于0℃冰箱过夜,抽滤,得黄色固体,产率为34.96%。1H NMR(500MHz,D2O):δ4.00(m,2H,CH-NHBoc),3.62(m,2H,CH-NHCH2),2.81(t,4H,CH2-NH),1.86(m,8H),1.45~1.56(m,8H),1.29~1.40(m,4H),1.11~1.24(m,4H)。IR(KBr,cm-1):v(NH)br 3071,vs(CH),Vas(CH)2932,2889,vsh(C=O)1790,v(Pt=O)780。v(Pt=N)475。HR-MS(m/z):[C22H34N4O8Pt2+H]+=872.1733(100%,873.1732(74%),874.1742(54%))。
b、制备铂配合物(A-2)(R=R1,D=D2):
其制备方法同A-1,以2-乙基-1,3-二羧酸银替换草酸银,即0.662g(0.55mmol)胺铂碘与0.381g(1.1mmol)2-乙基-1,3-二羧酸银替换草酸银反应,得黄色固体,产率为33.45%。1H NMR(500MHz,D2O):δ4.00(m,2H,CH-NHBoc),3.62(m,2H,CH-NHCH2),3.27~3.31(t,2H),2.81(t,4H,CH2-NH),2.42~2.49(m,6H),2.24~2.34(m,4H),1.86(m,8H),1.45~1.56(m,8H),1.29~1.40(m,4H),1.12~1.24(m,4H)。IR(KBr,cm-1):v(NH)br 3101,vs(CH),Vas(CH)2937,2922,vsh(C=O)1608,v(Pt=O)777,v(Pt=N)463。HR-MS(m/z):[C28H46N4O8Pt2+H]+=956.2671(100%,957.2678(73%),958.2664(54%))。
c、制备铂配合物(A-3)(R=R1,D=D3):
其制备方法同A-1,以环丁二羧酸银替换草酸银,即0.662g(0.55mmol)胺铂碘与0.392g(1.1mmol)环丁烷-1,1-二羧酸替换草酸银反应,得黄色固体,产率为37.22%。1HNMR(500MHz,D2O):δ4.00(m,2H,CH-NHBoc),3.62(m,2H,CH-NHCH2),2.81(t,4H,CH2-NH),2.6(t,8H),2.3(m,4H),1.86(m,8H),1.45~1.56(m,8H),1.29~1.40(m,4H),1.11~1.24(m,4H)。IR(KBr,cm-1):v(NH)br 3081,vs(CH),Vas(CH)2943,2923,vsh(C=O)1627,v(Pt=O)777,v(Pt=N)481。HR-MS(m/z):[C30H46N4O8Pt2+Na]+=1002.2481(100%,1003.2492(52%),1004.2496(76%))
d、制备铂配合物(A-4)(R=R1,D=D4):
其制备方法同A-1,以3-羟基-环丁烷-1,1-二羧酸银替换草酸银,即0.662g(0.55mmol)胺铂碘与0.442g(1.1mmol)3-羟基-环丁烷-1,1-二羧酸银反应,得黄色固体,产率为36.68%。1H NMR(500MHz,D2O):δ6.5(m,2H),5.6(s,2H),4.00(m,2H,CH-NHBoc),3.62(m,2H,CH-NHCH2),2.81(t,4H,CH2-NH),2.6(t,8H),1.86(m,8H),1.45~1.56(m,8H),1.29~1.40(m,4H),1.11~1.24(m,4H)。1.05~1.18(t,8H)。IR(KBr,cm-1):v(OH)br 3408,v(NH)br3190,vs(CH),Vas(CH)2943,2865,vsh(C=O)1578,v(Pt=O)744,v(Pt=N)440。HR-MS(m/z):[C30H46N4O10Pt2+Na]+=1034.2381(100%,1035.2394(58%),1036.2388(63%)),
