CN105452258B - 使用双核金(i)化合物用于癌症治疗的方法 - Google Patents
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Abstract
本文提供通过给予有需要的患者双核金(I)化合物来治疗癌症的方法。所述药物化合物具有抗癌活性,例如体内诱导细胞死亡、抑制细胞增殖、抑制硫氧还蛋白还原酶活性和抑制肿瘤生长。
Description
相关申请
本申请要求2012年11月19日提交的美国临时申请顺序号:61/727,972的权益,其通过引用以其整体结合到本文中。
1.引言
总的来讲,本发明涉及通过给予双核金(I)化合物来治疗癌症的方法。在某些实施方案中,所述治疗和预防癌症或肿瘤的方法与其它癌症或肿瘤治疗组合。在某些实施方案中,癌症或肿瘤治疗法是化学疗法、放射疗法、基因疗法、手术或其组合。
2.发明背景
顺铂[顺式-二氯二氨合铂(II)]治疗癌症的成功激励了科学家研发顺铂类似物[Wong, E.等, Chem. Rev.1999, 99, 2451]和其它类别的基于金属的药物[Sadler, P.J.等, J. Am. Chem. Soc.2002, 124, 3064;Sadler, P. J. Curr. Opin. Chem. Biol.2008, 12, 197]。已证实各种金(I)和金(III)化合物克服顺铂相关耐药性,并诱导不依赖DNA的细胞凋亡[Berners-Price, S. J. (2011) Gold-Based Therapeutic Agents:A New Perspective (基于金的治疗剂的新前景), 载于Bioinorganic MedicinalChemistry (编辑E. Alessio), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim,Germany. doi:10.1002/9783527633104.ch7]。然而,临床上开发金化合物作为抗癌药的主要挑战之一是克服稳定性问题。各种已报告的金(III)化合物在生理条件下,尤其在生物还原剂(例如谷胱甘肽)存在下是不稳定的。另一方面,许多已报告的金(I)化合物可在到达实体瘤组织之前与生理硫醇(例如血清白蛋白中的游离半胱氨酸)进行快速的配体交换反应。因此,发现金(I)化合物(例如金诺芬)只对白血病有效,而对其它实体瘤不显示作用[Christopher 等, Cancer Res.1985, 45, 32]。
在文献中,已报告了几种生理上稳定的单核金(I)化合物,其对于与生理硫醇的配体交换反应是相对稳定的。发现这些实例之一的[Au(dppe)2]Cl (其中dppe = 1,2-双(二苯膦基)乙烷) (其是一种含膦金(I)化合物)对生理硫醇是惰性的,并且可在体内有效地抑制肿瘤生长[Berners-Price, S. J.等, Cancer Res. 1986, 46, 5486]。然而,该化合物显示由于线粒体功能障碍而对肺、心脏和肝有严重的副作用和毒性[Berners-Price, S.J.;Filipovska, A. Metallomics2011, 3, 863]。在最新研究中,开发了另一种抗癌金(I)化合物[Au(d2pypp)2]Cl (其中d2pypp = 1,3-双(二吡啶-2-基膦基)丙烷)。该化合物相对不太亲脂,对硫醇的反应性提高,并且可靶向线粒体硫氧还蛋白还原酶(TrxR)。一项基于细胞的研究显示,[Au(d2pypp)2]Cl可在癌细胞中但不在正常细胞中选择性地诱导细胞凋亡[Berners-Price, S. J.等, Dalton Trans2007, 4943]。我们认为,可通过对膦配体的适当结构修饰,进一步提高这种化合物的抗癌活性及其生物利用度。然而,对于化学家而言策略性地修饰这种含膦化合物仍存在巨大的挑战,因为对膦的修饰相当复杂,通常要求Schlenk技术和低温(-40℃)合成。
发现一系列双核金(I)化合物[Au2(dcpm)2]2+ (其中dcpm = 双(二环己基膦基(phosphanyl))甲烷)由于Au(I)•••Au(I)吸引而是高度发光的(Che, C. -M.等, Angew. Chem. Int. Ed.1999, 38, 2783.;Che, C. -M.等, J. Am. Chem. Soc.1999, 121,4799)。发现一些双核金(I)化合物例如[Au2(dppm)Cl2] (其中dppm = 双(二苯膦基)甲烷)在癌细胞中诱导自噬(Che, C.-M.等, Chem. Commun. 2011, 47, 9318)。除膦配体以外,在制备基于金属的抗癌药时还采用N-杂环卡宾(NHC)和二硫代氨基甲酸酯配体来稳定各种金属离子(Che, C.-M.等, Chem. Commun. 2010, 46, 3893;Che, C.-M.等, Chem. Sci.2011, 2, 728;Berners-Price, S. J.;Filipovska, A.等, J. Am. Chem. Soc.2008, 130, 12570;Fregona, D.等, Int. J. Cancer.2011, 129, 487)。鉴于这些成功的抗癌先例,我们认为,含有两种不同类型的二齿配体(包括二膦和二卡宾/二硫代氨基甲酸酯)的金(I)化合物对于癌症治疗将具有巨大前景。
3. 发明概述
本文描述了通过将双核金(I)化合物给予有需要的患者来治疗癌症的方法。下面对双核金(I)化合物进行了描述。所谓治疗,是指体内诱导细胞死亡、抑制细胞增殖、抑制硫氧还蛋白还原酶(TrxR)活性和抑制肿瘤生长。所给予的双核金(I)化合物的量是用于治疗性治疗前述抗癌活性的双核金(I)化合物的有效量。金(I)化合物的有效量取决于癌症的类型和位置。
本文描述了使用双核金(I)化合物(或金(I)络合物)用于癌症治疗的方法。
