CN1512982A - 可作为治疗剂和诊断剂的新多胺类似物 - Google Patents

可作为治疗剂和诊断剂的新多胺类似物 Download PDF

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CN1512982A
CN1512982A CNA018105106A CN01810510A CN1512982A CN 1512982 A CN1512982 A CN 1512982A CN A018105106 A CNA018105106 A CN A018105106A CN 01810510 A CN01810510 A CN 01810510A CN 1512982 A CN1512982 A CN 1512982A
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polyamines
derivative
cell
group
analogue according
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N��M��J��������
N·M·J·弗穆林
�´���
C·L·奥戴
��Τ����˹
H·K·韦伯
M·R·伯恩斯
D·E·伯格斯特龙
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MEDICAST THERAPY CO Ltd
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Abstract

本发明揭示了一类新的抑制多胺转运的“双多胺”化合物。此类化合物可作为药物通过抑制多胺转运蛋白或其他多胺结合蛋白来治疗诸如癌症和血管成形术后损伤等疾病。此类化合物适用于诊断、研究和治疗。

Description

可作为治疗剂和诊断剂的新多胺类似物
技术领域
本发明属于化学和生物化学领域，涉及新的多胺转运(PAT)抑制剂类化合物的合成和用途，所述用途包括药学用途或农业用途，作为探针用于生物化学试验或用于纯化选定多胺的结合性靶分子的用途。作为药物，此类化合物可单独或结合诸如多胺合成抑制剂等其他药物用于治疗与细胞恶性增殖相关的疾病，原发性癌症等疾病。
本发明还涉及可作为化合物文库组成部分的所述新多胺类化合物的合成和用途。此类文库可用于发现抑制PAT和/或结合细胞多胺转运蛋白(PATr)的组合物。此类文库中的各成员或用此类文库发现的化合物均可用作药物、农用化学品或探针。
背景技术
多年来对于多胺、腐胺、亚精胺和精胺在细胞活动中之生物活性的研究证明它们在生命活动中起着复杂而重要的作用(Cohen，S.S.，“有关多胺”1998，牛经大学出版社，纽约)。它们在生理pH下为聚阳离子，可与所有阴离子细胞组分紧密结合并调节其活性。已经发现，DNA和RNA与与之结合的染色质蛋白(Tabor，H等，1，4-二氨基丁烷(腐胺)、亚精胺和精胺，Ann.Rev.Biochem.，1976，45，285-306；Matthews，H.R.，多胺、染色质结构与转录，BioEssay，1993，15，561-566)之间存在特异性的强烈相互作用。已知，精胺可直接作为游离基清除剂保护DNA免受反应性氧的侵害(Ha，H.C.等，Proc.Natl.Acad.Sci.USA，1998，95，11140-11145)。最近发现聚阳离子形式的多胺与微管之间也存在特异性相互作用(Wolf，J.，寡聚阳离子对微管组装的促进作用：带电基团间的协作性，生物化学，1998，37，10722-10729；Webb，H.K.等，J.Med.Chem.，1999，在印)。已发现包括乙酰胆碱酯酶在内的膜结合酶类具有变构调节活性(Kowworotow，A.等，多胺类对于膜结合乙酰胆碱酯酶的调节作用，生物化学杂志，1974，144，21-27)。多胺对许多神经递质受体和离子通道具有直接影响(Carter，C.，多胺的神经药学，1994，AcademicPress，San Diego，CA；Williams，K.，多胺与离子通道之间的相互作用，生物化学杂志，1997，325，289-97)。NMDA受体复合物的特异性多胺结合位点也已被发现(Ransom，R.W.等，L-谷氨酸盐(酯)、甘氨酸和多胺对于[3H]MK-801与N-甲基-D-天冬氨酸盐(酯)受体-铁离子通道复合物之间结合作用的协同调节，J.Neurochem，1988，51，830-836；Williams，K.等，微观观察：多胺对于NMDA受体的调节，Life Sci.，1991，48，469-498)。
正常和瘤形成性生长过程中的许多刺激因素会激活多胺生物合成路径。大量跨学科研究显示：在多胺生物合成、代谢和转运过程的许多步骤，其细胞内浓度受到高度调控。细胞内包含着严密调控此类分子水平的复杂机制这一事实表明：此类分子的浓度只允许极其窄幅的波动。鸟氨酸脱羧酶(ODC)是多胺生物合成中的限速酶，它催化由鸟氨酸前体产生腐胺。该酶的生物学半寿期很短，是已知的最典型诱导型哺乳动物酶之一(Russell，D.等，生长旺盛组织中的胺合成：大鼠肝脏、鸡胚胎和各种肿瘤再生中的鸟氨酸脱羧酶活性。美国科学院院报，1968，60，1420-1427)。细胞生长中的许多刺激因素都被证明可诱导此酶，而且，ODC诱导具有独特的促生长作用(Alhonen-Hongisto，L.等，埃利希腹水-癌细胞的致肿瘤性，细胞表面糖蛋白改变和鸟氨酸脱羧酶基因方式。生物化学杂志，1985，229，711-715)。目前已确认，ODC活性增强与肿瘤生长之间存在关联(Jame，J.等，多胺与迅速生长和癌症。生物化学与生理学学报，1978，473，241-493)；Scalabrino，G.等，多胺与哺乳动物肿瘤，第一部分。癌症研究，1981，35，151-268；Scalabrino，G.等，多胺与哺乳动物肿瘤，第二部分。癌症研究，1982，36，1-102)。ODC-抗酶蛋白可介导对ODC活性的反馈抑制。当多胺浓度升高时会发生ODC-抗酶蛋白读码框的+1移码，于是引起ODC抑制性蛋白水平升高(Hayashi，S.等，鸟氨酸脱羧酶抗酶蛋白：一类新的调节蛋白。TIBS，1996，21，27-30；Matsufuji，S.等，EMBO杂志，1996，15，1360-1370)。ODC抗酶蛋白与ODC以高亲和性结合，形成无活性复合物，该复合物然后被26S蛋白体以ATP依赖性方式分解(Heller，J.S.等，美国科学院院报，1976，73，1858-62；Murakami，Y.等，26S蛋白体特异性地分解鸟氨酸脱羧酶。自然，1992，360，597-99)。ODC-抗酶蛋白还抑制细胞的多胺吸收系统(Suzuki，T.等，过量产生鸟氨酸脱羧酶的细胞内抗多胺异常累积和毒性的酶保护，美国科学院院报，1994，91，8930-34)。