实施例2:制备如式Ⅰ所示化合物,即:
1、制备化合物(R=R2,m=2)
将4.28g(20mmol)1-N-Boc-1R,2R-环己二胺溶于40mLDMF中,加入6g(40mmol)氢氧化铯和5g 4A分子筛,搅拌,称取2.32g(10mmol)2-溴乙醚溶于10mL DMF中,缓慢滴入DMF溶液中,搅拌反应12h,抽滤后旋干DMF,将所得白色固体加入二氯甲烷至刚好溶解,再加入石油醚至有絮状物产生,置于冰箱冷冻24h,过滤得白色固体,产率86%。1H NMR(500MHz,CDCl3):δ3.61(m,4H),3.55(m,2H),3.15(m,2H),2.71(t,4H),1.82(m,4H),1.64(m,4H),1.44(s,18H),1.11~1.24(m,8H)。HR-MS(m/z):[C26H50N4O5+H]+=499.3864
2、制备化合物(R=R2,m=2)
称取化合物2.50g(5mmol)溶于50mL乙酸乙酯,置于茄形瓶,滴加浓度1.5mol/L盐酸乙酸乙酯,使反应液呈强酸性(pH=1-2),室温反应12h后,抽滤,得浅褐色固体,产率94%。将该固体溶于蒸馏水,饱和Na2CO3中和盐酸盐,萃取,得白色晶体,产率78%。1H NMR(500MHz,CDCl3):1H NMR(500MHz,CDCl3):δ3.66(m,4H),3.52(m,2H),3.14(m,2H),2.71(t,4H),1.82(m,4H),1.64(m,4H),1.11~1.24(m,8H)。HR-MS(m/z):[C26H50N4O5+H]+=299.2814
3、胺铂碘的制备(R=R2,m=2)
准备温度为120℃油浴锅和0℃冰浴锅。称取化合物0.75g(2.5mmol)溶于5mL纯净水。将20mL纯净水置于双颈瓶,在油浴锅中预热至80℃。称取K2PtCl42.08g(5mmol),直接加入双颈瓶中,搅拌使其溶解。称取KI 8.3g(50mmol),加入少量纯净水避光溶解且预热至80℃后,将其迅速加入双颈瓶并不断搅拌2.5min。迅速将双颈瓶取出,置于冰浴锅,并不断搅拌,使温度迅速下降至25℃。再将化合物的溶液缓慢滴加至双颈瓶,滴毕,将该反应置于45℃避光反应24h。抽滤,分别用纯净水、乙醚和乙醇洗涤数次,得滤饼,即为R为R2的胺铂碘,产率为91.78%。1HNMR(500MHz,CDCl3):δ4.01(m,4H),3.74(m,2H),3.42(m,2H),2.96(t,4H),2.01(m,4H),1.85(m,4H),1.22~1.36(m,8H)。IR(KBr,cm-1):v(NH)br 3407,vs(CH),vas(CH)2936,2847,vas(C-O-C)=1134,v(Pt=N)478。HR-MS(m/z):[C16H30N4OPt2I4+H]+=1191.7959(100%,1192.7964(44%),1193.7966(75%))。
4、铂配合物的制备(II)(R=R2,m=2)
a、制备铂配合物(A-5)(R=R2,m=2,Z=Z1)
