CN101631466B - 新钯络合物体外抑制n-肉豆蔻酰基转移酶活性和体内抑制癌生长 - Google Patents
新钯络合物体外抑制n-肉豆蔻酰基转移酶活性和体内抑制癌生长 Download PDFInfo
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Abstract
黑色素瘤是一种众所周知耐化疗的实体瘤，且其发病率快速增加。近年来，已经证实数种信号途径有助于黑色素瘤的肿瘤发生，包括MAP激酶、Akt和stat-3的组成激活。多个途径的激活可能部分地解释了黑色素瘤治疗的困难。在最近的化合物筛选中，发现有机钯络合物表现出对黑色素细胞显著的抗增殖活性。这种络合物，三(二亚苄基丙酮)二钯(Tris DBA)，具有体内抗B16鼠和A375人黑色素瘤的活性。Tris DBA抑制多种信号途径，包括MAP激酶、Akt、stat-3的激活以及S6激酶激活。因此，三(二亚苄基丙酮)二钯是一种新化合物，其是一类具有潜在抗肿瘤活性的贵金属络合物中的一员。Tris DBA及相关络合物的进一步临床前评估被批准。
Description
发明背景
黑色素瘤是常见的实体瘤，以其高转移率及耐化疗和放射而众所周知。多种因素可能解释黑色素瘤对现有治疗的耐受。首先，黑色素瘤源自黑色素细胞，特异性产生黑色素的专门的神经嵴细胞。黑色素的产生导致生成毒性活性氧物质和细胞毒性酚衍生物，因此黑色素细胞具有抵抗这些危害的机制。近来，已经证明作为黑色素细胞的主控转录开关的小眼畸形基因(MITF)具有抗凋亡活性，并且以高的频率在转移病灶中发现(25)(26)。第二，多重信号途径是在黑色素瘤中被激活。B-raf在多种黑色素瘤中突变，导致MAP激酶信号转导的组成激活(1，27)。N-ras在黑色素瘤中也常常发生突变，导致激活MAP激酶、磷酸肌醇-3激酶/akt信号转导以及S6激酶激活(28，29)。尽管B-raf和组成型MAP激酶激活足以引起黑色素细胞转化成黑色素瘤(3，4)、但是其他信号传导事件经常在B-raf突变型黑色素瘤中发现，所述事件例如肿瘤抑制物PTEN的丧失(29，30)。PTEN丧失的结果是磷酸肌醇-3激酶/akt激活。
已经尝试多种给药方案用于治疗局部进展和转移的黑色素瘤。几十年前最初的试验使用药物如羟基脲，更近使用的抗黑色素瘤的药物包括氮烯唑胺和基于铂的治疗(包括顺铂和卡铂)。包括生物化疗在内的其他治疗包括白细胞介素-2输注和淋巴细胞输注，该淋巴细胞存在于黑色素瘤病灶中并已被离体扩增(31)。所有这些治疗在少数患者中已取得适度的成功，但是具有显著的毒性，包括肺气漏综合征(32-36)。目前，干扰素-α用于高危患者，延长的治疗产生10％长期存活益处。
靶向治疗已经在黑色素瘤中尝试。基于观察到B-raf突变在黑色素瘤中是常见的，开发索拉非尼(Sorafenib)作为B-raf抑制剂。然而，黑色素瘤中索拉非尼的最初实验的结果令人失望(15)。还尝试了依维莫司抗人黑色素瘤，但作为单一药物尚未成功(37)。信号转导的现有知识可能解释先前的治疗失败的原因。已表明磷酸肌醇-3激酶激活介导抗凋亡的外部途径，凋亡包括由于TRAIL、TNF-α和干扰素引起的凋亡(38)。这些细胞因子的单一治疗在面对磷酸肌醇-3激酶激活时可能受挫。类似地，肿瘤浸润淋巴细胞引起的凋亡可能由于磷酸肌醇-3激酶激活而受挫。磷酸肌醇-3激酶还激活VEGF表达，并且除了刺激血管发生之外，VEGF还抑制树突细胞功能，损害对黑色素瘤的免疫反应(39-43)。
靶向MAP激酶作为黑色素瘤的单一治疗显然不足以清除大多数患者中的黑色素瘤。MAP激酶在包括缺少B-raf突变(3)在内的大多数的人黑色素瘤中被激活。在人黑色素瘤的先前研究中，发明人证实一亚类进展性黑色素瘤具有降低的MAP激酶激活，这意味着另外的信号转导途径是体内起作用的。这一假设的进一步支持是发明人先前的发现，用抗氧化剂治疗EBV-诱导的伯基特淋巴瘤导致代偿的MAP激酶激活(17)。使用索拉非尼治疗黑色素瘤患者导致非MAP激活途径的代偿激活是有可能的。类似地，已经证明由于雷怕霉素及衍生物的mTOR抑制导致代偿性Akt激活(44)。
Tris-DBA具有的益处是其抑制黑色素瘤的肿瘤生成所需的多个途径，包括MAP激酶激活、磷酸肌醇-3激酶/akt激活、stat-3激活和S6激酶激活。这些途径参与基本上人肿瘤的所有形式以及自身免疫性疾病如狼疮、湿疹(特应性皮炎)、哮喘、银屑病和关节炎。虽然没有药物作为黑色素瘤的单一治疗可能完全有效，但是Tris-DBA在小鼠中有很好的全身耐受，并且同其他临床所用的化学治疗药相比具有新的活性特征。其抑制磷酸肌醇-3激酶激活的能力可能增强最佳活性需要akt失活的细胞因子的活性，并且可能增强其他化疗药的活性。Tris-DBA还可以增强索拉非尼的活性，该增强通过阻断由于MAP激酶阻断而可能体内存在的代偿信号来实现。发明人的研究提供Tris-DBA在恶性黑色素瘤治疗中进一步研究的理论。
发明概述
