CN105713047A - 一类铂(ii)配合物及其制备方法和用途 - Google Patents
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- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 claims abstract description 21
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开的是一类铂(II)配合物及其制备方法和用途，以齐墩果酸、熊去氧胆酸等活性天然产物及其衍生物为配体。是以四氯合铂酸钾在碘化钾存在的条件下与氨或(R,R)?环己二胺配位反应，再在避光条件下通过硝酸银除去碘离子，再与熊去氧胆酸或齐墩果酸或齐墩果酸衍生物的钠盐反应得到产物。上述铂(II)配合物具有良好的体外抗肿瘤活性，可以应用于制备恶性肿瘤的治疗的药物中。
Description
技术领域
本发明涉及一类以齐墩果酸、熊去氧胆酸等活性天然产物及其衍生物为配体的新型铂(II)配合物和制备方法，以及其在恶性肿瘤治疗方面的用途。
背景技术
以顺铂、奥沙利铂等为代表的抗肿瘤铂药是目前临床癌症治疗的一线药物。在多类肿瘤的化疗方案中，抗肿瘤铂药通过其单独给药或与其他抗癌药物配伍用药过程中发挥着不可或缺的作用。然而，现有铂药也存在着诸多缺陷，典型的有严重的毒副作用以及交叉耐药性。为了克服这些缺陷，研究人员设计、合成了多类非经典铂(II)配合物，如反铂、多核铂、四价铂等等。将具有生物活性的小分子作为配体与铂(II)配位形成新型配合物也是行之有效的研究策略，该类配合物有以下的特点：(1)活性小分子与铂(II)的配位键较弱，在体内条件下易于断裂释放出活性小分子，从而获得活性小分子与铂(II)配合物的协同作用，提升抗肿瘤活性；(2)由于活性小分子与铂(II)配合物的作用靶点不同，可以通过多个路径阻断肿瘤细胞的增值，因而能够有效避免肿瘤的耐药性。
熊去氧胆酸、齐墩果酸均为五环三萜类天然产物，其具有抗炎、抗病毒、抗肿瘤等广泛的生物活性，同时还有确切的保肝功能。研究发现，将一氧化氮(NO)供体如furoxan、有机硝酸酯等连接至齐墩果酸上可显著提升其抗癌特别是抗肝癌活性。
发明内容
技术问题：本发明的主要目的是提供一类铂(II)配合物及其制备方法和用途，以齐墩果酸、熊去氧胆酸以及齐墩果酸NO供体型衍生物为配体的新型铂(II)配合物，在制备恶性肿瘤治疗药物方面的应用。
技术方案：一类铂(II)配合物，以齐墩果酸、熊去氧胆酸及其衍生物为配体，结构如下：
所述的铂(II)配合物的制备方法，四氯合铂酸钾在碘化钾存在的条件下与氨或(R,R)-环己二胺配位反应后，在避光条件下通过硝酸银除去碘离子，再与熊去氧胆酸或齐墩果酸或齐墩果酸衍生物的钠盐反应得到产物。
所述的铂(II)配合物在制备治疗恶性肿瘤药物中的应用。
所述的铂(II)配合物在制备治疗肝癌、胃癌、肺癌、结肠癌药物中的应用。
有益效果：该类新型铂(II)配合物在体外对人体肝癌细胞HepG2、人体胃癌细胞SGC7901、人体肺癌细胞A549以及人体结肠癌细胞HCT-116显示出良好的体外抑制活性，且配合物对人体正常肝细胞未表现出明显毒性，表现出肿瘤选择性细胞毒性。此外，配合物3还具有温和的体外一氧化氮释放活性。上述生物活性测试结果表明本发明所披露的新型铂(II)配合物具有抗肿瘤潜在疗效。
附图说明
图1配合物3和4的NO释放活性曲线。
具体实施方式
本发明由下述实施例得到进一步说明，但这些说明并不限制本发明的实施。
本发明利用熊去氧胆酸及齐墩果酸的羧酸基团，以齐墩果酸、熊去氧胆酸或齐墩果酸NO供体衍生物为离去基团，以单氨或(R,R)-环己二胺为载体基团，设计了一系列新型铂(II)配合物，其结构如式(1)所示：
本发明的新型铂(II)配合物的制备方法为反应式(I)所示：