称取步骤3中制备的胺铂碘0.656g(0.55mmol)置于圆底烧瓶,加入80mL纯净水溶解。将其温度为55℃,避光搅拌1h,得悬浊液,称取醋酸银0.367g(2.2mmol)加入反应瓶,并于55℃避光反应24h。抽滤,除去AgI沉淀,得黄色澄清透明溶液,减压浓缩至5mL,至于0℃冰箱过夜,抽滤,得黄色固体,产率为38.36%。1H NMR(500MHz,D2O):δ4.03(m,4H),3.75(m,2H),3.44(m,2H),2.91(t,4H),2.44(s,12H),2.01(m,4H),1.79(m,4H),1.21~1.36(m,8H)。IR(KBr,cm-1):v(NH)br 3411,vs(CH),vas(CH)2915,2834,vsh(C=O)1642,vas(C-O-C)=1108,v(Pt=N)468。HR-MS(m/z):[C24H42N4O9Pt2+H]+=920.2301(100%,921.2316(65%),922.2318(71%))
b、制备铂配合物(A-6)(R=R2,m=2,Z=Z2)
其制备方法同A-5,以一氯乙酸银替换醋酸银,即0.656g(0.55mmol)胺铂碘与0.442g(2.2mmol)一氯乙酸银替换醋酸银反应,得黄色固体,产率为34.28%。1H NMR(500MHz,H2O):δ4.52(s,8H),4.05(m,4H),3.78(m,2H),3.51(m,2H),2.97(t,4H),2.08(m,4H),1.83(m,4H),1.24~1.39(m,8H)。IR(KBr,cm-1):v(NH)br 3423,vs(CH),vas(CH)2940,2832,vsh(C=O)1655,vas(C-O-C)=1142,v(Pt=N)488。HR-MS(m/z):[C24H38N4O9Cl4Pt2+H]+=1058.0720(100%,1059.0724(65%),1060.0722(47%))
c、制备铂配合物(A-7)(R=R2,m=2,Z=Z3)
其制备方法同A-5,以庚酸银替换醋酸银,即0.656g(0.55mmol)胺铂碘与0.552g(2.2mmol)庚酸银替换醋酸银反应,得黄色固体,产率为37.47%。1H NMR(500MHz,H2O):1HNMR(500MHz,H2O):δ4.52(s,8H),4.05(m,4H),3.78(m,2H),3.51(m,2H),2.97(t,4H),2.45(t,8H)2.08(m,4H),1.83(m,4H),1.74(m,8H),1.24~1.45(m,32H),1.01(m,12H)。IR(KBr,cm-1):v(NH)br 3410,vs(CH),vas(CH)2922,2818,vsh(C=O)1615,vas(C-O-C)=1124,v(Pt=N)475。HR-MS(m/z):[C48H90N4O9Pt2+H]+=1256.6066(100%,1257.6071(42%),1258.6079(64%))
d、制备铂配合物(A-8)(R=R2,m=2,Z=Z4)
称取(3)中制备的胺铂碘0.656g(0.55mmol)置于圆底烧瓶,加入80mL纯净水溶解。将其温度为55℃,避光搅拌1h,得悬浊液。于上述溶液中加入0.1mol/L新配的硝酸银溶液22mL,50℃避光反应24h后除去碘化银沉淀。滤液中加入0.145g(2.5mmol)的氯化钠后避光50℃反应24h,得黄色固体,产率为34.28%。δ4.00(m,4H),3.72(m,2H),3.38(m,2H),2.79(t,4H),2.01(m,4H),1.79(m,4H),1.20~1.33(m,8H)。IR(KBr,cm-1):v(NH)br 3342,vs(CH),vas(CH)2901,2821,vas(C-O-C)=1077,v(Pt=N)449。HR-MS(m/z):[C16H31Cl4N4OPt2+H]+=824.0529(100%,825.0533(75%),826.0538(64%))。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也视为本发明保护范围。