黑色素瘤是最常见实体瘤之一，而且众所周知难以治疗。近来，多种信号途径的组成激活已经在黑色素瘤中证实。许多黑色素瘤在B-raf中具有突变，其引起MAP激酶的组成激活(1，2)。甚至不携带激活的B-raf的黑色素瘤证实MAP激酶的激活，并且激活的MAP激酶激酶的组成表达足以将黑色素细胞转化成黑色素瘤(3-5)。已知在进展期黑色素瘤中被激活的其他途径包括磷酸肌醇-3激酶/akt和核因子κB(NFκB)(6-10)。所有这些途径给予黑色素瘤存活和增殖的优势，例如诱导血管源性因子，该血管源性因子包括血管内皮生长因子、白细胞介素-8、存活素、IAP和mcl-2(11-13)。
铂化合物是多种实体瘤治疗方案的支柱，特别是睾丸癌。然而，还表明包括顺铂和卡铂在内的铂化合物在黑色素瘤中具有活性，并被引入黑色素瘤治疗方案中(14)。其他抑制剂如索拉非尼、B-raf抑制剂虽然强有力的抑制B-raf，但是对于具有B-raf突变的黑色素瘤具有适中的作用(15)。这可能归因于侵袭性肿瘤转换信号转导途径的能力(16)。在伯基特淋巴瘤中观察到这一现象，其中当NFκB下调(17)时MAP激酶激活。类似地，使用万珂抑制NFκB在黑色素瘤具有适中的功效(18，19)。
在发明人对血管发生抑制剂的筛选中，已经鉴定结构类似姜黄素和查耳酮的小分子钯络合物，姜黄素和查耳酮是具有已知化学预防活性的化合物(20，21)。尽管化学预防剂是有效的抗小鼠和人中癌前病变药，但是它们对已经建立的肿瘤是较少有效的(22，23)。因此，我们研究这种新的钯络合物并发现其具有体内抗黑色素瘤的活性。Tris DBA的进一步临床前研究得到批准。
附图说明
图1：三(二亚苄基丙酮)二钯体外抑制血管发生。三(dba)二钯在浓度5μg/ml和10μg/ml时降低SVR细胞生存力超过90％。对照是采用载体、DMSO。各柱形代表三份实验的平均值，误差柱反映了平均值的标准误差。
图2：使用磷酸化形式的MAPK、Akt(a)、p70 S6激酶(b)、Stat-3(c)进行的蛋白质印迹分析。用10μg/ml三(二亚苄基丙酮)二钯处理的B16和A 375细胞在T1、T2、T4、T8、T24时的蛋白质印迹分析。将细胞裂解并使用特异性用于非磷酸化形式的MAPk、磷酸化形式的MAPk、Akt、p70-S6激酶和Stat3的抗体进行分析。使用单克隆抗β微管蛋白抗体，将微管蛋白用作上样对照。
图3：用10μg/ml三(二亚苄基丙酮)二钯处理的B16和A375细胞降低VEGF mRNA(对于18S RNA校正)的水平。显示的柱形表示三份实验的平均值，误差柱表示平均值的标准误差。
图4：三(dba)二钯体内对黑色素瘤的作用。六只小鼠注射1000000的B16，六只小鼠注射A375细胞，并腹膜内注射三(dba)二钯及载体对照。继发于对照动物中肿瘤负荷，将动物在第15天处死。以上照片表示A 375组中每一个的平均肿瘤负荷，并用图表描述肿瘤体积(mm3)。误差柱表示平均值的标准误差。
图5：三(dba)二钯对于肉豆蔻酰基转移酶活性的作用。Tris dba钯是有效的NMT-1抑制剂，具有大约1微摩尔的抑制浓度(IC50)。
发明详述
以下术语将应用于整个说明书以描述本发明。
术语“患者”在整个说明书中用于描述对其提供用本发明的化合物治疗的动物，优选人，所述治疗包括预防治疗。对于那些对于特定的动物如人患者所特有的感染、病症或疾病状态的治疗，术语患者指的是特定的动物。在大多数实例中，术语患者指的是人患者。
术语“有效量”在整个说明书中用于描述本发明化合物的浓度或量，该浓度或量在治疗的疾病或病症中可用于产生良好的改变，不论该改变是缓解、降低癌症的生长或大小、肿瘤或其他生长，有益的生理学结果包括皮肤或组织的清洁等，其取决于治疗的疾病或病症。
术语“血管发生”在整个说明书中用于描述导致生物体中血管形成或组织中血管形成增加的生物学过程。关于本发明，术语血管发生定义作这样的过程，即通过该过程肿瘤或其他快速增殖组织通过微血管产生获得血液供给。
术语“肿瘤”用于描述组织中异常生长，其在细胞增殖快于正常组织时存在并在启动新生长停止的刺激之后继续生长。肿瘤通常显示出部分或完全缺乏正常组织的结构组成和功能协调，通常形成良性的(良性肿瘤)或恶性的(癌)显著量的组织。肿瘤趋向于高度血管化。术语“癌”在此用作一般术语用于描述恶性肿瘤或癌。这些恶性肿瘤可以侵入周围组织，可以转移至多个部位，以及在尝试除去之后可能复发，并且如果不充分治疗造成患者死亡。如在此所用，术语癌是包含在术语肿瘤中。
术语“血管源性疾病”、“血管源性病症”以及“血管源性皮肤病症”在整个说明书中用于描述作为组织中血管化增加的结果发生的或导致组织中血管化增加的病症，通常是皮肤病症或相关病症。经常地，血管源性疾病的病因是未知的。然而，不论血管发生是疾病状态的实际原因还是疾病状态的病症是不重要的，而在治疗或逆转疾病状态或病症中抑制血管发生是本发明的重要方面。可使用本发明的化合物治疗的血管源性皮肤疾病的实例包括，例如银屑病、痤疮、酒渣鼻、疣、脂溢性皮炎、湿疹(特应性皮炎)、血管瘤和淋巴管生成，以及其他，包括斯德奇-韦伯综合征、神经纤维瘤病、结节性硬化症、慢性炎症性疾病和关节炎。具有原发性和继发性特征、增加的血管化的任何皮肤疾病被认为是用于本发明目的的血管源性皮肤疾病并且可采用本发明的化合物治疗。