在一个实施方案中,用于导致体内诱导细胞死亡、抑制细胞增殖、抑制硫氧还蛋白还原酶(TrxR)活性或抑制肿瘤生长的癌症治疗的方法包括给予有需要的患者包含有效量的双核金(I)化合物的组合物。所述双核金(I)化合物是可用I的结构式表示的本文所述的金(I)化合物或其药学上可接受的盐,
其中,
R1、R2、R3、R4各自独立地选自环己基或苯基环;
R5、R6、R7、R8、R9、R10、R11、R12各自独立地选自—H、—CH3、—C2H5、—C4H9;
A为—(CH2)m—;m为1-3范围的整数;
各个B独立地为药学上可接受的反荷离子;
a为+1至+2范围的整数;
b为-3至-1范围的整数;
y等于a/b的绝对值。
这些双核金(I)化合物的合成在室温下进行,其总收率高达90%。这些双核金(I)化合物在空气中是稳定的,对生理硫醇较少反应性。所述金(I)化合物全部都显示比临床上使用的顺铂高的抗癌活性。使用化合物1为实例,该双核金(I)化合物在动物模型中显示有前景的抗癌活性。
4.附图简述
图1A和B显示(A)双核金(I)化合物的化学结构;(B) 1的晶体结构(金(I)•••金(I)距离:3.083 Å)。
图2显示HeLa细胞用1和3处理1小时后基于细胞的TrxR活性。
图3A-B显示(A)在用5 mg/kg的1或溶剂治疗后HeLa异种移植物-裸小鼠模型的肿瘤体积(a)和体重(b)的图示;(B)不同组中小鼠的典型照片。
图4A-C显示在用15 mg/kg的1或溶剂治疗后小鼠B16-F10黑素瘤模型的(A)肿瘤体积的图示;(B)体重的图示;(C)不同组中小鼠肿瘤的典型照片。
图5A-B显示(A)在用5 mg/kg的1或溶剂治疗后携带HeLa异种移植物的小鼠的肿瘤组织中CD31的免疫组织化学检测。箭头指向CD31-阳性微血管;(B)每个显微视野微血管的平均数的图示。
图6A-C显示稳定性试验:(A)在不同时间点在PBS (含有5%乙腈,v/v)中1的UV/可见光吸收;(B) 1的ESI-MS强度与浓度的线性反应;(C) 1与GSH的反应的动力学分析,金诺芬用作参比化合物。汇总在不同时间点各10次扫描的MS强度然后除以初始浓度的预定MS强度,计算未反应的化合物百分比。
5.发明详述
公开了药用双核金(I)化合物和使用这些化合物用于癌症治疗的方法。癌症治疗意指含有用于抗癌活性的有效量的至少一种双核金(I)化合物的药物组合物,所述抗癌活性例如体内诱导细胞死亡、抑制细胞增殖、抑制硫氧还蛋白还原酶(TrxR)活性、抑制肿瘤生长。本文所述“双核金(I)化合物”是指含有两个金(I)离子且每个金(I)离子与两个二齿配体连接的分子(其可用结构式I表示)或其可接受的盐:
其中,
R1、R2、R3、R4各自独立地选自环己基或苯基环;
R5、R6、R7、R8、R9、R10、R11、R12各自独立地选自—H、—CH3、—C2H5、—C4H9;
A为—(CH2)m—;m为1-3范围的整数;
各个B独立地为药学上可接受的反荷离子;
a为+1至+2范围的整数;
b为-3至-1范围的整数;
y等于a/b的绝对值。
本文所用术语“二齿配体”是指具有2个供电子原子的一个配体。二齿配体的非限制性实例为:
。
本文所用短语“反荷阴离子”是指与带正电荷的双核金(I)化合物缔合的阴离子。反荷离子的非限制性实例包括卤素离子例如氟离子、氯离子、溴离子、碘离子;硫酸根离子;磷酸根离子;三氟甲烷磺酸根离子;乙酸根离子;硝酸根离子;高氯酸根离子;乙酰丙酮根离子;六氟磷酸根离子和六氟乙酰丙酮根离子。
在一个实施方案中,本发明涉及通过体内诱导细胞死亡、抑制细胞增殖、抑制TrxR活性、抑制肿瘤生长来治疗癌症的包含有效量的双核金(I)化合物的药物组合物。双核金(I)化合物具有式I或其药学上可接受的盐,其中,
R1、R2、R3和R4各自为环己基;
R5、R6各自为—C4H9;
R7、R8、R9、R10各自为—H;
A为—CH2—;
a为+2,和
yBb为2PF6 – (化合物1)。
在另一个实施方案中,本发明涉及通过体内诱导细胞死亡、抑制细胞增殖、抑制TrxR活性、抑制肿瘤生长来治疗癌症的包含有效量的双核金(I)化合物的药物组合物。双核金(I)化合物具有式I或其药学上可接受的盐,其中,
R1、R2、R3和R4各自为环己基;
R5、R6各自为—CH3;
R7、R8、R9、R10各自为—H;
A为—CH2—;
a为+2,和
yBb为2PF6 – (化合物2)。
在另一个实施方案中,本发明涉及通过体内诱导细胞死亡、抑制细胞增殖、抑制TrxR活性、抑制肿瘤生长来治疗癌症的包含有效量的双核金(I)化合物的药物组合物。双核金(I)化合物具有式I或其药学上可接受的盐,其中,
R1、R2、R3和R4各自为环己基;
R11、R12各自为—C2H5;
A为—CH2—;
a为+1,和
yBb为OTf– (化合物3)。
在另一个实施方案中,本发明涉及通过体内诱导细胞死亡、抑制细胞增殖、抑制TrxR活性、抑制肿瘤生长来治疗癌症的包含有效量的双核金(I)化合物的药物组合物。双核金(I)化合物具有式I或其药学上可接受的盐,其中,
R1、R2、R3和R4各自为苯基;
R11、R12各自为—C2H5;
A为—CH2—;
a为+1,和
yBb为OTf–(化合物4)。
5.1.人类治疗
5.1.1 制剂
可将本文提供的双核金(I)化合物以制剂的常规形式(例如注射剂)给予患者。可使用常规的有机或无机添加剂,例如选自填充剂或稀释剂、粘合剂、崩解剂、润滑剂、矫味剂、防腐剂、稳定剂、助悬剂、分散剂、表面活性剂、抗氧化剂或增溶剂的赋形剂,通过常用的方法制备合适的制剂。