以MTT法测试了本发明所得新型双核铂配合物对人体结肠癌细胞HCT-116、人肝癌细胞HEPG-2、人肺腺癌细胞A549和人乳腺癌细胞MCF-7的体外抑制作用,分别以顺铂、卡铂和/或奥沙利铂作为阳性对照。肿瘤细胞株培养及试验方法如下所述:
结肠癌细胞系HCT-116培养在含10%胎牛血清的mcCoy’s5A中,MCF-7和HEPG-2培养在10%小牛血清的RPM I 1640培养基中,培养条件为:37℃,饱和湿度,5%CO2的培养环境。细胞培养条件取对数生长期的细胞计数,调整细胞密度,每孔4000-8000个细胞。在孔板中,设加药、对照即只加细胞不加药物和调零即只加无细胞培养液三个组别。培养24小时贴壁,化合物提前溶解在DMSO或葡萄糖中,当测试时用完全培养基稀释成所需浓度,注意DMSO终浓度不能超过0.1%。每个浓度设6个复孔。加药后培养48小时,加20μl浓度为5mg/mL的MTT孵育4小时,吸去液体,加入150μl的DMSO,使甲瓒完全溶解。30min内,用酶标仪490波长测定OD值,并计算抑制率。试验平行进行3次,根据抑制率计算半数抑制率IC50值,结果列于表1中。
表1.部分双核铂配合物对HCT-116、A549、HEPG-2和MCF-7的体外抑制作用
实验结果表明,所测试的8个化合物对所选的4种癌细胞均具有一定的细胞毒性,并且部分化合物的细胞毒性高于现有药物卡铂、奥沙利铂,有成为新一代抗癌药物的潜力。
Claims (3)
1.结构式为式Ⅰ或式Ⅱ所示的以饱和链为桥的手性双核铂配合物:
其中R选自n=4-12,m=1-5;
D选自
Z选自CH3COO-、CICH2COO-、CH3(CH2)6COO-、CH3(CH2)8COO-、Cl-。
2.权利要求1所述的以饱和链为桥的手性双核铂配合物的制备方法,其特征在于按以下步骤进行:
(1)以1-N-Boc-1R,2R-环己二胺为原料,溶于无水DMF中并加入4A分子筛和氢氧化铯,然后滴入二卤代烷或二卤代醚,常温下反应12-24小时,抽滤后旋干,使用二氯甲烷/石油醚体系重结晶得到以饱和链为桥的含boc保护基的多胺配体,其中1-N-Boc-1R,2R-环己二胺与二卤代烷或二卤代醚的摩尔比为2:1,氢氧化铯的用量大于1-N-Boc-1R,2R-环己二胺的摩尔数;
其中R选自n=4-12,m=1-5;
(2)将步骤(1)制得的以饱和链为桥的含boc保护基的多胺配体加入1-1.5mol/L的盐酸乙酸乙酯中脱去boc保护基制得多胺配体的盐酸盐,将多胺配体盐酸盐溶于水,加入饱和碳酸钠溶液后使用乙酸乙酯萃取,取有机相干燥后得到以饱和链为桥的多胺配体;
其中R选自n=4-12,m=1-5;
(3)将步骤(2)制得的以饱和链为桥的多胺配体溶于水后,滴加到K2PtI4水溶液中,40-50℃反应24h,过滤,依次用冰水、乙醚和乙醇洗涤固体,真空干燥后制得胺铂碘,其中以饱和链为桥的多胺配体与K2PtI4的摩尔比为1:2;
其中R选自n=4-12,m=1-5;
(4)将胺铂碘溶于纯净水中,加热至50-60℃,称取AgZ或D(OAg)2加入溶液中,50-60℃搅拌反应2h,过滤洗涤,制得以饱和链为桥的手性双核铂配合物,其中胺铂碘与D(OAg)2摩尔比为1:2,胺铂碘与AgZ摩尔比为1:4;或在胺铂碘溶液中加入硝酸银后除去碘化银沉淀再加入氯化钠,过滤洗涤得以饱和链为桥的手性双核铂配合物,其中胺铂碘与AgNO3、NaCl的摩尔比为1:4:4;
其中R选自n=4-12,m=1-5;
D选自
Z选自CH3COO-、CICH2COO-、CH3(CH2)6COO-、CH3(CH2)8COO-、Cl-。所述二卤代烷为其中n=4-12,X为Cl或Br,二卤代醚为其中m=1-5,X为Cl或Br。
3.权利要求1所述的以饱和链为桥的手性双核铂配合物在制备抗肿瘤药物中的应用。
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