术语“酒渣鼻”用于描述痤疮酒渣鼻或红斑痤疮，其特征在于涉及鼻和面颊的连续部分的血管和小囊扩张。酒渣鼻可以从非常轻微但是持久的红斑变成皮脂腺的广泛增生且具有深在的丘疹和脓疱并伴有受侵袭的红斑部位的毛细管扩张。也称为增生性酒渣鼻或肥大性酒渣鼻，取决于病症的严重程度。
术语“疣”用于描述皮肤上小的，通常硬的肿瘤样生长物。疣也称为瘊，是皮肤的肉色生长物，其特征在于真皮乳头的局限性肥大，表皮的生发层、颗粒形成层和角质层增厚。寻常疣是疣或瘊的亚类，其特征在于人乳头瘤病毒感染角质形成细胞。
术语“银屑病”用于描述皮肤病症，其特征在于局限性的、离散的和融合性的出疹、淡红色的银色鳞状斑丘疹，病灶主要发生于肘、膝、头皮和躯干，显微镜下显示特征性的角化不全和网嵴的延伸。
术语“痤疮”用于描述皮肤的病症，其特征在于涉及分泌皮脂的器官的炎性滤泡、丘疹和小脓疱的出疹。尽管存在多种形式的痤疮，但是最常见的形式已知是单纯性痤疮或寻常痤疮，其特征在于脸部、背和胸的上部出疹，主要包括炎症基础上的粉刺、囊肿、丘疹和脓疱。该病症主要发生在青春期和青少年期，由认为是受激素活性影响的过于活跃的分泌皮脂的器官所导致。
术语“湿疹”是用于描述皮肤的急性或慢性炎性病症的一般术语，典型的是红斑的、水肿性、丘疹的、泡状的和起痂，之后通常有苔藓样变和脱皮，有时有红斑变黑，不常有色素沉着过多。湿疹通常伴有瘙痒和灼烧的感觉。湿疹小囊泡是由表皮内棘细胞层水肿形成。湿疹有时俗称皮疹、干性湿疹和鳞屑性湿疹。存在湿疹的大量亚类，其全部通过本发明的一种或多种化合物治疗。湿疹的另一个术语是特应性皮炎。
本发明的化合物用于治疗良性和恶性肿瘤，包括多种癌症如颈部、肛门和口腔癌、胃、结肠、膀胱、直肠、肝、胰、肺、胸、子宫颈、子宫体、卵巢、前列腺、睾丸、肾、脑/中枢神经系统(cns)(例如，胶质瘤)、头颈、眼或眼睛、咽喉、皮肤黑色素瘤、非黑色素瘤皮肤癌和癌前病变(包括基底细胞癌、鳞状细胞癌和光化性角化病)、急性淋巴细胞性白血病、急性髓细胞性白血病、尤因氏肉瘤、卡波西氏肉瘤、基底细胞癌和鳞状细胞癌、小细胞肺癌、绒毛膜癌、横纹肌肉瘤、血管肉瘤、血管内皮瘤、肾母细胞瘤、成神经细胞瘤、口/咽、食管、喉、肾和淋巴瘤等等。此外，可以用本发明的化合物有效地治疗例如神经纤维瘤病、结节性硬化症(各个病症产生皮肤的良性肿瘤)、血管瘤和淋巴管生成等等病症。
本发明的治疗肿瘤和/或癌症的方法包括向需要其的患者给药有效量的本发明的一种或多种化合物。
使用一种或多种公开的组合物治疗血管源性皮肤病症的方法是本发明的其他创造性方面，所述病症包括银屑病、痤疮、酒渣鼻、疣和湿疹，以及其他，包括斯特奇-韦伯综合征及相关病症。此外，本发明的化合物也可以用于治疗皮肤的静脉性溃疡。这些方法包括向需要处理或治疗的患者给药有效量的至少一种本发明的化合物。
本发明进一步的创造性方面涉及在治疗关节炎和慢性炎症性疾病中使用本发明的组合物，所述病症包括风湿性关节炎和骨关节炎等，包括狼疮和硬皮病。这些方法也涉及向需要处理或治疗的患者给药有效量的本发明的至少一种化合物。
本发明进一步的方面涉及在HIV治疗中所考虑的组合物的应用。HIV蛋白nef的活性需要肉豆蔻酰化。
本发明的组合物包括与具有已知化学预防活性的姜黄素和查耳酮具有结构相似性的小分子钯络合物。特别地，本发明考虑三(二亚苄基丙酮)二钯及包含这种化合物的组合物。
本发明的组合物还包括类姜黄素(curcuminoid)和查耳酮的钯络合物。所述类姜黄素和查耳酮是众所公知的并已经描述在文献中，所述文献包括Bowen等人的美国专利公开号2005/0148599，Snyder等人的美国专利公开号2004/0176384及美国专利号6,673,843、6,664,272和6,462,075，其全部在此引入作为参考。
基于这些新化合物的药物组合物包括上述用于治疗病症或疾病治疗有效量的化合物，任选与药学可接受的添加剂、载体或赋形剂组合，所述病症或疾病例如瘤形成包括癌、血管源性皮肤疾病或炎症性疾病或有关病症或疾病。
某些药用剂型的化合物可以用作防止疾病或病症本身显露的预防药。在某些药用剂型中，可以优选本发明的化合物的前药形式。
包括这些药物的前药形式在内的本发明的化合物及其衍生物可以药学可接受的盐的形式提供。如在此所用，术语药学可接受的盐或络合物指的是本发明的活性化合物的适合的盐或络合物，其保持母体化合物的期望的生物活性并显示了对于正常细胞的有限的毒性作用。这种盐的非限制性实例是(a)与无机酸(例如，盐酸、氢溴酸、硫酸、磷酸、硝酸等)形成的酸加成盐及与有机酸如乙酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、双羟萘酸(pamoic acid)、藻酸和多聚谷氨酸等形成的盐，(b)与金属阳离子如锌、钙、钠、钾等形成的碱加成盐，以及其他。