可以选择的赋形剂对本领域技术人员而言是已知的,包括但不限于填充剂或稀释剂(例如蔗糖、淀粉、甘露糖醇、山梨糖醇、乳糖、葡萄糖、纤维素、滑石、磷酸钙或碳酸钙等)、粘合剂(例如纤维素、羧甲基纤维素、甲基纤维素、羟甲基纤维素、羟丙基甲基纤维素、聚丙基吡咯烷酮、聚乙烯吡咯烷酮、明胶、阿拉伯树胶、聚乙二醇或淀粉等)、崩解剂(例如羟基乙酸淀粉钠、交联羧甲基纤维素纳等)、润滑剂(例如硬脂酸镁、轻质无水硅酸、滑石或十二烷基硫酸钠等)、矫味剂(例如柠檬酸或薄荷脑等)、防腐剂(例如苯甲酸钠、亚硫酸氢钠、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯等)、稳定剂(例如柠檬酸、柠檬酸钠或乙酸等)、助悬剂(例如甲基纤维素、聚乙烯吡咯烷酮或硬脂酸铝等)、分散剂(例如羟丙基甲基纤维素等)、表面活性剂(例如十二烷基硫酸钠、泊洛沙姆(polaxamer)、聚山梨醇酯等)、抗氧化剂(例如乙二胺四乙酸(EDTA)、丁基化羟基甲苯(BHT)等)和增溶剂(例如聚乙二醇、SOLUTOL®、GELUCIRE®等)。本文提供的双核金(I)化合物在药物组合物中的有效量将处于可发挥所需作用的水平。
在另一个实施方案中,本文提供包含有效量的本文提供的双核金(I)化合物和药学上可接受的载体或溶媒的组合物,其中药学上可接受的载体或溶媒可包含赋形剂、稀释剂或其混合物。在一个实施方案中,组合物是药物组合物。
可配制组合物以含有呈剂量单位的日剂量或日剂量的合适分数。一般来说,按照制药化学中的已知方法制备组合物。可通过将本文提供的双核金(I)化合物与合适的载体或稀释剂混合,并将适量的混合物灌装入胶囊中,来制备胶囊剂。
5.2使用方法
可通过本文提供的方法治疗的实体瘤癌症包括但不限于肉瘤、癌和淋巴瘤。在具体的实施方案中、可按照本文所述方法治疗的癌症包括但不限于乳腺癌、肝癌、成神经细胞瘤、头癌、颈癌、眼癌、口癌、咽癌、食管癌、食管癌、胸癌、骨癌、肺癌、肾癌、结肠癌、直肠癌或其它胃肠道器官癌、胃癌、脾癌、骨骼肌癌、皮下组织癌、前列腺癌、乳腺癌、卵巢癌、睾丸癌或其它生殖器癌、皮肤癌、甲状腺癌、血癌、淋巴结癌、肾癌、肝癌、胰癌和脑癌或中枢神经系统癌。
在具体的实施方案中,本文提供的用于治疗癌症的方法抑制、减小、缩小、阻止或稳定与癌症相关的肿瘤。在其它实施方案中,本文提供的用于治疗癌症的方法抑制、减少、缩小、阻止或稳定与癌症相关的肿瘤中的血流量、代谢或水肿或其一个或多个症状。在具体的实施方案中,本文提供的用于治疗癌症的方法引起肿瘤、肿瘤血流量、肿瘤代谢或肿瘤周围水肿和/或与癌症有关的一个或多个症状消退。在其它实施方案中,本文提供的用于治疗癌症的方法保持肿瘤的大小,使得肿瘤不增大,或使得肿瘤的增大小于给予标准疗法后肿瘤的增大,如通过本领域技术人员可利用的常规方法测量,常规方法例如直肠指检、超声(例如经直肠超声)、CT扫描、MRI、动态对比增强MRI或PET扫描。在具体的实施方案中,本文提供的用于治疗癌症的方法减小肿瘤大小。在某些实施方案中,本文提供的用于治疗癌症的方法减少肿瘤形成。在某些实施方案中,本文提供的用于治疗癌症的方法根除、消除或控制与癌症有关的原发性、区域性和/或转移性肿瘤。在一些实施方案中,本文提供的用于治疗癌症的方法降低与癌症有关的转移瘤的数目或大小。
在某些实施方案中,与给予双核金(I)化合物之前的肿瘤大小(例如体积或直径)相比,本文提供的用于治疗癌症的方法减小受试者的肿瘤大小(例如体积或直径)的至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、80%、85%、90%、95%、99%或100%,如通过本领域众所周知的方法评价,所述方法例如CT扫描、MRI、DCE-MRI或PET扫描。在具体的实施方案中,与给予双核金(I)化合物之前受试者的肿瘤大小(例如直径)相比,本文提供的用于治疗癌症的方法减小受试者的肿瘤体积或肿瘤大小(例如直径)的量范围为约5%-20%、10%-20%、10%-30%、15%-40%、15%-50%、20%-30%、20%-40%、20%-50%、30%-60%、30%-70%、30%-80%、30%-90%、30%-95%、30%-99%、30%-100%或介于之间的任何范围,如通过本领域众所周知的方法评价,所述方法例如CT扫描、MRI、DCE-MRI或PET扫描。
在某些实施方案中,与给予双核金(I)化合物之前的肿瘤灌注相比,本文提供的用于治疗癌症的方法降低受试者的肿瘤灌注至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、80%、85%、90%、95%、99%或100%,如通过本领域众所周知的方法评价,所述方法例如MRI、DCE-MRI或PET扫描。在具体的实施方案中,与给予双核金(I)化合物之前的肿瘤灌注相比,本文提供的用于治疗癌症的方法降低受试者的肿瘤灌注的量的范围为约5%-20%、10%-20%、10%-30%、15%-40%、15%-50%、20%-30%、20%-40%、20%-50%、30%-60%、30%-70%、30%-80%、30%-90%、30%-95%、30%-99%、30%-100%或介于之间的任何范围,如通过本领域众所周知的方法评价,所述方法例如MRI、DCE-MRI或PET扫描。
在具体方面,本文提供的用于治疗癌症的方法抑制或降低受试者的肿瘤代谢,如通过本领域众所周知的方法评价,所述方法例如PET扫描。在具体的实施方案中,与给予双核金(I)化合物之前的肿瘤代谢相比,本文提供的用于治疗癌症的方法抑制或降低受试者的肿瘤代谢至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、80%、85%、90%、95%或100%,如通过本领域众所周知的方法评价,所述方法例如PET扫描。在具体的实施方案中,与给予双核金(I)化合物之前的肿瘤代谢相比,本文提供的用于治疗癌症的方法抑制或降低受试者的肿瘤代谢的范围为约5%-20%、10%-20%、10%-30%、15%-40%、15%-50%、20%-30%、20%-40%、20%-50%、30%-60%、30%-70%、30%-80%、30%-90%、30%-95%、30%-99%、30%-100%或介于之间的任何范围,如通过本领域众所周知的方法评价,所述方法例如PET扫描。
5.3患者群
在一些实施方案中,按照本文提供的方法接受癌症治疗的受试者是患有或被诊断患有癌症的人。在其它实施方案中,按照本文提供的方法接受癌症治疗的受试者是易患或易感癌症的人。在一些实施方案中,按照本文提供的方法接受癌症治疗的受试者是有发生癌症的风险的人。