多胺代谢路径对于防止过量多胺的细胞毒性作用具有重要意义(Seiler，N.，多胺乙酰化的作用，加拿大生理学与药物学杂志，1987，65，2024-35；Seiler，N.，多胺氧化酶，特性与功能。大脑研究进展，1995，106，334-44)。细胞利用这一路径进行各种多胺的相互转化，避免过量多胺到达毒性水平。该路径不向多胺循环引入新的碳前体。
多胺向哺乳动物细胞内部的转运依赖于能量和温度，是可饱和的，由载体介导，并逆高浓度梯度运行(Seiler，N.等，哺乳动物细胞内的多胺转运。世界生物化学杂志，1990，22，211-18；Khan，N.A.；Quemener，V.等，多胺转运路径的描述，多胺的神经药物学Carter，C主编)，1994，Academic，San Diego，pp.37-60)。大量实验证明：多胺浓度的动态平衡由该转运系统介导。生长刺激引起的多胺需求改变将反映为转运活性的升高。用血清或表皮生长因子刺激人成纤维细胞增殖令腐胺的吸收提高了18-100倍(DiPasquale，A.等，表皮生长因子刺激人成纤维细胞培养物内腐胺的转运和鸟氨酸脱羧酶活性。实验细胞研究，1978，116，317-323；Pohjanpelto，P.，开始增殖的人成纤维细胞内的腐胺转运活性显著升高。细胞生物学杂志，1976，68，512-20)。已证明，肿瘤的腐胺吸收速度加快(Volkow，N.等，以标记的腐胺作为探针用于脑肿瘤内。科学，1983，221，673-75；Moulinoux，J-P.等，循环多胺在肿瘤学中的生物学意义。细胞分子生物学杂志，1991，37，773-83)。用α-二氟甲基鸟氨酸(DFMO)—一种作用机制清楚的ODC抑制剂—抑制细胞培养物中多胺的生物合成引起细胞内腐胺和亚精胺的显著减少，并最终导致细胞生长抑制。向培养基中补加外源多胺后，上述减少令多胺转运活性提高了数倍(Bogle，R.G.等，内皮多胺吸收：L-精氨酸缺乏或多胺缺乏的选择性刺激。美国生理学杂志，1994，266，C776-C783；Alhonen-Hongisto，L.等，胞内腐胺缺乏诱导自发的多胺和甲基乙二醛双(脒基腙)的吸收。生物化学杂志，1980，192，941-945)。于是，细胞生长速度恢复正常。
有不少证据支持这样的结论，即，干扰多胺转运可更有效地提高ODC抑制的效率。一种突变L1210白细胞系被证明在经甲基乙二醛双(脒基腙)(MGBG)抗性选择后的多胺转运活性大大降低，MGBG是一种高细胞毒性AdoMetDC抑制剂，它与多胺由同一转运系统吸收。与接受母细胞系接种的小鼠(22％的存活时间中值升高)相比，接受此类突变细胞接种的小鼠对DFMO处理的应答性明显更高(87％的存活时间中值升高；40个小鼠中有13个痊愈)。参见Persson，L.等，d，1，2-二氟甲基鸟氨酸对携多胺吸收缺陷型突变L1210白细胞小鼠的治疗效果。癌症研究，1988，48，4807-11。胃肠道内微生物群是产生细胞外多胺的重要源头(Sarhan，S.等，胃肠道是促进肿瘤生长的多胺的来源。抗癌研究，1989，9，215-24)。当通过清除这些微生物群而消除了这一多胺源头后，DFMO对Lewis肺癌细胞或L1210异种移植物(zenografts)的前述中度生长抑制作用显著增强(Hessels，J.等，饮食中多胺和精氨酸的限制和胃肠道内腐胺的合成增强了α-二氟甲基鸟氨酸对携L1210细胞小鼠的细胞生长抑制。对多胺的生物化学和临床学研究世界学会，Sorrento(Italy)，1988，摘要，P105)。多胺的另一来源是饮食(Bardocz，S.等，食物中的多胺；对于发育和健康的影响。生物化学与营养学杂志，1993，4，66-71)。与单用DFMO处理相比，给经DFMO处理的裸鼠饲以无多胺饮食，所含的MCF-7人乳房癌异种移植物显著降低腐胺的水平(Leveque，J.等，胃肠道多胺源头缺失体内增强MCF-7人乳房癌细胞内DFMO诱导的多胺减少。抗癌研究，1998，18，2663-68)。在其他动物模型中，多胺的完全缺失也增强DFMO的生长抑制作用(Moulinoux，J.P.等，多胺缺乏对裸鼠体内U-251人神经胶质瘤生长的抑制。抗癌杂志，1991，11，175-180；Quemener，V.等，多胺缺乏增强化学治疗的抗肿瘤效果。抗癌杂志，1992，12，1447-54；Chamaillard，L.等，多胺缺乏可预防肿瘤引起的免疫抑制。英国癌症杂志，1997，76，365-70)。
多胺转运蛋白(PATr)
迅速的生长、转化的癌细胞需要更多的多胺，但合成速度的提高只能部分满足这样的需求。为了利用这种多胺需求的增加，一直以来都在寻找其合成的抑制剂。此外，多胺浓度的降低会引起染色质结构异常，从而导致细胞死亡或细胞增殖抑制(Quemener，V.等，抗癌研究，14：443-448，1994；Porter，C.W.等，癌症研究，53：581-86，1993)。目前越来越清楚的是，早前使用多胺合成抑制的临床结果令人失望是因为一种特异性活性转运系统发生了补偿性的转运活性增强(Seiler，N.等，世界生物化学杂志，22：211-218，1990；Sieler，N.等，生物化学和细胞生物学杂志，28：843-61，1996)。在细胞培养物中，使用鸟氨酸脱羧酶的自杀性底物型抑制剂α-二氟甲基鸟氨酸(DFMO)或S-腺苷甲硫氨酸脱羧酶抑制剂甲基乙二醛基双(脒基腙)(MGBG)获得了很有希望的结果，但尚未转到人类临床试验(Schecter，P.J.等，多胺合成代谢的抑制，生物学意义和新的治疗方法的基础；McCann，P.P.等编，1987，345-64)。由于将碳引入多胺循环仅有的两条途径是合成和转运，本发明构想：同时抑制这两条路径将是一种很有希望的抗癌治疗方法。
验证这一化学治疗方法可行性的一项研究使用移植了PAT缺陷型L1210白细胞的小鼠。移植了野生型L1210癌细胞(PAT健全)的小鼠即使接受DFMO处理，仍在12天后死亡。相比之下，移植PAT缺陷型L1210细胞的经DFMO处理小鼠则可或60天以上(Ask，A.等，癌症杂志，66：29-34，1992)。该论文的作者还证明：用(1)DFMO+(2)低多胺饮食+(3)抗生素(降低消化道微生物的多胺产生)联合处理携野生型L1210细胞的小鼠，结果，其存活时间比单用DFMO处理长。