活性化合物的修饰可能影响活性物质的溶解度、生物利用度和代谢速率，因此对活性物质的递送提供控制。进一步，修饰可能影响化合物的抗血管发生活性，在某些情况下，增加超过母体化合物的活性。这可以通过制备该衍生物并根据本领域常规技术内的已知方法试验其活性来容易地评估。
本发明的化合物可以掺入制剂中用于全部给药途径，包括例如口服、局部和肠胃外包括静脉内、肌内、眼或眼睛、腹膜内、口内、透皮和栓剂形式。
基于这些新化学化合物的药物组合物包括用于治疗疾病治疗有效量的上述化合物，任选与药学可接受的添加剂、载体和/或赋形剂组合，所述疾病指瘤形成、癌和本文描述的其他疾病和病症，包括银屑病、静脉性溃疡、痤疮、酒渣鼻、疣、湿疹、血管瘤、淋巴管生成和慢性炎症性疾病包括关节炎等等。本领域普通技术人员将认识到，治疗有效量的本发明的一种或多种化合物将随待治疗的感染或病症、其严重程度、所用治疗方案、所用药物的药代动力学以及治疗的患者(动物或人)变化而不同。
在本发明的药用方面，本发明的化合物优选与药学可接受的载体、赋形剂或添加剂混合配制。通常，优选以口服给药形式给药所述药物组合物，但是对于大量病症的治疗而言，多种其他制剂可以通过局部、肠胃外、静脉内、肌内、经皮、口含、皮下、栓剂或者包括眼或眼睛途径在内的其他途径给药。静脉内和肌内制剂优选以无菌盐水给药。当然，本领域普通技术人员可以在说明书教导内改变制剂以提供多种用于特定给药途径的制剂，而不会使本发明的组合物不稳定或损害其治疗活性。特别地，例如，赋予本发明的化合物在水或其他载体中更稳定的修饰可以容易地通过本领域技术人员熟知的较小的修饰(形成盐、酯化等)来实现。改变具体化合物的给药途径和给药方案以便控制本发明化合物的药代动力学以对患者具有最大的益处是本领域技术人员熟知的。
药学可接受的盐形式可以是用于包含入本发明的药物组合物中的本发明化合物的优选化学形式。
包含在本发明治疗活性制剂中的化合物的量是用于治疗感染或病症的有效量。通常，剂型中本发明优选化合物的治疗有效量范围是略微小于约0.025mg/kg至约2.5g/kg，优选约2.5-5mg/kg至约100mg/kg患者或高得多，取决于所用的化合物、治疗的病症或感染以及给药途径，不过此剂量范围之外的可以由本发明考虑。以其最优选的形式，本发明的化合物的给药量范围是约1mg/kg至约100mg/kg。当药物递送是全身而不是局部时，这个剂量范围通常产生的活性化合物的有效的血液水平浓度范围是少于约0.04微克/cc至约400微克/cc或患者中更多的血液。
活性化合物的给药可以是连续的(静脉内滴注)至每天多次口服给药(例如，Q.I.D.)，可以包括口服、局部、眼或眼睛、肠胃外、肌内、静脉内、皮下、经皮(其可以包括渗透增强剂)、口含和栓剂给药，在其他给药途径中包括通过眼或眼睛途径。
为了制备本发明的药物组合物，根据常规药物复合技术将本发明的治疗有效量的一种或多种化合物优选与药学可接受的载体充分混合，以产生剂量。载体可以采用广泛的多种形式，取决于期望给药的制剂形式，例如口服、局部或肠胃外包括凝胶、乳膏、软膏、洗剂和缓释可植入制剂，等等。在口服剂型的药物组合物的制备中，可以使用任何常用的药物介质。因此，对于液体口服制剂如混悬剂、酏剂和溶液，适合的载体和添加剂包括水、二醇类、油类、醇类、调味剂、防腐剂、着色剂等可以使用。对于固体口服制剂如散剂、片剂、胶囊剂以及对于固体制剂如栓剂而言，适合的载体和添加剂包括淀粉、糖载体如葡萄糖、甘露糖醇、乳糖和相关载体、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可以使用。如果需要，片剂或胶囊剂可以通过标准技术包肠溶衣或缓释。
对于肠胃外制剂而言，载体将通常包括无菌水或氯化钠水溶液，不过可以包括其他成分，该其他成分包括有助于分散的成分。当然，当要使用无菌水并保持无菌时，组合物和载体也必须无菌。也可以制备可注射的混悬剂，在该情况下可以使用适合的液体载体、助悬剂等。
本发明的化合物可以用于治疗动物作为患者，特别是哺乳动物，包括人。因此，患有肿瘤尤其是癌症或本文所述的其他疾病的人和其他动物特别是哺乳动物可以通过向患者给药有效量的本发明的一种或多种化合物或其衍生物或药学可接受的盐治疗，任选在药学可接受的载体或稀释剂中，单独地或与其他已知的药物组合(取决于待治疗的疾病)。根据本发明的治疗也可以联合其他常规癌症治疗法如放疗或手术给药。
所述活性化合物以这样的量包含在药学可接受的载体或稀释剂中，所述量足以递送给患者对于期望的适应症治疗有效的量而没有在治疗的患者中引起严重的毒性作用。
所述化合物以适合的单位剂型便于给药，包括但不限于每单位剂型包含1-3000mg优选5-500mg活性成分的那种。10-250mg的口服剂量通常是方便的。