在一个实施方案中,按照本文提供的方法接受癌症治疗的受试者是人类婴儿。在另一个实施方案中,按照本文提供的方法接受癌症治疗的受试者是人类幼儿。在另一个实施方案中,按照本文提供的方法接受癌症治疗的受试者是人类儿童。在另一个实施方案中,按照本文提供的方法接受癌症治疗的受试者是成人。在另一个实施方案中,按照本文提供的方法接受癌症治疗的受试者是中年人。在另一个实施方案中,按照本文提供的方法接受癌症治疗的受试者是老年人。
在某些实施方案中,按照本文提供的方法接受癌症治疗的受试者患有转移到身体其它区域(例如骨、肺和肝)的癌症。在某些实施方案中,按照本文提供的方法接受癌症治疗的受试者处于癌症缓解期。在一些实施方案中,按照本文提供的方法接受癌症治疗的受试者患有癌症复发。在某些实施方案中,按照本文提供的方法治疗的受试者正经受与癌症相关的一种或多种肿瘤复发。
在某些实施方案中,按照本文提供的方法接受癌症治疗的受试者是约1-约5岁、约5-10岁、约10-约18岁、约18-约30岁、约25-约35岁、约35-约45岁、约40-约55岁、约50-约65岁、约60-约75岁、约70-约85岁、约80-约90岁、约90-约95岁或约95-约100岁或之间的任何年龄的人。在一个具体的实施方案中,按照本文提供的方法接受癌症治疗的受试者是18岁以上的人。在一个特定的实施方案中,按照本文提供的方法接受癌症治疗的受试者是年龄介于1岁-18岁之间的人类儿童。在某一实施方案中,按照本文提供的方法接受癌症治疗的受试者是年龄介于12岁和18岁之间的人。在某一实施方案中,受试者是男人。在另一个实施方案中,受试者是女人。在一个实施方案中,受试者未怀孕或未哺乳的女人。在一个实施方案中,受试者是怀孕或将要/可能怀孕或正在哺乳的女性。
在一些实施方案中,在对双核金(I)化合物以外的疗法出现任何不良反应或不耐性之前,将双核金(I)化合物或其药物组合物或组合疗法给予按照本文提供的方法接受癌症治疗的受试者。在一些实施方案中,按照本文提供的方法接受癌症治疗的受试者是难治性患者。在某一实施方案中,难治性患者是对标准疗法(例如手术、放射、抗雄激素疗法和/或药物疗法例如化学疗法)不应的患者。在某些实施方案中,当癌症未被显著消除和/或一个或多个症状未被显著减轻时,癌症患者对某一疗法不应。确定患者是否是难治性的可利用在这种情况下行业公认的“难治性”含义,在体内或体外通过本领域已知的测定癌症治疗有效性的任何方法进行。在不同的实施方案中,当与癌症相关的一个或多个肿瘤不减小或增加时,癌症患者是难治性的。在不同的实施方案中,当一个或多个肿瘤转移和/或扩散到另一个器官时,癌症患者是难治性的。
在一些实施方案中,按照本文提供的方法接受癌症治疗的受试者是对用双核金(I)化合物治疗以外的疗法不应,然而不再继续这些疗法的人。在某些实施方案中,按照本文提供的方法接受癌症治疗的受试者是已接受一种或多种常规抗癌疗法(例如手术、药物疗法例如化学疗法、抗雄激素疗法或放射)的人。这些患者中有难治性患者、太年幼无法接受常规疗法的患者和尽管用现行疗法治疗仍复发肿瘤的患者。
5.4剂量
一方面,本文提供的用于治疗癌症的方法包括给予其单位剂量的双核金(I)化合物。每当确定有效时可给予剂量(例如每天一次、两次或三次、每隔一天、每周一次或两次、两周一次或每月一次)。在某些实施方案中,本文提供的用于治疗癌症的方法包括给予有需要的受试者单位剂量的双核金(I)化合物,这可通过本领域技术人员确定。
在一些实施方案中,每天一次、每天两次、每天三次;每隔一天一次、两次或三次(即隔日);每两天一次、两次或三次;每三天一次、两次或三次;每四天一次、两次或三次;每五天一次、两次或三次;每周一次、两次或三次、两周一次或每月一次将单位剂量的双核金(I)化合物或其药物组合物给予受试者,且剂量可口服给予。
5.5组合疗法
本文提供治疗癌症的组合疗法,其包括将与一种或多种另外的疗法组合的双核金(I)化合物给予有需要的受试者。在一个具体的实施方案中,本文提供治疗癌症的组合疗法,其包括将与有效量的另一种疗法组合的有效量的双核金(I)化合物给予有需要的受试者。
本文所用术语“组合”在给予双核金(I)化合物的情况下是指在给予用于治疗癌症的一种或多种另外的疗法(例如药剂、手术或放射)之前、同时或之后给予双核金(I)化合物。术语“组合”的使用不限制其中将双核金(I)化合物和一种或多种另外的疗法给予受试者的顺序。在具体的实施方案中,给予双核金(I)化合物和给予一种或多种另外的疗法之间的时间间隔可为约1-5分钟、1-30分钟、30分钟-60分钟、1小时、1-2小时、2-6小时、2-12小时、12-24小时、1-2天、2天、3天、4天、5天、6天、7天、1周、2周、3周、4周、5周、6周、7周、8周、9周、10周、15周、20周、26周、52周、11-15周、15-20周、20-30周、30-40周、40-50周、1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、12个月、1年、2年或之间的任何时段。在某些实施方案中,双核金(I)化合物和一种或多种另外的疗法的给予相隔少于1天、1周、2周、3周、4周、1个月、2个月、3个月、6个月、1年、2年或5年。
在一些实施方案中,本文提供的组合疗法包括每日给予双核金(I)化合物,并且一周一次、每2周一次、每3周一次、每4周一次、每月一次、每2月一次(例如约8周)、每3月一次(例如约12周)或每4月一次(例如约16周)给予一种或多种另外的疗法。在某些实施方案中,将双核金(I)化合物和一种或多种另外的疗法周期性给予受试者。周期性疗法包括给予双核金(I)化合物一段时间,接着给予一种或多种另外的疗法一段时间,并重复这种序贯给药。在某些实施方案中,周期性疗法还可包括休息期,其中不给予双核金(I)化合物或另外的疗法一段时间(例如2天、3天、4天、5天、6天、7天、1周、2周、3周、4周、5周、10周、20周、1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、12个月、2年或3年)。在一个实施方案中,给药的周期数为1-12个周期、2-10个周期或2-8个周期。