增强癌细胞内的PAT可促进细胞的死亡。J.L.Holley等(癌症研究，52：4190-95，1992)证明，瘤可宁-亚精胺偶合物的细胞毒性比瘤可宁本身高225倍。许多硝基咪唑-多胺偶合物也同样有效(Holley，J.L.等，生物化学与生理学，43：763-69，1992)。其他研究证明，感染了疟疾多药物抗性株的小鼠可用氯喹啉-腐胺偶合物来治疗(Singh，S.等，生物学与化学杂志，272，13605-11，1997)。因此，细胞毒性化合物的效力可用它们与多胺的偶合物来增强。这样的效果可能是因为PAT系统被用来将这些化合物传递到癌细胞内部。
已经克隆了大肠杆菌的多胺转运蛋白基因，最近还克隆了酵母的(Kashiwagi，K.等，生物学化学杂志，1990，265，20893-97；Tomitori，H.等，一种酵母多胺转运蛋白基因的鉴定。生物学化学杂志，1999，274，3265-7)。哺乳动物该转运蛋白的基因尚有待鉴定。已结晶获取了大肠杆菌的转运蛋白，并测定了其X射线结构(Sugiyama，S.等，大肠杆菌多胺转运系统的主要受体，PotD的晶体结构，生物学化学杂志，1996，271，9519-25)。该结构代表数量尚少但越来越多的已知亚精胺结合性蛋白质结构的一种。由于该结构是原核生物的，因此它被认为对于涉及哺乳动物转运抑制剂来说价值有限。尽管如此，在对该结构的分析中已获得并运用了数种发现。除了如所预料存在着位于适当位置以便与亚精胺的质子化氨基形成盐桥的羧酸残基之外，还有大量芳族残基—尤其是色氨酸残基—可增强与底物的众多亚甲基基团之间的疏水相互作用。此外，亚精胺底物的一端有一个H2O分子，在该位置提供与离子残基间更强的相互作用。
许多研究者还研究了多胺类似物抑制细胞吸收3H-亚精胺的能力。Bergeron及其同事研究了在亚精胺或精胺类似物的末端氮原子上添加不同烷基取代基的影响(Bergeron，R.J.等，多胺类似物的抗增殖特性：结构-活性研究。医学化学杂志，1994，37，3464-76)。他们发现大烷基会降低类似物抑制吸收放射性标记亚精胺的能力。此后，他们得出结论：随着氮原子之间亚甲基数量的增加，竞争3H-亚精胺吸收的能力下降(Bergeron，R.J.等，亚精胺和精胺类抗癌药物之间结构-活性关系的比较。医学化学杂志，1997，40，1475-94)。对本发明来说更重要的是他们的以下结论：多胺转运只需要三个阳离子中心用于多胺识别和转运(Porter，C.W.等，癌症研究杂志，1984，44，126-8)。有两个研究组用CoMFA法和QSAR法(Li.Y.等，L1210细胞内多胺转运抑制剂的结构-功能关系的基于分子领域比较分析的预示模型。癌症研究，1997，57，234-9；Xia，C.Q.等，L1210细胞内对多胺转运抑制剂的QSAR分析，药物靶向杂，1998，6，65-77)对文献中多胺类似物抑制L1210细胞3H-亚精胺摄取的例子进行了分析。
多胺转运(PAT)试验
目前尚没有高处理量的测定PAT的试验方法。目前用一种放射性化学试验被用来进行转运的生物化学分析，并用于研究酵母和多种哺乳动物细胞内的PAT(Kakinuma，Y.等，生物化学和生物物理学研究通讯，216：985-992，1995；Seiler，N.等，世界生物化学细胞生物学杂志，28：843-861，1996)。见，例如，Huber，M.等的癌症研究，55：934-43，1995。
放射性检测试验采用放射性标记的腐胺、亚精胺或精胺等多胺，但是，由于信号弱，需要大量粘附性或非粘附性细胞。采用精胺时还需要格外小心，因为它与细胞和塑料的吸附是没有特异性的。试验开始时，将细胞与待测化合物和带放射性标记的多胺混合。根据细胞类型，培养1-60分钟。去除培养基并将培养板冷却至4℃以终止试验。然后用冷的培养基洗涤细胞三次，溶于0.1％的十二烷基硫酸钠，然后通过闪烁计数法测定溶液的放射性。由于放射性标记的信号很弱，而且，放射性方法在操作上存在着固有的限制，该试验难以放大为高处理量的方法。
最近，在蜘蛛、黄蜂等节肢动物的毒液中发现了大量多胺酰胺类天然产物。已发现，这些酰基多胺类似物与昆虫的神经肌肉连接点(junctions)之间具有特异性的强相互作用(Moya，E.等，节肢动物多胺酰胺类毒素的合成和神经药学特性。多胺的神经药学(Carter，C.等)，1994，Academic，San Diego，PP.167-184)。这些毒素的这一能力使得这些昆虫猎杀者能够将它们的猎物麻痹或将其杀死。大多数此类天然产物具有共同的分子特征，即通过酰胺键与芳族氨基酸结构类似物连接的多胺部分(许多具有结构不同的多胺类似物)。曾经试图寻找更简单的合成类似物，以期获得与甲壳类神经肌肉神经键或哺乳动物谷氨酸盐(酯)受体之间的最强相互作用(Asami，T.等，酰基多胺模拟Joro蜘蛛毒素(JSTX)对甲壳类肌肉谷氨酸盐(酯)受体的作用。生物医学研究，1989，10，185-189；Raditsch，M.等，多胺类蜘蛛毒素与哺乳动物N-甲基-D-天冬氨酸盐(酯)受体。欧洲生物化学杂志，1996，240，416-26；Tsubokawa，H.等，蜘蛛毒素及其类似物对缺血后谷氨酸盐(酯)激活的Nippocanpal CAI神经元内的电流的作用，神经物理学杂志，1995，74，218-25)。
引用以上文献并非指认以上都是相关的现有技术。以上给出的文献日期或其中内容都是基于申请人现有的信息，并不确保其准确性。
发明概述
本发明涉及多种多胺类似物及其衍生物，以及它们作为药物、农用制剂或环保制剂的用途。本发明明确了这些化合物内与膜(和可溶)蛋白—尤其是PATr—结合相关的关键位点和结构。
本发明的组合物包括在一个或多个位置取代的多胺衍生物。单取代多胺的取代宜发生在末端氮原子上，但也可以发生在内部的氮原子和/或碳原子上，或在末端氮原子和内部氮原子和/或碳原子上都有。
优选实施方式之一是一种可用作抗癌化学治疗剂的特异性PAT抑制剂。此类抑制剂包含两条相互连接的线性多胺的多胺衍生物。这两条多胺可以相同也可以不同，并可以在一个内部碳原子和/或氮原子上含取代。较好的是，各多胺的一个末端位置用于连接。另一末端也可以含取代。
优选的取代基是能够增强所述化合物与多胺结合性分子—例如PATr、酶或DNA—结合亲和力或增强结合不可逆性的结构。此类结构包括：氮丙啶基团和多种其他脂族、芳族、脂族-芳族混合、或杂多环结构。不可逆地与PATr或其他多胺结合性分子结合的反应性部分—例如氮丙啶—也包括在本发明范围内。与亲核基团反应形成共价键的反应性基团的例子包括氯乙酰胺，溴乙酰胺和碘乙酰胺，磺酰氟，酯，氮芥等。此类反应性部分可在诊断或研究中被用于亲和性标记，并可作为药物内抑制PAT或多胺合成的位点促进药学活性。所述反应性基团可以是一个反应性光亲和性基团，例如叠氮基或苯甲酮基团。用于光亲和性标记的化学试剂是本领域所熟知的(Flemming，S.A.，Tetrahedron，51：12479-520，1995)。用于治疗癌症的光反应性化合物也是本领域所已知的。