所述药物组合物中活性化合物的浓度将取决于药物的吸收、分布、失活和排泄速率以及本领域技术人员已知的其他因素。应当注意，剂量值也将随要改善的病症的严重程度而变化。进一步应理解，对于任何具体患者，特定的给药方案应当根据个体需要和管理或监督给药组合物的人的专业判断随时间调整，并且本文提出的浓度范围仅仅是示例性的不意欲限制所保护的组合物的范围或实践。所述活性成分可以一次给药，或者可以分成多个较小剂量以在变化的时间间隔给药。
口服组合物通常将包含惰性稀释剂或食用载体。它们可以包封在明胶胶囊中或压制成片剂。为口服治疗给药的目的，活性化合物或其前药衍生物可以掺合赋形剂并以片剂、锭剂或胶囊剂的形式使用。可以包含药学上相容的粘合剂和/或助剂物质作为组合物的一部分。
片剂、丸剂、胶囊剂、锭剂等可以包含任何以下成分或类似性质的化合物：粘合剂如微晶纤维素、黄蓍树胶或明胶；赋形剂如淀粉或乳糖、分散剂如海藻酸或玉米淀粉、润滑剂如硬脂酸镁、助流剂如胶态二氧化硅、甜味剂如蔗糖或糖精；或者调味剂如薄荷油、水杨酸甲酯或橙味调味剂。当单位剂型是胶囊剂时，除了以上类型的物质之外其可以包含液体载体如脂肪油。此外，单位剂型可以包含改变剂量单位的物理形式的各种其他物质，例如糖、虫胶或肠溶衣剂。
所述活性化合物或其药学可接受的盐也可以作为酏剂、混悬剂、糖浆剂、薄膜剂(wafer)、口香糖等的组分给药。除了所述活性化合物之外，糖浆剂可以包含作为甜味剂的蔗糖或果糖以及某些防腐剂、颜料和着色剂和调味剂。
所述活性化合物或其药学可接受的盐也可以与不损害期望作用的其他活性物质混合，或者与增强期望作用的物质混合，所述物质例如其他抗癌剂，以及在某些情况下取决于期望的治疗或目的，与抗生素、抗真菌药、抗炎药、抗病毒化合物或具有不同药理学作用的其他药剂混合。
用于肠胃外、皮内、皮下或局部施用的溶液或混悬剂可以包括以下成分：无菌稀释剂如注射用水、盐水溶液、不挥发性油、聚乙二醇、甘油、丙二醇或其他合成溶剂；抗菌剂如苯甲醇或对羟苯甲酸甲酯；抗氧化剂如抗坏血酸或亚硫酸氢钠；螯合剂如乙二胺四乙酸；缓冲剂如醋酸盐、柠檬酸盐或磷酸盐以及张力调节剂如氯化钠或葡萄糖。肠胃外制剂可以包封在玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。如果静脉内给药，优选的载体包括，例如生理盐水或磷酸盐缓冲盐水(PBS)。
在一个实施方案中，所述活性化合物用保护该化合物免于从身体快速消除的载体制备，如控释制剂，包括植入剂和微囊递送系统。可以使用生物可降解的、生物相容的聚合物如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯类和聚乳酸。制备这些制剂的方法对于本领域技术人员而言是清楚的。
脂质体悬浮液也可以是药学可接受的载体。这些也可以根据本领域技术人员已知的方法制备。例如，脂质体制剂可以通过将适合的脂质溶解在无机溶剂中，随后蒸发，在容器表面留下干燥脂质的薄膜来制备。然后将所述活性化合物的水溶液引入容器中。然后，将容器用手动漩涡以使容器边上不含脂质材料并分散脂质聚集物，借此形成脂质体混悬液。本领域技术人员熟知的其他制备方法也可以用于本发明的这个方面。
被本领域技术人员所接受的大量的生物学测定法已经使用来评估本发明化合物的抗肿瘤和抗癌活性。这些方法中的任何一种可以用于评估本文公开的化合物的活性。
评估活性的一种常见方法是通过使用癌细胞系的试验组。这些试验评估癌细胞系中特定化合物的体外抗癌活性，并提供关于试验化合物体内使用的预测性数据。其他测定法包括体内评价化合物对于人的作用，或者在例如使用小鼠肿瘤细胞植入或移植到小鼠上等适宜的动物模型中的作用，或者在其他适宜的动物模型中的作用。
在试验本发明化合物的抗血管源性/抗癌活性的情况下，可以应用基于SVR细胞的测定。参见例如Arbiser等人，J Am Acad Derm，925-929页(1999年6月)。在该测定法中，将SVR细胞接种在24孔皿上，并用本发明的化合物以已知的浓度进行处理，所述SVR细胞来自根据Arbiser等，Proc Natl AcadSci USA 1997，94：861-6的方法依次引入SV40大T抗原和活化的H-ras的原代鼠内皮细胞。计数细胞数并与对照相比较。由获得的数据容易地测定百分比抑制率。也可以使用本领域熟知的其他方法。
实施例
细胞
B16细胞(鼠黑色素瘤细胞)在Dulbeccos改良的Eagle培养基(1000mg葡萄糖/L，Sigma-Aldrich，St.Louis，MO)中培养，所述培养基补充有10％胎牛血清、L-谷氨酰胺(14ml/L)和抗生素/抗真菌剂(14ml/L，Sigma-Aldrich)的。A375细胞(鼠黑色素瘤细胞)在Dulbeccos改良的Eagle培养基(4500mg葡萄糖/L，Sigma-Aldrich，St.Louis，MO)中培养，所述培养基补充有10％胎牛血清、L-谷氨酰胺(14ml/L)及抗生素/抗真菌剂(14ml/L，Sigma-Aldrich)。
实施例1：细胞增殖测定