在一些实施方案中,本文提供的用于治疗癌症的方法包括在给予与另外的疗法组合的双核金(I)化合物之前给予作为单独药剂的双核金(I)化合物一段时间。在某些实施方案中,本文提供的用于治疗癌症的方法包括在给予与另外的疗法组合的双核金(I)化合物之前给予单独的另外的疗法一段时间。
在一些实施方案中,按照本文提供的方法给予双核金(I)化合物和一种或多种另外的疗法相对于单独给予双核金(I)化合物或所述一种或多种另外的疗法具有相加效应。在一些实施方案中,按照本文提供的方法给予双核金(I)化合物和一种或多种另外的疗法相对于单独给予所述化合物或所述一种或多种另外的疗法具有协同效应。
本文所用术语“协同的”是指给予与一种或多种另外的疗法(例如药剂)组合的双核金(I)化合物的效应,所述组合比任两种或更多种单一疗法(例如药剂)的相加效应更有效。在一个具体的实施方案中,组合疗法的协同效应允许使用较低剂量(例如亚最佳剂量)的双核金(I)化合物或另外的疗法和/或较不频繁地给予受试者双核金(I)化合物或另外的疗法。在某些实施方案中,使用较低剂量的双核金(I)化合物或另外的疗法和/或较不频繁地给予双核金(I)化合物或所述另外的疗法的能力降低与分别给予受试者双核金(I)化合物或所述另外的疗法有关的毒性,而不降低双核金(I)化合物或所述另外的疗法各自在癌症治疗中的功效。在一些实施方案中,协同效应导致双核金(I)化合物和每种所述另外的疗法在治疗癌症中的功效改进。在一些实施方案中,双核金(I)化合物和一种或多种另外的疗法的组合的协同效应避免或降低与使用任何单一疗法有关的不良或有害的副作用。
可将双核金(I)化合物和一种或多种另外的疗法的组合在同一药物组合物中给予受试者。或者,可将双核金(I)化合物和一种或多种另外的疗法以单独的药物组合物同时给予受试者。可将双核金(I)化合物和一种或多种另外的疗法以单独的药物组合物序贯给予受试者。还可通过相同或不同的给药途径将双核金(I)化合物和一种或多种另外的疗法给予受试者。
本文提供的组合疗法包括将与治疗癌症的常规或已知疗法组合的双核金(I)化合物给予有需要的受试者。用于癌症或与之有关的病况的其它疗法的目的在于控制或缓解一个或多个症状。因此,在一些实施方案中,本文提供的组合疗法包括给予有需要的受试者止痛药或目的在于缓解或控制与之有关的一个或多个症状或与之有关的病况的其它疗法。
可与双核金(I)化合物组合使用的抗癌药的具体实例包括:激素药剂(例如芳香酶抑制剂、选择性雌激素受体调节剂(SERM)和雌激素受体拮抗剂)、化学治疗剂(例如微管装配阻断剂、抗代谢药、拓扑异构酶抑制剂和DNA交联剂或损伤剂)、抗血管生成剂(例如VEGF拮抗剂、受体拮抗剂、整联蛋白拮抗剂、血管靶向剂(VTA)/血管破坏剂(VDA))、放射疗法和常规手术。
可与双核金(I)化合物组合使用的激素药剂的非限制性实例包括芳香酶抑制剂、SERM和雌激素受体拮抗剂。是芳香酶抑制剂的激素药剂可以是甾体或非甾体化合物。非甾体激素药剂的非限制性实例包括来曲唑、阿那曲唑、氨鲁米特、法倔唑和伏氯唑。甾体激素药剂的非限制性实例包括aromasin (依西美坦)、福美坦和睾内酯。是SERM的激素药剂的非限制性实例包括他莫昔芬(以Nolvadex®为商标/销售)、阿莫昔芬、阿佐昔芬、巴多昔芬、氯米芬、femarelle、拉索昔芬、奥美昔芬、雷洛昔芬和托瑞米芬。是雌激素受体拮抗剂的激素药剂的非限制性实例包括氟维司群。其它激素药剂包括但不限于阿比特龙和lonaprisan。
可与双核金(I)化合物组合使用的化学治疗剂的非限制性实例包括微管装配阻断剂、抗代谢药、拓扑异构酶抑制剂和DNA交联剂或损伤剂。是微管装配阻断剂的化学治疗剂包括但不限于紫杉烷类(taxenes) (例如紫杉醇(以TAXOL®为商标/销售)、多西他赛、abraxane、拉罗他赛、奥他赛和替司他赛);埃坡霉素(例如伊沙匹隆);和长春花属生物碱(例如长春瑞滨、长春碱、长春地辛和长春新碱(以ONCOVIN®为商标/销售))。
是抗代谢药的化学治疗剂包括但不限于叶酸抗代谢药(例如甲氨蝶呤、氨基蝶呤、培美曲塞、雷替曲塞);嘌呤抗代谢药(例如克拉屈滨、氯法拉滨、氟达拉滨、巯基嘌呤、喷司他丁、硫鸟嘌呤);嘧啶抗代谢药(例如5-氟尿嘧啶、卡培他滨(capcitabine)、吉西他滨(GEMZAR®)、阿糖胞苷、地西他滨、氟尿苷、替加氟)和脱氧核糖核苷酸抗代谢药(例如羟基脲)。
是拓扑异构酶抑制剂的化学治疗剂包括但不限于I类(喜树(camptotheca))拓扑异构酶抑制剂(例如托泊替康(以HYCAMTIN®为商标/销售)伊立替康、卢比替康和贝洛替康);II类(鬼臼(podophyllum))拓扑异构酶抑制剂(例如依托泊苷或VP-16和替尼泊苷);蒽环类(例如多柔比星、表柔比星、Doxil、阿柔比星、氨柔比星、柔红霉素、伊达比星、吡柔比星、戊柔比星和佐柔比星)和蒽二酮类(例如米托蒽醌和匹蒽醌)。
是DNA交联剂(或DNA损伤剂)的化学治疗剂包括但不限于烷化剂(例如环磷酰胺、氮芥、异环磷酰胺(以IFEX®为商标/销售)、曲磷胺、苯丁酸氮芥、美法仑、泼尼莫司汀、苯达莫司汀、乌拉莫司汀、雌莫司汀、卡莫司汀(以为BiCNU®商标/销售)、洛莫司汀、司莫司汀、福莫司汀、尼莫司汀、雷莫司汀、链佐星、白消安、甘露舒凡、曲奥舒凡、卡波醌、N,N'N'-三乙烯硫代磷酰胺、三亚胺醌、曲他胺);烷基化样剂(alkylating-like agent) (例如卡铂(以PARAPLATIN®为商标/销售)、顺铂、奥沙利铂、奈达铂、四硝酸三铂、沙铂、吡铂);非经典DNA交联剂(例如丙卡巴肼、达卡巴嗪、替莫唑胺(以TEMODAR®为商标/销售)、六甲蜜胺、二溴甘露醇)和插入剂(例如放线菌素、博来霉素、丝裂霉素和普卡霉素)。