更具体地说，本发明的多胺类似物或衍生物包括与分子内多胺结合位点结合并且/或者抑制多胺转运的化合物，它具有以下结构式：
                            R1-X-R2
其中，R1和R2各自为多胺，或其类似物或衍生物；X是连接两多胺的连接基。
多胺类似物或衍生物(宜在末端之一具有一反应性基团)也可用于试验或用作生物化学探针。
所述类似物或衍生物(含有或没有报道基团)的多胺部分可包含的取代基是能够提高结合亲和力或增强与多胺结合性分子—例如PARr、酶或DNA—结合不可逆性的结构。此类结构包括氮丙啶基团和多种其他脂族、芳族或杂多环结构。
也可以考虑能够与PATr或其他多胺结合性分子的反应性部分，例如氮丙啶。可与亲核基团反应形成共价键的基团例如：氯乙酰胺，溴乙酰胺和碘乙酰胺，磺酰氟，酯，氮芥等。此类反应性部分可在诊断或研究中被用于亲和性标记，并可作为药物内抑制PAT或多胺合成的位点促进药学活性。所述反应性基团可以是一个反应性光亲和性基团，例如叠氮基或苯甲酮基团。用于光亲和性标记的化学试剂是本领域所熟知的(Flemming，S.A.，Tetrahedron，51：12479-520，1995)。用于治疗癌症的光反应性化合物也是本领域所已知的。
对本发明的多胺类似物和衍生物可按多种方法分类。一类多胺类似物和衍生物是双多胺，即包含彼此相连的两个相同或不同多胺。优选实施方式中，所述多胺基团都呈线型，各自具有两个末端氨基。此类多胺可以天然多胺为例，例如腐胺，亚精胺和精胺。各多胺可用各自的一个末端氨基相互连接，另一末端氨基则可以保持游离，或形成衍生物。
可连接成双多胺的多胺的例子包括：N1-丹酰基精胺(又称一丹酰基精胺或MDS( 1)，N1-丹酰基亚精胺(又称一丹酰基亚精胺或MDSd，N1-[(N6-丹酰基)-6-氨基辛酰基]精胺(即DACS， 4)，N1-[(N6-丹酰基)-6-氨基辛酰基]亚精胺(即DACSd)，N1-[(N6-5-(4-氯苯甲酰氨基甲基)噻吩-2-磺酰基)-6-氨基辛酰基精胺 5，或N1-[(N6-(2-二苯并呋喃基磺酰基)-6-氨基辛酰基]精胺 6。
可连接成双多胺的多胺还包括N1-酰基氨基酸-精胺共轭物，这包括天然和非天然的精胺与氨基酸形成的酰胺，它们本身就是非常有效的多胺转运抑制剂。这样的例子包括L-Lys-精胺(化合物1202)，L-Val-精胺(化合物1157)和L-Orn-精胺(化合物1224)。
可连接成双多胺的多胺还包括酰基多胺，例如N1-单取代多胺。N1-单取代多胺又可再分为酰胺类，磺酰胺类，N1-单取代胺类等。酰胺类又可再细分为不含连接基的，含连接基的，含氨基烷基的和含氨基酸首基的。氨基酸首基又可细分为被保护的，天然α-氨基酸，非天然α-氨基酸，和氨基酸衍生物。
一旦鉴定到一种能以理想水平抑制多胺转运的多胺类似物，就可十分方便地通过与同类或非同类其他多胺类似物进行结构和功能上的比较来进一步优化从而增强其功用。此类优化改进的例子包括但不限于：提高抑制活性，增强代谢稳定性，增强特异性，改善加工性和给药方便性，提高结合亲和力，不参与细胞多胺循环，降低副作用。
本发明还涉及用于通过抑制多胺转运来治疗疾病或症状的药物组合物，它包含以上所述组合物和药用赋形剂。所述药物组合物可进一步包含多胺合成抑制剂，以DFMO为佳。类似组合还包括所述药物组合物与一种或多种其他已知可用于治疗相关疾病或症状的药物联用。
本发明还提供一种治疗与细胞恶性增殖相关并/或可通过抑制多胺转运来治疗的疾病或症状的方法，该方法包括给予有效量的所述药物组合物。与所述细胞恶性增殖相关的可能是免疫系统细胞、脉管neontima细胞、肿瘤细胞的增殖或恶性血管生成。以上所述方法的适应症包括癌症或血管成形术后损伤。
因此，本发明所述类似物和衍生物可以单用或与其他药物联用用于治疗癌症等恶性细胞增殖相关性疾病，包括血管生成和损伤后细胞生长。较好的是，所述治疗方法通过抑制PAT、deoxyhypysyl合成酶或细胞生长，或通过诱导凋亡起效。这样，它们可以通过细胞生长抑制和/或细胞毒性机制起作用。本发明的类似物和衍生物可以单独或与其他药物联用用于治疗高血压、骨质疏松、阿尔茨海默症、缺血、自体免疫疾病、精神病、抑郁、中风、心血管疾病、微生物或寄生虫或真菌等植物病原感染。易因本发明类似物和衍生物单用或与其他药物联用而受到抑制的细胞活动包括那些与核酸(例如DNA或RNA)相关的活动，例如复制、转录和翻译。本发明类似物和衍生物还是有效的抗痢疾药，抗蠕动药，抗痉挛药，抗病毒药，抗牛皮癣药和杀昆虫剂。
本发明的另一部分还涉及对许多此类类似物和衍生物向细胞内转运进行快捷、高效试验的方法。通过创建此类类似物和衍生物的结构-活性相关性(SARs)数据库，本发明鉴定了多胺与PATr等膜蛋白或可溶蛋白结合中的关键因素。基于这些信息，本发明使得预测新多胺类似物和衍生物的可转运性和活性成为可能。
本发明的多胺类似物和衍生物还可以用作试验或生物化学探针。优选的试验方法之一采用了含有可测标记部分(“报道基团”)的多胺类似物或衍生物，所述标记部分优选荧光团，尤其是丹酰基，但也可以是能用多种其他手段—例如ELISA—测得的其他取代基。优选试验方法之一采用了固定于固相载体上的类似物或衍生物。
本发明还涉及可用于诊断组合物的一系列多胺类似物，以及合成此类化合物的方法。
有关SARs数据库，多胺类似物作为试验探针的用途，以及诊断组合物的详细信息，可参考PCT/US98/14896。
本发明还鉴定了多胺与PATr等膜蛋白或可溶蛋白结合的关键因素。
附图说明
图1：多胺、MDS和DACS之间的结构与活性关联性(SAR)。Ki是PAT抑制试验测得的抑制常数。
图2：接受对细胞生长作用试验的化学结构3-98的表格。R是生长抑制活性指数，即待测化合物存在下的细胞生长与待测化合物加DFMO存在下的细胞生长之比。Ki(抑制常数)反映化合物对细胞培养物内PAT的抑制程度。这些生物学效果为SAR分析提供了基础。
图3A：制备本发明双多胺的合成途径示意图。该合成示意图中，精胺衍生物通过4-硝基苯酯连接，形成包含两个N1-tBoc-精胺的双多胺。该反应的粗产物，经蒸发和/或高真空去除溶剂甲醇(MeOH)和二甲基甲酰胺(DMF)后，可溶于水或50％MeOH/水，以便进一步通过柱层析(例如阳离子交换柱)纯化。洗脱用0至2N的NH4OH梯度进行。
图3B：图3A所示合成途径另加了用3M HCl去除N1-tBoc-保护基的步骤。