为了评估三(二亚苄基丙酮)二钯作为血管发生抑制剂的效力，使用SVR细胞进行增殖测定，SVR细胞是建立的血管发生鼠模型(24)。根据Arbiser实验室先前所述的方法进行该测定法。将1万个SVR细胞/孔铺板在24-孔板中。在37度和5％CO2下培养24小时之后，细胞用5μg/mL或10μg/mL的三(二亚苄基丙酮)二钯或对照量的DMSO处理。处理来自溶解在DMSO中的10mg/ml三(二亚苄基丙酮)二钯原液。细胞允许培养另外的48小时，然后计数(图1)。发现，用三(dba)二钯处理48小时显著地降低了活细胞数。5μg/ml浓度的三(二亚苄基丙酮)二钯导致细胞数减少97％，而10μg/ml浓度导致减少92％(图1)。
实施例2：蛋白质印迹分析
我们试图测定三(二亚苄基丙酮)二钯在鼠黑色素瘤模型中抑制MAPK、Akt的程度以及在人黑色素瘤模型中抑制pStat3、PS6激酶的程度。
为了检查此效果，使用B16黑色素瘤细胞测试10μg/ml的三(dba)二钯对于MAPK和Akt信号转导途径的作用。为信号转导分析，将未处理的和在时间间隔用10μg/ml三(二亚苄基丙酮)二钯处理的B16细胞在NonidetP-40裂解缓冲液(1％Nonidet P-40、150mM NaCl、10％甘油、20mM HEPES、1mM苯基甲基磺酰氟、2.5mM EDTA、100μM Na3VO4和1％抑肽酶)中裂解。将裂解物在微量离心机中离心，去掉沉淀。通过Bradford测定法使用BSA作为标准测定上清液的蛋白浓度。样品用Laemmli样品缓冲液处理，加热至90℃持续5分钟，然后进行SDS-PAGE(National Diagnostics，Atlanta，GA)，转移至硝酸纤维素膜。然后，膜用在10mM Tris/0.1％Tween 20/100mMNaCl中的5％脱脂乳粉封闭，接着与p42/44MAP激酶抗体、磷酸化-p44/42MAP激酶(Thr202/Tyr204)抗体、磷酸化-Akt(Ser-473)和磷酸化-p70S6激酶(Thr421/Ser424)抗体(Cell Signaling Laboratories，Beverly，MA)一起温育。单克隆抗-β-微管蛋白抗体(目录编号TO198，Sigma)用作上样对照并使用辣根过氧化物酶结合的二抗检测。通过增强的化学发光(Amersham Biosciences)肉眼观测免疫反应带。如Lin等人(45)所述进行蛋白质印迹分析(图2A和2B)。
发明人发现三(二亚苄基丙酮)二钯抑制两个下游的磷酸化形式(图2a)。发明人进一步测试了三(dba)二钯对人黑色素瘤细胞系的作用，并发现其抑制S6激酶下游的磷酸化形式(图2b)，并在比处理24小时之后更短的时间区间(1和4小时)下调磷酸化-Stat-3(图2c)。
实施例3：用于用载体对照和10μg/ml三(二亚苄基丙酮)二钯处理的B16细胞和A375细胞中的VEGF的定量RT-PCR及所述VEGF
进行RT-PCR以确定三(二亚苄基丙酮)二钯是否体外抑制鼠和人黑色素瘤细胞中VEGF表达。
B16细胞和A 375细胞各自相同地接种在2T-25烧瓶中，24小时之后用在DMSO中的0和10μg/ml三(二亚苄基丙酮)二钯(Aldrich 328774)处理24小时。提取RNA，使用TRIZOL(Sigma T 9424)纯化，并使用分光光度计(Perkin-Elmer UV/VIS)测量。使用1μg的RNA用于DNase Amplification(脱氧核糖核酸酶扩增)(Invitrogen，目录号18068-015)，接着使用用于RT-PCR的First-Strand Synthesis(第一链合成)(Superscript，目录号12371-019)。96-孔光学反应板(ABI PRISM，代码128)用于RT-PCR反应。已经在交联水中稀释成1∶10的2.5μl模板用于各孔，并且实验一式三份进行。将Vegfa(AppliedBiosystems，Taqman Gene Expression Assay，Mm00437304_ml)和18S(AppliedBiosystems Taqman Gene Expression Assay，Hs99999901_sl)引物与交联分子级水(Cellgro)和通用混合试剂(master mix)(Applied Biosystems TaqMan FastUniversal PCR Master Mix(2X))一起使用。反应在用于96孔板的绝对定量7500 Applied Biosystems Reader下开始。通过ΔΔCt方法分析Ct值，并计算平均值的标准误差(图3)。
当测试10μg/ml三(dba)二钯对于B16细胞上VEGF表达时，发现同对照相比VEGF表达减少60％。进一步测试10μg/ml的相同化合物对于A 375细胞的作用，发现同对照相比VEGF表达减少80％(图3)。
实施例4：体内肿瘤生长
使用鼠黑色素瘤模型和人黑色素瘤模型进行实验以测定三(二亚苄基丙酮)二钯是否体内抑制黑色素瘤。