四氯合铂酸钾在碘化钾存在的条件下与氨或(R,R)-环己二胺配位得到中间体2或2’，然后在避光条件下通过硝酸银除去碘离子，再与熊去氧胆酸或齐墩果酸或齐墩果酸衍生物的钠盐反应得到式(1)所示的配合物。
本发明的新型铂(II)配合物的药物用途是，该类新型铂(II)配合物用于治疗恶性肿瘤，其在体外对人体肝癌细胞HepG2、人体胃癌细胞SGC7901、人体肺癌细胞A549以及人体结肠癌细胞HCT-116显示出良好的体外抑制活性。
实施例1.齐墩果酸·二氨合铂(化合物1)的制备
二碘二氨合铂(0.5g,1mmol)和硝酸银(0.3g,2mmol)溶于100ml水中，40℃下避光搅拌反应24h，过滤的澄清溶液。然后将配好的齐墩果酸钠(1.0g,2mmol)的四氢呋喃/水混合溶液加入到上述反应液中，40℃下避光搅拌反应24h，过滤，滤液浓缩至约10ml，冷却，有白色固体析出，过滤，四氢呋喃重结晶，得白色产物，收率40％。1HNMR(DMSO-d6,500MHz):δ5.30-5.28(m,2H,2CH＝C),4.20(br,6H,2NH 3),3.24-3.18(m,2H,2C3-H),2.90-2.86(m,2H,2C18-H),1.14(s,6H,2CH 3),0.99(s,6H,2CH 3),0.93(s,6H,2CH 3),0.91(s,6H,2CH 3),0.90(s,6H,2CH 3),0.78(s,6H,2CH 3),0.72(s,6H,2CH 3)cm-1；ESI-MS:1140.5[M+H]+.
实施例2.齐墩果酸·环己二胺合铂(化合物2)的制备
由二碘环己二胺合铂在硝酸银存在条件下与齐墩果酸钠盐反应制备得到，方法同实施例1，收率29％。1HNMR(DMSO-d6,500MHz):δ5.96(br,2H,NH 2),5.30-5.28(m,2H,2CH＝C),5.25(br,2H,NH 2),3.23-3.19(m,2H,2C3-H),2.91-2.86(m,2H,2C18-H),1.14(s,6H,2CH 3),0.99(s,6H,2CH 3),0.93(s,6H,2CH 3),0.91(s,6H,2CH 3),0.90(s,6H,2CH 3),0.78(s,6H,2CH 3),0.72(s,6H,2CH 3)cm-1；ESI-MS:1250.7[M+H]+.
实施例3.3-硝氧基乙酰基齐墩果酸·二氨合铂(化合物3)的制备
由二碘二氨合铂在硝酸银存在条件下与3-硝氧基乙酰基齐墩果酸钠盐反应制备得到，方法同实施例1，收率41％。1HNMR(DMSO-d6,500MHz):δ5.30-5.28(m,2H,2CH＝C),4.66(s,4H,2CH 2 ONO2),4.20(br,6H,2NH 3),3.27-3.22(m,2H,2C3-H),2.93-2.88(m,2H,2C18-H),1.15(s,6H,2CH 3),0.99(s,6H,2CH 3),0.95(s,6H,2CH 3),0.92(s,6H,2CH 3),0.90(s,6H,2CH 3),0.78(s,6H,2CH 3),0.72(s,6H,2CH 3)cm-1；ESI-MS:1346.6[M+H]+.
实施例4.3-硝氧基乙酰基齐墩果酸·环己二胺合铂(化合物4)的制备
由二碘环己二胺合铂在硝酸银存在条件下与3-硝氧基乙酰基齐墩果酸钠盐反应制备得到，方法同实施例1，收率37％。1HNMR(DMSO-d6,500MHz):δ5.96(br,2H,NH 2),5.30-5.28(m,2H,2CH＝C),5.25(br,2H,NH 2),4.66(s,4H,2CH 2 ONO2),3.23-3.19(m,2H,2C3-H),2.91-2.86(m,2H,2C18-H),1.14(s,6H,2CH 3),0.99(s,6H,2CH 3),0.93(s,6H,2CH 3),0.91(s,6H,2CH 3),0.90(s,6H,2CH 3),0.78(s,6H,2CH 3),0.72(s,6H,2CH 3)cm-1；ESI-MS:1456.7[M+H]+.