图4：由相应酰卤转化为对硝基苯基活化的酯的合成途径示意图。
图5：用二叔丁基二碳酸酯保护末端氨基的反应示意图。
图6：可连接成双多胺的本发明优选多胺类似物。
图7：多胺通过脂族或芳族二酸链连接而成的二酰胺的结构通式。
图8：优选精胺连接而成的二酰胺二聚体。
图9a至9j：可用于形成本发明双多胺的大量N1-单取代多胺的分类表。
图10：4类构象限制的多胺(111-114)，最末行是确定了立体化学特征的内环多胺类似物(116)，它们都可用于制备本发明的双多胺。
图11：可用于制备本发明双多胺的化合物1202即L-Lys-精胺及其变体。
图12：氨基酸-多胺共轭物，其中的氨基酸部分可具有不同的手性。这些氨基酸可用于形成本发明的双多胺。
图13和14：生物素修饰的多胺N1-[(N6-(生物素)-6-氨基辛酰基)]精胺和N1-(生物素)-精胺，它们可用于制备本发明的双多胺。
图15包括分图A和B，显示多胺上可接受修饰而形成“固定化柄”和“报道基柄”的可能性位点。这些修饰后多胺可用于制备本发明的双多胺。
图16：本发明优选去保护双多胺的列表。
图17：本发明优选被保护双多胺的列表。
图18：一些适合用于制备双多胺的活化酯。
详细描述
本发明的发明人设计了一类新的可用于治疗的化合物，还设计了用此类化合物作为探针检测PAT和多胺结合情况的高效、高处理量试验方法。发明人们已经用此类新方法筛选并发现了对PATr具有高亲和力因而能竞争性和非竞争性抑制吸收的化合物。此类化合物可用作药物治疗多种疾病，尤其是癌症。它们还可以作为组分之一与DFMO(抑制鸟氨酸脱羧酶)之类多胺合成抑制剂或其他药物组合成新的药物组合物。本发明的化合物还可以用于治疗诸如前文所述有多胺参与的其他疾病或症状，还可以用于农业和环保。
本发明发现，由单独的多胺形成双多胺的优点在于可用作PAT抑制剂，或用作PAT试验和药物筛选中的探针。这样的化学修饰不会破坏多胺衍生物与PATr的有效结合，相反，实际上是增强了对PATr的亲和性。因此，可用此类化合物来开发新的多胺吸收抑制剂。
定义
本发明中，“多胺”包括：腐胺、精胺或亚精胺，以及更长的线型多胺、支链多胺等，它们可含有2-10个氮原子。所述“多胺”还包括多胺的衍生物或类似物，即，具有多胺主链以及与碳原子或末端氮原子或内部氮原子相连的多种官能团。多胺衍生物可包含一个位于多胺核心和衍生官能团之间的末端连接基或间隔基。
“首基”指与多胺直接相连，或本身与一连接基，该连接基与多胺相连的部分。所述首基优选芳族或杂环基团，但也包括脂族基团或芳烷基。因此，首基可以是作为“报道基”的荧光部分。
“抑制剂”部分或基团指将多胺衍生化而具备以下特性的化学基团：(1)使衍生物以高于天然多胺的亲和力与PATr结合；并/或(2)通过其他机制阻断多胺向细胞内或被亚细胞PATr制备物吸收。本发明在此揭示了能够有效抑制MDA-MB-231人乳房癌细胞等细胞对PAT吸收的化合物。本发明合成了大量不同类型的所述抑制剂；并公开了各种合成方案。
“报道基团”指作为探针一部分，令探针可被测知(直接测知或通过例如酶增强反应而被测知)，并可籍此测定与探针结合的PATr活性的化学部分。报道基团可以因其本身发出可测信号而被测知，也可以利用其与某种该报道基特异性结合配体的亲和性，而后因该配体具有可测性或在与该报道基结合或反应后具有可测性，从而被测知。优选实施方式中，所述多胺类似物固定于固相载体上，该载体能从复杂的混合物中分离出所述类似物等相互作用性/结合性分子。
在此揭示的各种抑制剂化合物用不同的数字加以区分，包括顺序编号(1到166或以上)和编码编号(用四位数的化合物编号或与“ORI”或“Ori”组合加以区分)。不论用什么方法区分，编号仅代表对应化合物的实际分子结构，并非对该化合物的限定。
结构-活性关联性(SARs)
本发明的PAT抑制剂是通过对转运蛋白的天然底物亚精胺进行修饰来制备的。本发明发现：在亚精胺的二氨基丁基部分引入一个3-酰氨基丙基可生成性能明显更优的转运抑制剂，见图1。本发明发现，最适合的酰胺基或磺酰胺基是中等大小的芳族部分，因此，N1-丹酰基精胺(MDS)既是转运抑制剂，又是转运试验的报道分子。MDS与细胞的亲和力高于精胺和N1-乙酰基精胺。在MDS的芳族“首基”和多胺核心之间引入一个6碳连接基显著增强了对细胞生长和PAT的抑制。这一新分子，即N1-[(N6-丹酰基)-6-氨基辛酰基]精胺(或DACS) 4，是最强的已知PAT抑制剂之一。在与生物学系统的相互作用中，DACS显示出许多前文所述的优良特性。本发明还对DACS及相关类似物进行了广泛的研究。
对以DACS 4为代表的先导(lead)化合物的SARs已有了广泛的研究，见图2(尤其是化合物73-98)。如前所述，对DACS的数个区域进行了改变，并测定了它们对于转运蛋白结合的影响。为了研究改变芳族“首基”的影响，合成了大量不同的4-硝基苯基酯，它们在远端的氨基末端带有不同的芳族或非芳族N-磺酰胺。还合成了一系列“无首基”类似物，用于研究具有疏水性芳族部分的重要性。总而言之，本发明设计并合成了大量能有效抑制PAT的化合物。如前所述，不同取代基的单、二或多取代多胺都可用作药物。
N1-取代多胺类似物可参照相关美国专利申请US09/341,400和US09/396,523来制备，所述申请只是以精胺为例提供了代表性的反应，不应据此将可用于本发明的多胺局限于精胺。用于制备双多胺的单保护多胺中间体优选氨基末端tBoc衍生物，可参照Blagbrough等所述(Tetrahedron Lett.，35：2057-2060，1994)，用二叔丁基二碳酸酯以四氢呋喃为溶剂来制备。
先导多胺类似物还可以进一步修饰成用于制造双多胺的类似物。例如，在研究了酰胺、磺酰胺或脲取代基的结构之后发现，在多胺核心和首基之间引入一个6碳直链脂族连接基可使与PATr的结合性增强10倍(见图1)。基于化合物DACS 4与其靶分子的高亲和性，可选择其作为先导化合物接受进一步的修饰。对该先导化合物进行进一步修饰的方法可参考相关美国专利申请US09/341,400和09/396,523。
实现与靶分子(例如蛋白质)特异性结合的通用有效方法之一是合成某结合性分子的具有特定构象或立体化学特征的类似物。通过大幅减少某分子可能的旋转异构体或构象，可以实现与所需位点更强的结合。由于该分子不必再对整个“构象区间”进行搜索，其与靶分子相互作用的能量可增强数倍。