可与金(I)络合物双核金(I)化合物立体环式卡宾配体组合给予受试者的其它疗法的非限制性实例包括:
(1) 他汀,例如洛伐他汀(例如以MEVACOR®为商标/销售);
(2) mTOR抑制剂,例如西罗莫司(亦称雷帕霉素) (例如以RAPAMUNE®为商标/销售)、坦罗莫司(例如以TORISEL®为商标/销售)、依维莫司(evorolimus) (例如以AFINITOR®为商标/销售)和deforolimus;
(3) 法呢基转移酶抑制剂,例如替匹法尼;
(4) 抗纤维化剂,例如吡非尼酮;
(5) 聚乙二醇化干扰素,例如PEG-干扰素α-2b;
(6) CNS兴奋剂,例如哌甲酯(以RITALIN®为商标/销售);
(7) HER-2拮抗剂例如抗HER-2抗体(例如曲妥珠单抗)和激酶抑制剂(例如拉帕替尼);
(8) IGF-1拮抗剂例如抗IGF-1抗体(例如AVE1642和IMC-A11)或IGF-1激酶抑制剂;
(9) EGFR/HER-1拮抗剂例如抗EGFR抗体(例如西妥昔单抗、帕尼单抗)或EGFR激酶抑制剂(例如埃罗替尼、吉非替尼);
(10) SRC拮抗剂,例如波舒替尼;
(11) 细胞周期蛋白依赖性激酶(CDK)抑制剂,例如塞利西利;
(12) Janus激酶2抑制剂,例如来他替尼;
(13) 蛋白酶体抑制剂,例如硼替佐米;
(14) 磷酸二酯酶抑制剂,例如阿那格雷;
(15) 肌苷一磷酸脱氢酶抑制剂,例如噻唑呋林;
(16) 脂加氧酶抑制剂,例如马索罗酚;
(17) 内皮素拮抗剂;
(18) 类视黄醇受体拮抗剂,例如维A酸或阿利维A酸;
(19) 免疫调节剂,例如来那度胺、pomalidomide或沙利度胺;
(20) 激酶(例如酪氨酸激酶)抑制剂,例如伊马替尼、达沙替尼、埃罗替尼、尼洛替尼、吉非替尼、索拉非尼、舒尼替尼、拉帕替尼或TG100801;
(21) 非甾体抗抗炎药,例如塞来考昔(以CELEBREX®为商标/销售);
(22) 人粒细胞集落刺激因子(G-CSF),例如非格司亭(以NEUPOGEN®为商标/销售);
(23) 亚叶酸或亚叶酸钙;
(24) 整联蛋白拮抗剂,例如整联蛋白á5â1-拮抗剂(例如JSM6427);
(25) 核因子κβ (NF-êâ)拮抗剂,例如OT-551,其还是抗氧化剂。
(26) hedgehog抑制剂,例如CUR61414、cyclopamine、GDC-0449和抗hedgehog抗体;
(27) 组蛋白脱乙酰酶(HDAC)抑制剂,例如SAHA (亦称为伏林司他(以ZOLINZA为商标/销售))、PCI-24781、SB939、CHR-3996、CRA-024781、ITF2357、JNJ-26481585或PCI-24781;
(28) 类视黄醇,例如异维A酸(例如以ACCUTANE®为商标/销售);
(29) 肝细胞生长因子/分散因子(HGF/SF)拮抗剂,例如HGF/SF单克隆抗体(例如AMG 102);
(30) 合成化学品,例如抗瘤酮;
(31) 抗糖尿病药,例如罗格列酮(例如以AVANDIA®为商标/销售)
(32) 抗疟疾药和杀阿米巴药,例如氯喹(例如以ARALEN®为商标/销售);
(33) 合成缓激肽,例如RMP-7;
(34) 血小板衍生生长因子受体抑制剂,例如SU-101;
(35) Flk-1/KDR/VEGFR2、FGFR1和PDGFR β的受体酪氨酸激酶抑制剂,例如SU5416和SU6668;
(36) 抗炎药,例如柳氮磺吡啶(例如以AZULFIDINE®为商标/销售);和
(37) TGF-β反义疗法。
6.实施例
实施例6.1:双核金(I)化合物的制备和表征
实施例1说明双核金(I)化合物的合成和表征。
一般来说,1的合成包括两个步骤,其中不需要加热和保护反应物免于氧气。可在24小时内得到产物,其总收率高(>90%)。可通过简单的重结晶得到纯产物。合成路线可描述如下:
合成详情
化合物1 [Au2-dcpm-双NHC(2C4)](PF6)2
向Au2[双NHC(2C4)])Cl2 (50 mg,0.069 mmol)的CH2Cl2 (10 mL)溶液中加入28.2mg dcpm (0.069 mmol)。在室温下搅拌3小时后,加入10 mL饱和的含NH4PF6的CH3CN,再搅拌0.5小时。然后将混合物蒸发,将固体溶于水中,并用CH2Cl2萃取。在蒸发有机层后,使固体重结晶,用热的乙醇重结晶后,得到纯的白色固体。通过将乙醚扩散到CH2Cl2/EtOH (2:1 v/v)中,得到晶体。收率:95%。1H NMR (400M, MeOD, 298 K):7.78 (d, 2 H, J = 1.6 Hz),7.49 (d, 2 H, J = 1.5 Hz), 7.06 (d, 1 H, J = 14.3 Hz), 6.23 (d, 1 H, J = 14.3Hz), 4.25 (m, 4 H), 1.36-2.60 (m, 52 H), 0.97 (t, 6 H, J = 7.4 H)。31P NMR(400M, MeOD, 298 K):50.12。MS-FAB(+):1061 (M-2PF6-1), 1207 (M-PF6), 531 ([M-2PF6]/2)。元素分析:计算值:C,35.51;H,5.22;N,4.14;实测值:C,35.21;H,5.23;N,4.19。
化合物2 [Au2-dcpm-双NHC(2Me)] (PF6)2
合成类似于化合物1。收率:60%。1H NMR (300M, MeOD, 298 K):7.76 (d, 2 H, J= 2.2 Hz), 7.44 (d, 2 H, J = 2.3 Hz), 6.74 (d, 1 H, J = 18.8 Hz), 6.28 (d, 1H, J = 19.2 Hz), 3.94 (s, 4 H), 3.1-2.8 (m, 2 H), 2.72 (m, 2 H), 2.7-1.2 (m,36 H), 0.97 (t, 6 H, J = 7.4 H)。
化合物3 [Au2-dcpm-dedt] (OTf)