为了测定在体外抑制VEGF、磷酸化形式的MAPK、Akt、Stat 3和p-70S6激酶的化合物是否将体内影响黑色素瘤形成，小心地将1百万B16细胞皮下注入六只裸鼠，并将1百万A 375细胞皮下注入六只裸鼠。开始两天之后，小鼠接受每周三次腹膜内注射三(二亚苄基丙酮)二钯或对照。1mg/小鼠的三(dba)二钯悬浮于0.3ml花生油中，对照仅仅是0.3ml花生油。作为治疗的结果，在任何裸鼠中既没有观察到局部毒性也没有观察到全身毒性。两周时间内共计给予六次注射，之后，因对照组中无法抵抗肿瘤负荷，将小鼠处死。继发于对照动物中的肿瘤负荷，将动物在第15天处死。图表示有对照的两组中各组的平均肿瘤体积(mm3)(图4)。误差棒表示平均值的标准误差。
当使用B16鼠黑色素瘤模型时，同对照相比，采用载体对照和三(二亚苄基丙酮)二钯腹膜内治疗产生97.46％的肿瘤体积减少。在A 375人黑色素瘤模型中，同对照相比，肿瘤体积减少65.67％(图4)。作为治疗的结果，在任何裸鼠中既没有观察到局部毒性也没有观察到全身毒性。
实施例5：N-肉豆蔻酰基转移酶测定
[3H]肉豆蔻酸(39.3Ci/mmol)从NEN Life Science Products获得。假单胞菌(Pseudomonas)酰基CoA合成酶和辅酶A从Sigma-Aldrich Canada获得。基于cAMP-依赖性蛋白激酶的II型催化亚单位的NH2-末端序列的肽(GNAAAAKKRR)从Alberta Peptide Institute，University of Alberta，Edmonton，Canada获得。重组体人NMT的表达和纯化按照以前所述(46)进行。NMT活性按照以前所述(47，48)测量。对于标准酶测定而言，反应混合物在25μl的总体积内含有0.4μM[3H]肉豆蔻酰-CoA、50mM Tris-HCl，pH 7.8、0.5mMEGTA、0.1％Triton X-100、500μM合成肽和作为NMT来源的细胞溶解产物。通过加入放射标记的[3H]肉豆蔻酰-CoA开始反应，并在30℃下孵育10-30分钟。通过将等分部分的孵育混合物点样在P81磷酸纤维素纸盘上并在暖气流下干燥来终止反应。P81磷酸纤维素纸盘用三次40mM Tris-HCl，pH 7.3洗涤90分钟。使用Beckman液体闪烁计数器(Beckman Liquid ScintillationCounter)在7.5ml的Beckman Ready Safe Liquid Scintillation混合物中定量放射性。一个单位的NMT活性表示为形成1pmol的肉豆蔻酰基-肽/min/mg蛋白。NMT1抑制测定使用不同的化合物根据以前描述的方法(48)进行。
实施例6：三(二亚苄基丙酮)二钯是N-肉豆蔻酰基转移酶的抑制剂。
A 375人黑色素瘤细胞的基因芯片分析揭示，用三(二亚苄基丙酮)二钯处理下调了N-肉豆蔻酰基转移酶1。因为n-肉豆蔻酰基转移酶是激活上游激活剂包括stat-3所需的，我们假定抑制n-肉豆蔻酰基转移酶活性可能导致作为下游结果的n-肉豆蔻酰基转移酶信使水平的减少。因此，测试了三(二亚苄基丙酮)二钯作为NMT抑制剂的活性。观察到有力的抑制活性，EC50为1μM(图5)。
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Claims (3)
1.包含有效量的小分子钯络合物的组合物在制备用于治疗黑色素瘤的药物中的用途，其中所述小分子钯络合物包含三(二亚苄基丙酮)二钯。
2.根据权利要求1的用途，其中，所述黑色素瘤选自：胃黑色素瘤、结肠黑色素瘤、膀胱黑色素瘤、直肠黑色素瘤、肝黑色素瘤、胰黑色素瘤、肺黑色素瘤、乳腺黑色素瘤、子宫颈黑色素瘤、子宫体黑色素瘤、卵巢黑色素瘤、前列腺黑色素瘤、睾丸黑色素瘤、肾黑色素瘤、脑/中枢神经系统黑色素瘤、头颈黑色素瘤、咽喉黑色素瘤和皮肤黑色素瘤。
3.包含有效量的小分子钯络合物的组合物在制备用于抑制血管发生的药物中的用途，其中所述小分子钯络合物包含三(二亚苄基丙酮)二钯。
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| US87551706P | 2006-12-18 | 2006-12-18 | |
| US60/875,517 | 2006-12-18 | ||
| PCT/US2007/087741 WO2008076965A1 (en) | 2006-12-18 | 2007-12-17 | Novel palladium complexes inhibit n-myristoyltransferase activity in vitro and cancer growth in vivo |
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| SK288437B6 (sk) | 2013-04-26 | 2017-01-03 | Univerzita Komenského v Bratislave | Paládnaté komplexy kurkumínu a jeho analógov a spôsob ich prípravy |