另有研究者曾试图通过合成构象限制的类似物来解决多胺类似物的选择性问题。Ganem用2-丁烯和2-丁炔二氨基衍生物取代精胺的丁基(Ganem，B.J.等，有机化学杂志，1987，52，5044-46)。Rajeev，K.G.等，有机化学杂志，1997，62，5169-73，在精胺的骨架内引入立体化学限制、构象限制的吡咯烷环(图10； 115，x＝1)。Brand，G.等，Tetrahedron Lett.，1994，35，8609-12，合成了精胺和亚精胺的环多胺类似物。例如图10( 113，x＝3，4和5)。本发明发明人在这些工作的基础上进一步合成了图10中的其他类似物。这些类似物可通过对已知方法加以改进而制得。x＝1的类似物由精胺或N，N’-双(3-氨基丙基)-1，3-丙二胺与甲醛反应制得，如Ganen，B.所述(Acc.Chem.Res.，1982，15，290)。可将伯胺保护成例如类似物 111和 113的N-tBoc衍生物。然后可通过酸去保护得到所需产物。x＝1的衍生物 112也按照Ganem的方法制得。x＝2至4的衍生物 111和 113通过还原性烷基化来制备。N1，N14-双(tBoc)精胺与二醛(OHC(CH2)x-2CHO)和NaBH4在EtOH中反应。化合物 112和 114则由合适的N1，N4-双保护精胺衍生物按照相同的方法制得。
特定立体化学特征的内环结构(图10， 115)则用相应醇形成的醛作为中间体合成而得。可用Swern条件将该被保护醇氧化成醛。然后用甲酰基亚甲基三苯基正膦经Wittig反应进行醛延长，然后还原(过还原生成的醇可用氯铬酸吡啶重新氧化为醛)，还原性胺化/环化，最终制得x＝2的类似物。通过与溴化3-溴丙基鏻的Wittig反应、去保护和分子内烷化性环化，可制得x＝3的类似物。以L-或D-鸟氨酸可制得以上两种立体异构体。含胍鎓(guanidinium)基团的多胺可参知Iwanowicz，E.J.等(合成学通讯，23，1443-45，1993)所述的方法制备。
天然多胺—包括腐胺、亚精胺和精胺—通过与不同的“首基”和“连接基”偶联而引入本发明的组合物。同样可用的其他天然多胺包括：N1-乙酰基精胺，N1-乙酰基亚精胺，N8-乙酰基亚精胺，N1-胍基精胺，尸胺，氨基丙基尸胺，高亚精胺，caldine(去甲亚精胺(norspermidine))，7-羟基亚精胺，热胺(thermine(去甲精胺(norspermine))，热精胺(thermospermine)，canavalmine，氨基丙基高亚精胺，N，N’-双(3-氨基丙基)尸胺，氨基戊基去甲亚精胺，N4-氨基丙基去甲亚精胺，N4-氨基丙基亚精胺，caldo戊胺，高caldo戊胺，N4-双(氨基丙基)去甲亚精胺，热戊胺(thermopentamine)，N4-双(氨基丙基)亚精胺，caldo己胺，高热己胺(homothermohexamine)和高caldo己胺。
通过修饰以抵抗酶分解可提高单取代多胺类似物的体内代谢稳定性。例如，以烷基取代末端伯胺基团可通过避免氧化代谢提高稳定性。本发明还包括具有烷基化仲氨基的化合物。酰胺氮的N-烷基化可降低蛋白酶分解的速度。
避免酰胺键代谢分解的另一种方法是生成硫代酰胺衍生物。图11a显示了先对化合物1202即L-Lys-精胺共轭物进行这种改变，然后用到本发明的双多胺中。本发明还包括将以上各种改变联合运用。
以上各种改变可通过多种合成途径实现。仲氮原子α位碳原子上的取代和氮原子的酰化也可降低多胺氧化酶的速度。此类化学修饰可以将化合物的药理副作用降至最低。
或者，可以在精胺末端氨基的α位引入甲基(Lakanen，J.R.等，医学化学杂志，35：724-34，1992)。1，12-二甲基精胺类似物 121对于正常的代谢分解具有很高的耐性。该化合物很容易偶联成为双多胺的一部分。
本发明还合成了具有乙酰基(47)，N-乙基(35)和α-二甲基(66)取代的 4的多胺类似物，它们的Ki分别为2100，41，18nM。
带有可测标记的多胺衍生物可用放射性标记的14C-精胺或其他放射性标记的多胺作为起始物来合成。
还可以合成中间碳原子被烷基化的各种多胺类似物。5-羧基精胺，四叔丁基-5-羧基精胺及其酰氯可参照Huber，H.等，生物化学杂志，271：27556-63，1994来合成。所的的酰氯可进一步与各种亲核试剂反应，在去除叔丁基后生成羧基取代的多胺类似物。这些类似物然后可偶合到连接基和/或首基上。或者，可将羧基中间体还原成用于合成不同类似物的中间体。这些类似物在本发明中是烷基化剂(例如内氮丙啶精胺衍生物)或是参与多胺生物合成、利用和分解的酶(例如精胺合成酶，脱氧8-羟基-2，7，10-三氨基癸酸合酶，多胺氧化酶)的酶促非可逆抑制剂。所有作用于取代碳原子的酶都会产生一种高活性中间体，该中间体能够将酶的活性位置的残基烷基化。
许多多胺衍生物有市售的，这些衍生物可方便地进一步衍生为本发明的多胺类似物。
优选的双多胺
优选的双多胺包括图2和图9a-9j所示的多胺类似物连接而成的化合物以及它们的具有药学价值的衍生物，所述药学用途例如作为抗癌、抗病毒、抗微生物或抗真菌化学治疗剂。特别优选的化合物包括图16和17所示的化合物及它们的衍生物。
对具有所需活性的双多胺化合物的进一步衍生或优化可借助于与本发明其他双多胺类似物和衍生物进行结构和功能比较，然后将其他类似物的特定结构元素引入待优化的化合物。可选的结构元素取决于期望改进的性能，例如但不限于抑制活性、代谢稳定性、特异性、加工性和给药途径、结合亲和性、不参与细胞多胺循环，降低副作用。
通过引入此类结构元素修饰所得的化合物可以是各种结构的，包括本发明所述的双多胺类似物和衍生物结构。换言之，优化所得的化合物可能增加一个或多个原子或官能团并/或缺失一个或多个原子或官能团，从而形成不限于本文所述双多胺和衍生物结构。
可用多种优化方法进一步改善双多胺类似物。
本发明某些双多胺类似物和衍生物的设计是为了满足令化合物可与ODC抑制剂在联合治疗中联用，通过生物合成和转运两条途径减少细胞多胺的化合物的复合要求。此类化合物必须是优良的细胞外多胺(腐胺、亚精胺和精胺)吸收抑制剂，但其本身不能是多胺转运蛋白或用于恒定细胞多胺水平的底物。如果它们是转运蛋白的底物，并具有天然多胺的功能(或经代谢而成为多胺)，这些化合物就无法实现降低细胞多胺水平的目的。
除了利用氨基之外，本发明的双多胺类似物和衍生物还可以是连有首基的多胺，其中，将“首基”与连接基相连的偶联基(coupler)有：-C(＝O)NH-，-S(＝O)2NH-，-NHC(＝O)-，-HNS(＝O)2-，-HNC(＝O)NH-，-HNC(＝S)NH-，O-C(＝O)NH-，-O-，-S-，-CH2-或-NH-。
首基
1.概述
如前所述，本发明的双多胺由多胺衍生物通过末端氨基连接而成。可作为双多胺一部分的多胺衍生物的例子是含有首基的先导多胺的衍生物。
以下先导化合物的一般结构显示了首基，连接基和多胺之间的连接。