实施例5.熊去氧胆酸·二氨合铂(化合物5)的制备
制备方法同实施例1，产率42％。1HNMR(DMSO-d6,500MHz):δ4.45(m,2H,2C3-H),4.25(br,6H,2NH 3),3.88(m,2H,2C7-H),1.13(s,6H,2CH 3),0.93(s,6H,2CH 3),0.69(s,6H,2CH 3)cm-1；ESI-MS:1012.3[M+H]+.
实施例6.熊去氧胆酸·环己二胺合铂(化合物6)的制备
制备方法同实施例1，收率32％。1HNMR(DMSO-d6,500MHz):δ5.96(br,2H,NH 2),5.25(br,2H,NH 2),4.45(m,2H,2C3-H),3.88(m,2H,2C7-H),1.13(s,6H,2CH 3),0.93(s,6H,2CH 3),0.69(s,6H,2CH 3)cm-1；ESI-MS:1122.5[M+H]+.
实施例7.典型化合物的体外细胞毒性。
对配合物1-6进行了体外抗肿瘤活性测定，被筛选的细胞株有：人体肝癌细胞HepG2、人体正常肝细胞L02、人体胃癌细胞SGC7901、人体肺癌细胞A549和人体结肠癌细胞HCT-116,选用奥沙利铂为阳性对照。实验采用CCK-8试剂盒法，具体操作如下：将选用的肿瘤细胞株(100微升5000个细胞)接种于96孔板上，同时加入10μL受试化合物4‰DMSO水溶液(受试化合物浓度依次0.1，0.4，2，10，50μg/mL)进行培养。然后每孔加入10μLCCK-8溶液，在细胞培养箱内继续孵育0.5-4h。在450nm波长处测定吸光度，并计算受试化合物IC50值。测试结果见表一。
表一、配合物1-6的体外细胞毒活性
从测试结果可见，本发明的配合物均显示了较好的体外抗肿瘤活性，其中配合物3对HepG2和A549两个肿瘤细胞株的抑制活性都要优于阳性对照奥沙利铂，而对SGC7901和HCT-116两个肿瘤细胞株的抑制活性与奥沙利铂相当。并且所有配合物对人正常细胞L02均为显现出明显毒性，而奥沙利铂则表现出较强的细胞毒性，提示本发明的配合物对正常细胞毒性较小，因而具有更好的安全性。
实施例8.体外NO释放实验
应用Griess方法测试配合物3和4的NO体外释放。磺胺4g，N-萘乙烯二胺盐酸盐0.2g，85％磷酸10ml，用蒸馏水溶解并定容至100ml，配制得到Griess试剂。
标准曲线的绘制：配制0.01、0.03、0.05、0.07、0.09、0.2、0.4μg/ml的亚硝酸盐系列标准溶液，各取10ml与2.5mlGriess试剂充分混匀，室温放置10min后，与540nm测定其吸光度。并据此作标准曲线。
配合物3和4的NO释放量的测定：将测试化合物用磷酸缓冲液溶解。缓冲液中分别加有半胱氨酸(5mol/l)，将溶液置于37℃水浴，于不同是啊今年点取该溶液2ml与500μlGriess试剂混匀，室温放置8min，并在540nm处测吸收值。结果见图1。从测试结果可见，由于配合物3和4带有有机硝酸酯NO供体基团，其在体外均显示了温和的NO释放活性。在测试条件下，其在12小时左右即达到释放峰值，释放量为理论值的7％左右，配合物3的释放量略高于4。
Claims (4)
1.一类铂(II)配合物，其特征在于，以齐墩果酸、熊去氧胆酸及其衍生物为配体，结构如下：
2.权利要求1所述的铂(II)配合物的制备方法，其特征在于，四氯合铂酸钾在碘化钾存在的条件下与氨或(R,R)-环己二胺配位反应后，在避光条件下通过硝酸银除去碘离子，再与熊去氧胆酸或齐墩果酸或齐墩果酸衍生物的钠盐反应得到产物。
3.权利要求1所述的铂(II)配合物在制备治疗恶性肿瘤药物中的应用。
4.权利要求1所述的铂(II)配合物在制备治疗肝癌、胃癌、肺癌、结肠癌药物中的应用。
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