| EP3325662B1 (en) | 2015-07-17 | 2023-08-30 | Pacylex Pharmaceuticals Inc. | Epigenetic silencing of nmt2 |
| EP3793525A4 (en) * | 2018-05-16 | 2022-02-16 | Emory University | HYALURONIC ACID AND PALLADIUM PARTICLES AND METHODS FOR MANAGING CANCER OR ANGIOGENIC CONDITIONS |
| TWI738156B (zh) * | 2019-12-24 | 2021-09-01 | 國防醫學院 | Ｔｒｉｓ ＤＢＡ醫藥組合物及其用於自體免疫疾病之用途 |
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| US5463093A (en) * | 1993-11-26 | 1995-10-31 | Garnett; Merrill | Palladium complexes and methods for using same in the treatment of tumors or Psoriasis |
| AU728515B2 (en) * | 1995-09-28 | 2001-01-11 | Redox Pharmaceutical Corporation | Metal complexes as cysteine protease inhibitors |
| US6673843B2 (en) * | 1999-06-30 | 2004-01-06 | Emory University | Curcumin and curcuminoid inhibition of angiogenesis |
| CA2393440A1 (en) | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogs with anti-tumor and anti-angiogenic properties |
| WO2001046110A2 (en) * | 1999-12-23 | 2001-06-28 | The University Of Georgia Research Foundation, Inc. | Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states |
| BR0204160A (pt) * | 2002-08-30 | 2004-06-01 | Fundacao De Amparo A Pesquisa | Composto ciclopaladado, composição e unidade de dosagem, seus usos, método para inibir a atividade de proteìnas e enzimas e método de tratamento de distúrbios ou doenças associadas às mesmas e método de modulação do sistema imunológico |
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| FURNESS M S ET AL.Antiangiogenic agents:Studies on fumagillin and curcumin analogs.《current pharmaceutical design 2005》.2005,第11卷(第3期),357-373. * |
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| EP2099305B1 (en) | 2015-07-15 |
| HK1137622A1 (zh) | 2010-08-06 |
| EP2099305A4 (en) | 2010-04-28 |
| WO2008076965A1 (en) | 2008-06-26 |
| US8030299B2 (en) | 2011-10-04 |
| CN101631466A (zh) | 2010-01-20 |
| IL198942A (en) | 2015-08-31 |
| IL198942A0 (en) | 2010-02-17 |
| CA2670837C (en) | 2016-03-29 |
| US20100076076A1 (en) | 2010-03-25 |
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