首基——偶联基1——连接基——偶联基2——多胺
其中的偶联基1是-C(＝O)NH-，-S(＝O)2NH-，-NHC(＝O)-，-HNS(＝O)2-，-HNC(＝O)NH-，-HNC(＝S)NH-，O-C(＝O)NH-，-O-，-S-，-CH2-或-NH-；偶联基2是-C(＝O)NH-，-S(＝O)2NH-，-NHC(＝O)NH-，-HNC(＝S)NH-或-NH-。有许多偶联方法可用于将“首基”与连接基部分相连。后文揭示了“首基”的类型，其中，这些首基上还可以有其他取代基。
以下，在说明连接基之前，先说明一下多胺与连接基之间的偶联。
优选首基的结构多样性非常大，大多数能与胺共价连接的有机基团都在候选之列。下表指示了部分较好的首基基团，但绝非仅限于此。适用于本发明多胺类似物的首基还包括Dhainaut等(1996)“作为多药物抗性调节剂的新的嘌呤和嘌呤类似物”，医学化学杂志，39：4099-4108中表1的“R2”。本发明还包括环结构上有单取代或多取代的首基。
首基取代基列表
卤素       环己基      乙氧基      丙酯
甲基       环庚基      丙氧基      异丙酯
乙基      环辛基      硫代基       氰基
丙基      环壬基      甲硫基       异氰酸根合
异丙基    环癸基      乙硫基       三氟甲基
丁基      己基        丙硫基       三氯甲基
异丁基    2-己基      丁硫基       三溴甲基
叔丁基    3-己基      异丙硫基     叠氮基
戊基      烯丙基      硝基         乙酰氧基
2-戊基    乙烯基      氨基         甲酰胺
3-戊基    炔属        乙酰胺       N-甲基甲酰胺
新戊基    炔丙基      甲酰胺       N，N-二甲基甲酰胺
环戊基    高炔丙基    羧基         N-乙基甲酰胺
环丙基    羟基        甲酯         N，N-二乙基甲酰胺
环丁基    甲氧基      乙酯
2. 芳族部分
芳族部分包括：苯基萘基，1-、2-或3-联苯基，茚基，苊基，蒽基，菲基，phenalenyl，苯并菲基芘基，联苯基亚甲基等。
3. 杂环基团
杂环基团包括：吡咯烷基，哌啶基，哌嗪基，吗啉基，联苯基，呋喃基，吡咯基，1，2-二唑基，咪唑基，1H，1，2，3-三唑基，1H-1，2，3，4-四唑基，噻唑基，噁唑基，1，3，4-噻二唑基，吡啶基，嘧啶基，1，2-二嗪基，1，4-二嗪基，1，3，5-三嗪基，二苯并呋喃基，吖啶基，2，1，3-苯并噻二唑基，异喹啉基，喹啉基，苯并呋喃基，异苯并呋喃基，1，3-苯并二嗪基，吩嗪基，吩噁嗪基，酚噻嗪基，吡喃基，色烯基，呫吨基，中氮茚基，异氮杂茚基，吲哚基，嘌呤基，2，3-二氮杂萘基，1，5-二氮杂萘基，喹喔啉基，喹唑啉基，噌啉基，ptericinyl，咔唑基，β-咔啉基，菲啶基，吖啶基，萘嵌间二氮杂苯基，菲咯啉基，异噻唑基，呋咱基，吲哚基，异吲哚基，喹宁环基和生物素基。
4. 脂族基团
此类基团包括与连接基相连的直链、支链和环烃，包括：C2-10烷烃，含有1-3个不饱和键的C3-10烯烃，含有1-3个不饱和键的C3-10炔烃；支链C3-10烷烃、烯烃和炔烃；包括C3-8环烷基、金刚烷基、樟脑基、胆甾烯基等的多环脂族烃和甾体样环系统。
5. 其他
a. DNA嵌入剂
嵌入剂与多胺偶联会使其与核酸靶分子的亲和性更高。此类嵌入剂有：吖啶，9-氨基吖啶，原黄素，放线菌素D，柔红霉素，阿霉素，诺拉霉素，美诺立尔，玫瑰树碱，BD-40，安吖定，阿考达唑，2-苯基喹啉，羧酰胺，crisnatol，二胺硝吖啶，吡唑吖啶，米托萘胺，阿美蒽醌，米托蒽醌，氧化蒽醌，比生群，久莫霉素。有关DNA嵌入剂，可参考Baguley，B.C.，抗癌药物的设计，1991，6，1-35。
b. 生化共轭物
靶向特定细胞或细胞上的酶/受体可实现药物的选择性。以下生化物质可候选用于将多胺偶联成选择性药物：甾体，前列腺素，磷脂；酶的辅因子，包括含核苷酸的分子，例如NADH，乙酰辅酶A，AdoMet，黄素，色氨酸色氨酰鲲(TTQ)等。
另一类首基包括与不同大小的聚乙二醇(PEG)或O-甲基化PEG(MeOPEG)聚合物共轭的多胺。
6. 多环首基
首基可以是从简单的烷基取代基到多环和多单环取代基。美国专利申请09/341,400的图15列举了多种此类结构。
连接基
1. 概述
用于双多胺的多胺类似物的连接基部分的大致结构为一端为氨基，另一端为酸根。一类连接基含有二氨基，它们通过脲键与多胺相连，同时，通过酰氨键、脲键或磺酰胺键与首基相连。首基也可以通过其他偶联基—例如醚、硫醚和C-C键—与连接基相连。前文所示的结构(“首基，1.概述”部分)显示：连接基将首基与多胺相连，并具有适当的长度，以及适当的空间、构象和疏水性特征。该示意图还显示了可行的偶联方法的联用。在实施以上任一种偶联方法的同时，都可以在其他位置择一实施美国专利申请09/341,400中图3所示的三种方法，从而实现优选特性的多种组合。
连接基可具有多种特性，所述的多种特性可反映为有多少种以下所述的改变。连接基结构的改变会影响整个多胺类似物的特性，例如疏水性，亲水性，首基与多胺之间的距离，首基和多胺的空间排列，构象特征，溶解度和电子特性。
2. 脂族直链连接基
本发明合成了一系列连接基来测试首基与多胺之间不同距离的效果。这一系列连接基大致可表示为：不同碳链长度的脂族直链连接基，即以下化合物148：
Figure A0181051000211
n＝1至12
本发明发现，连接基长度对于PAT抑制活性和细胞生长抑制活性具有显著影响。当首基为芳族部分时，C6连接基最佳，此时的Ki很低。然而，没有首基时，未发现生长抑制或转运抑制活性发生明显变化。因此，“无首基”化合物的Ki约为25nM，但是对细胞(乳房癌细胞)生长的抑制更弱，这很可能是因为实际上它们本身能被转运。一种前列腺癌细胞受此类“无首基”抑制剂的抑制较强。C3无首基化合物对细胞生长有明显的抑制作用。
这一系列化合物的合成途径从不同的多胺和首基开始，可以美国专利申请09/341,400中图9所示 4的合成方案为代表。用N-tBoc保护氨基，然后通过形成对硝基苯酯激活羧酸。用酸去除N-tBoc保护基后，氨基可与所需首基的酰氯或磺酰氯反应。纯化后，直接与选定的多胺在甲醇中反应，于是得到所需的产物。产物可用以下两种方法纯化：1)反相硅胶层析，2：9的MeOH/0.5N HCl；或2)BioRex70树脂(NH4形式)阳离子交换层析，用O-2N的NH4OH线性梯度。