向Au2(dcpm)Cl2 (50 mg,0.057 mmol)的丙酮(10 mL)溶液中加入19.4 mg二乙基二硫代氨基甲酸钠(Et2NCS2Na 3H2O,0.086 mmol,1.5当量)。在室温下搅拌过夜后,混合物经蒸发,并用水洗涤。然后将固体重新溶于CH3CN中,接着加入过量的三氟甲磺酸锂(LiOTf),再在室温下搅拌0.5小时。然后将溶液蒸发,用CH2Cl2萃取,并用CH2Cl2/Et2O重结晶。得到黄白色固体。收率:60%。1H NMR (400M, CDCl3, 298 K):3.94 (q, 4 H, J = 1.6Hz), 2.61 (t, 2 H, J = 10.9 Hz), 2.26 (m, 4 H), 2.02 (m, 8 H), 1.90 (m, 8 H),1.74 (m, 4 H), 1.52-1.20 (m, 26 H)。
化合物4 [Au2-dppm-dedt] (OTf)
与化合物3类似,合成化合物4。得到黄白色固体。收率:60%。1H NMR (400M, CDCl3,298 K):7.65 (m, 8 H), 7.32 (m, 12 H), 3.99 (q, 4 H, J = 10.9 Hz), 3.86 (t, 2H, J = 12.2 Hz), 1.41 (t, 6 H, J = 7.1 Hz)。
实施例6.2:双核金(I)化合物的体外细胞毒性
实施例2描述了体外细胞毒性,其表明了对于宫颈上皮样癌(cervicalepithelioid carcinoma)、肺癌、肝细胞癌和乳腺癌,双核金(I)化合物诱导癌细胞的细胞死亡和/或抑制癌细胞的细胞增殖。
通过MTT测定法,针对一些已确立的人癌细胞系包括宫颈上皮样癌(HeLa)、肺癌(H1950、HCC827)、肝细胞癌(HepG2)、乳腺癌(MCF-7)和人鼻咽癌(HONE1、SUNE1),测定双核金(I)化合物(1–4)的细胞毒性性质。
双核金(I)化合物的IC50值(抑制50%细胞生长72小时所需的剂量)列于表1中。所有双核金(I)化合物都显示针对这些细胞系的有前景的细胞毒性。根据IC50值,所述化合物显示与参比化合物顺铂相比类似的细胞毒性性质。
表1. 双核金(I)化合物对选定的人癌细胞系的细胞毒性IC50值(µM,孵育72小时)
实施例6.3:对于生理硫醇的反应性
实施例3描述了对于生理硫醇的反应性的结果。
认为金(I)抗癌药针对生理硫醇的高反应性可使药物无法靶向实体瘤组织,从而妨碍体内癌症治疗的应用。因此,应用高分辨ESI-MS以监测1与含硫醇的GSH的反应。
首先,记录不同浓度的1的MS强度以得到MS强度相对于浓度的线性反应,结果表明,对于1×10-6 M-3×10-6 M的浓度,1具有线性强度反应(图6)。然后使用3×10-6 M初始浓度的1与1.5×10-5 M或5×10-5 M的GSH,每1 s测量1或金诺芬的强度(参比化合物)持续约45分钟。
结果显示,对于1与GSH的反应,在45分钟后强度不显著改变(图6);表明了1在该浓度下对GSH几乎无反应。如果使用较高浓度的GSH (5×10-5 M),1也对GSH几乎无反应。作为比较,对于金诺芬(一种临床上使用的抗风湿病药,其具有良好的体外抗癌作用,但对实体瘤无作用)与GSH反应,金诺芬对GSH具有快速反应(有关详情参见图6)。
实施例6.4:基于细胞的硫氧还蛋白还原酶活性
实施例4描述了基于细胞的硫氧还蛋白还原酶活性的结果。
据报告,含有硫醇/硒醇的蛋白质,像硫氧还蛋白还原酶(TrxR),是基于金(I)的抗癌药剂的主要靶标。因此,针对所有化合物测试了基于细胞的TrxR。
一般来说,将细胞以2 × 105/孔接种在6孔板中,孵育24小时。将化合物系列稀释,并加入细胞中(最终的DMSO浓度≤ 1%)。在孵育1、3、6和9小时后,细胞用PBS洗涤3次,并将100 μl冰冷的裂解缓冲液(50 mM磷酸盐缓冲液(pH 7.4)、1 mM EDTA、0.1% Triton-X100)加入细胞层中。在冰上进行细胞溶解5分钟,收集细胞裂解物,并保存在-80℃下或立即测定。
将细胞裂解物(10 μg蛋白质)加入含有50 mM磷酸钾(pH 7.4)、1 mM EDTA和0.2mM NADPH的缓冲液(100 μl)中。5分钟后,通过加入5,5’-二硫代双(2-硝基苯甲酸) (DTNB,3 mM最终)引发反应,TrxR活性测定为10-15分钟内O.D.412 nm的增加。
结果表明,HeLa细胞用1处理1、3、6和9小时导致29.3、18.7、16.6和10.5 µM的细胞裂解物各自的TrxR活性抑制IC50。而且这与24小时的9.66 µM、48小时的3.96 µM和72小时的2.44 µM的时间依赖性细胞毒性IC50值一致。1和3的1小时处理的细胞TrxR抑制见图3。
实施例6.5:通过用双核金(I)化合物治疗的体内肿瘤生长
实施例5描述了化合物1的体内细胞毒性研究结果。
受显著的体外细胞毒性和针对生理硫醇的低硫醇反应性提示,按照教学与研究活动物使用委员会(Use of Live Animals for Teaching and Research) (香港大学)许可使用小鼠模型,对化合物1的体内抗癌性质进行初步分析。
5-7周龄雌性BALB/cAnN-nu (裸)和雌性C57BL/6小鼠购自Charles RiverLaboratories (Wilmington,MA),并按照香港大学(HKU)实验室动物单位准则护理。
为了建立HeLa异种移植物模型,通过皮下注射,将悬浮于100 μl PBS中的4 ×106个HeLa细胞接种入雌性BALB/cAnN-nu (裸)小鼠后胁。在肿瘤体积达到约50 mm3 (肿瘤接种后4天)时,把小鼠随机分成不同的治疗组(5 mg/kg的1或溶剂对照)。将络合物1在PET稀释剂(60%聚乙二醇400、30%乙醇、10% Tween 80)中复溶。通过腹膜内注射,每三天一次给小鼠注射溶于PET稀释剂中且随后稀释于PBS或补充等量PET的PBS中的络合物1,直到将小鼠处死。
为了建立小鼠黑素瘤模型,通过皮下注射将4 × 105个B16-F10黑素瘤细胞接种到雌性C57BL/6N小鼠的右后胁。在肿瘤接种后5天,将小鼠随机分成不同的治疗组(溶剂对照或15 mg/kg的1)。通过腹膜内注射,每2-3天一次给小鼠注射溶剂对照或15 mg/kg溶于PET稀释剂且然后稀释于PBS中的1,直到将小鼠处死。在两个模型中,注射入各小鼠的PET稀释剂的体积≤ 6 μl。每2-3天一次测量肿瘤大小,通过公式V = ab2 × 0.52计算肿瘤体积(V),其中a和b为异种移植肿瘤的最长和最短直径。
计算肿瘤生长抑制[1 — (V治疗— V0) / ( V对照— V0’)] × 100%,其中V治疗为治疗组的最终肿瘤体积,V0为治疗组的初始体积。V对照为溶剂对照组的最终肿瘤体积,V0’为溶剂对照组的初始体积。
结果表明,HeLa异种移植物裸小鼠模型中肿瘤生长抑制为81%,B16-F10黑素瘤小鼠模型中肿瘤生长抑制为62%。对于这两个模型,未发现小鼠死亡或体重减轻。
实施例6.6:双核金(I)化合物的体内血管生成
实施例6描述了化合物1的体内血管生成研究结果。
将小鼠肿瘤组织中CD31的免疫组织化学检测并入不同的治疗组中。所示照片以200×放大倍数拍摄。随机选择10个视野,并进行每个视野的微血管数目计数。
结果显示,与用溶剂对照治疗的小鼠相比,在用1治疗的小鼠中微血管的数目显著较低,表明了肿瘤生长抑制由抑制血管生成引起。
金(I)的剂量是抑制肿瘤生长的充足量,并且可取决于癌症的类型和癌症的位置。对于小鼠和人,该量可为约0.1 mg/kg-约100 mg/kg。优选金(I)药物的腹膜内注射、静脉内注射或直接肿瘤内注射。可获得许多药物剂型用于给予金(I)化合物。优选适于注射或输注的药物剂型包括包含金(I)的无菌含水溶液剂或分散体,或使用无菌散剂(其适于无菌可注射或可输注溶液剂或分散体的简易制备)。在所有情况下,剂型应是无菌流体,且在生产和储存条件下是稳定的。液体载体或溶媒可为溶剂或液体分散介质,包括例如水、乙醇、多元醇、植物油、无毒甘油酯及合适的混合物。
本文所描述的仅仅说明双核金(I)化合物及其活性。在不偏离本发明的范围和精神的情况下,本领域技术人员可实施其它的实施方案。
本文引用的所有参考文献均通过引用以其整体结合到本文中用于任何目的,其程度与每个出版物或专利或专利申请具体而单独指明通过引用以其整体予以结合用于所有目的一样。
Claims (15)
1.具有下式I的“双核金(I)化合物”在制备用于治疗癌症的药物中的用途,其中所述癌症是宫颈上皮样癌、肺癌、肝细胞癌、乳腺癌、黑素瘤的一种或多种,其中,
R1、R2、R3和R4各自独立地选自环己基或苯基环;
R5、R6、R7、R8、R9、R10、R11和R12各自独立地选自—H、—CH3、—C2H5、—C4H9;
A为—(CH2)m—;m为1-3范围的整数;
各个B独立地为药学上可接受的反荷离子;
a为+1至+2范围的整数;
b为-3至-1范围的整数;
y等于a/b的绝对值。
2.权利要求1的用途,其中,
R1、R2、R3和R4各自为环己基;
R5和R6各自为—C4H9;
R7、R8、R9和R10各自为—H;
A为—CH2—;
a为+2,和
yBb为2PF6 – (化合物1)。
3.权利要求1的用途,其中,
R1、R2、R3和R4各自为环己基;
R5和R6各自为—CH3;
R7、R8、R9和R10各自为—H;
A为—CH2—;
a为+2,和
yBb为2PF6 – (化合物2)。
4.权利要求1的用途,其中,
R1、R2、R3和R4各自为环己基;
R11和R12各自为—C2H5;
A为—CH2—;
a为+1,和
yBb为OTf– (化合物3)。
5.权利要求1的用途,其中,
R1、R2、R3和R4各自为苯基;
R11和R12各自为—C2H5;
A为—CH2—;
a为+1,和
yBb为OTf– (化合物4)。
6.权利要求1的用途,其中所述药物抑制细胞增殖、诱导细胞死亡、抑制TrxR活性并抑制肿瘤生长。
7.权利要求1的用途,其中“双核”意指单个分子含有两个金原子。
8.一种合成权利要求1的式I的双核金(I)化合物的方法,所述方法包括:使双NHC-Au2Cl2与双膦反应以形成式I的双核金(I)化合物。
9.一种合成权利要求1的式I的双核金(I)化合物的方法,所述方法包括:使双膦-Au2Cl2与二硫代氨基甲酸酯反应以形成式I的双核金(I)化合物。
10.权利要求6的用途,其中式I的双核金(I)化合物的给予量有效抑制细胞增殖、诱导细胞死亡、抑制TrxR活性和抑制肿瘤生长。
11.权利要求10的用途,其中式I的双核金(I)化合物的给予量为0.1 mg/kg-100 mg/kg。
12.一种具有下式I的“双核金(I)化合物”,其中
R1、R2、R3和R4各自独立地选自环己基或苯基环;
R5、R6、R7、R8、R9、R10、R11和R12各自独立地选自—H、—CH3、—C2H5、—C4H9;
A为—(CH2)m—;m为1-3范围的整数;
各个B独立地为药学上可接受的反荷离子;
a为+1至+2范围的整数;
b为-3至-1范围的整数;
y等于a/b的绝对值。
13.权利要求12的化合物,其中,
R1、R2、R3和R4各自为环己基;
R5和R6各自为—C4H9;
R7、R8、R9和R10各自为—H;
A为—CH2—;
a为+2,和
yBb为2PF6 – (化合物1)。
14.权利要求12的化合物,其中,
R1、R2、R3和R4各自为环己基;
R5和R6各自为—CH3;
R7、R8、R9和R10各自为—H;
A为—CH2—;
a为+2,和
yBb为2PF6 – (化合物2)。
15.权利要求12的化合物,其中,
R1、R2、R3和R4各自为环己基;
R11和R12各自为—C2H5;
A为—CH2—;
a为+1,和
yBb为OTf– (化合物3)。
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