3. 不饱和直链脂族连接基
如后文所示，可在连接基部分引入不同的不饱和度(稀键或炔键)和几何异构的烯烃衍生物( 149和 150)。这些变化可在最终产物中引入构象限制。
E和Z异构体
其中，n＝0至7，m＝l至4。
4. 碳-取代连接基和脂环族连接基
支链和饱和脂环族连接基可为所需多胺类似物引入构象限制。化合物 151和152体现了此类结构：
其中，n＝l至10；R和R’彼此无关联，可以是H或CH3(CH2)m，m＝l至10。
5. 手性碳-取代的氨基连接基
选用众多市售手性氨基酸中任何一种即可赋予多胺类似物极大的结构多样性。许多手性氨基酸中间体有市售的，包括某些N-tBoc保护的氨基酸和N-tBoc保护的氨基酸对硝基苯酯。图12( 153)展示了用该方法制得的多种衍生物。这些氨基酸-多胺共轭物的氨基酸部分具有不同的手性。这些氨基酸也可作为“连接基”与其他N-取代的“首基”相连。
另有众多本领域已知的α-氨基酸类似物可用于形成多胺加合产物。参照美国专利申请09/341,400图8和图9所示的合成步骤可方便地将此类化合物用于本发明。几个重要的例子是：叔丁基甘氨酸，鸟氨酸，α-氨基异丁酸，2-氨基丁酸，α-氨基辛二酸，4-氯苯丙氨酸，瓜氨酸，β-环己基丙氨酸，3，4-脱氢脯氨酸，3，5-二碘酪氨酸，高瓜氨酸，高丝氨酸，羟脯氨酸，β-羟缬氨酸，4-硝基苯丙氨酸，去甲亮氨酸，去甲缬氨酸，苯基甘氨酸，焦谷氨酸，β-(2-噻吩基)丙氨酸等。几种重要的β-氨基酸也可按照以上所述的方法用于本发明，例如β-丙氨酸等。
不论是天然L-氨基酸(L＝S)还是D-氨基酸(D＝R)的立体异构体都可用于本发明。由于各种异构体可以各自使用，因而显著扩大了结构多样性。
6. “无首基”连接基
所需的生物学特性并非都取决于首基。因此，本发明合成并试验了多种含有多胺和连接基但没有首基的所谓“无首基”衍生物。这些衍生物由N-tBoc氨基酸的活性酯(对硝基苯酯或N-羟基琥珀酰亚胺)与选定多胺反应制得。所得N-tBoc保护的衍生物然后可用0-2N的NH4OH线性梯度，以BioRex70树脂(NH4形式)进行阳离子交换层析纯化。然后，用酸去除tBoc保护基。既测定了tBoc保护衍生物的生物学活性，也测定了酸去保护衍生物的生物学活性。本发明合成了以上所述的全系列氨基酸，以及其他衍生物。
反应活性、不可逆多胺转运抑制剂
A. 烷基化剂
1. 氮丙啶
已发现，萤光团或其他大末端基团取代的多胺的固有性质之一就是对PATr的高结合亲和性。这表明，除用作诊断工具和研究工具之外，它们还可以用作需要抑制PAT的疾病或症状的治疗剂。它们对其他多胺靶分子例如DNA的固有亲和性进一步扩大了它们的治疗性用途范围。因此可以预计，含有此类修饰多胺的双多胺也可能具有相同的活性。
优选实施方式之一中，多胺核心含有吖丙啶取代基。吖丙啶基取代的多胺与靶分子结合性复合物(受体、转运蛋白、酶和和酸)中的亲核基团反应。此外，它们还可以用于将其他反应性部分与多胺相连。这些单取代和双取代多胺类似物可用作药物，因为它们能够：a)抑制PATr，b)抑制多胺合成和c)抑制以核酸为底物的反应。
另一实施方式中，在已含有首基和连接基取代的多胺中引入了一个非氮丙啶反应性基团。该反应性基团使得含标记多胺能与多胺结合性靶分子—例如PATr—上相适的亲核性位点共价结合。本发明用此类化合物标记受体、酶或核酸；这样，如此修饰后的多胺既可作为亲和性标记在诊断试验中，又可用作分离多胺结合性靶分子的工具。同样，这些化合物也能用于治疗可通过抑制PAT或DNA-多胺相互作用来治疗的疾病或症状。由于它们结合的相对不可逆性，与已知化合物相比，此类化合物的使用剂量和频率可以更低。
双取代多胺可用氨基被适当保护的多胺来合成。分步骤进行精胺官能化的试剂是已知的(Bergeron，R.J.等，有机化学杂志，53：3108-11(1988)；Byk，G.等，Tetrahedron Lett.，38：3219-3222(1997))。Bergeron等使用了4种胺保护基：苄基，叔丁氧基羰基，三氟乙酰基和2，2，2-三氯叔丁氧基羰基。该论文还说明了选择性去除以上各保护基的条件。这些反应条件能够互不相关且选择性地官能化精胺的各个氮原子。因此，本发明包括用连接基/首基在精胺4个氮原子中任意一个上单官能化，以及合成含有一个以上官能化氮原子的多胺类似物。
在精胺和亚精胺上引入氮丙啶基团的方法都是已知的，分别为Li等，医学化学杂志，39：339-41(1996)和Yuan等，美国癌症研究协会会议记录，34：380(1993)。
2. 其他反应性基团
除氮丙啶之外其他可加入并与亲核试剂反应形成共价键的部分包括：氯乙酰胺、溴乙酰胺和碘乙酰胺，磺酰氟，酯，氮芥等。
化学反应性2-卤乙酰胺基团通过与合适的2-卤代酰卤反应可方便地引入任一多胺类似物。其他反应性基团则如下所述。
B. 光化学活化的试剂
在生物学活性分子上使用光化学活化官能团是已知技术(Fleming，S.A.，Tetrahedron，51：12479-50，1995)。在多胺领域，Felschow等将叠氮基苯甲酸部分与精胺相连，并检测了所得加合产物与细胞表面蛋白的相互作用(Felschow，DM等，生物化学杂志，328：889-95，1997；Felschow，DM等，生物学与化学杂志，270：28705-11，1995)。由于它们的光标记探针竞争亚精胺与PATr结合的表观Ki为1μM，这些光标记蛋白质是多种多胺结合性蛋白质的混合物。本发明最强的PAT抑制剂之一是DACS，它的Ki小于10nM，这表明它的亲和性比Felschow等报道的产物高100倍。所以，在该分子上引入光可活化基团就用于分离PATr蛋白而言前景广大。
1. 氮化物(azide)
用叠氮化合物取代丹酰氯中的二甲基氨基可生成光化学活性基团。1-叠氮基-5-萘基磺酰氯的制备是已知的(Muramaoto，K.，农学、生物学与化学，1984，48(1)：2695-99)，也可向Molecular Probe Inc.(Eugene，Oregon)购买。将该化合物用于DACS合成方法显而易见，只需要进行丹酰氯的取代即可。
这一叠氮基衍生物能够分离和鉴定PATr类蛋白，并可用作不可逆的光可活化药物分子。
2. 二氮丙啶
首基上的二氮丙啶取代也可实现以上所述的各种目的。
3. 重氮基团
具有光可活化首基的多胺类似物可用对硝基-3-重氮基丙酮酸盐(酯)来制备，后者可用于在脂族胺上引入光可活化的3-重氮基丙酮酸盐(酯)基团。该化合物也向Molecular Probe Inc.(Eugene，Oregon)购买。所需衍生物制备可通过：该试剂与游离氨基、对硝基苯基活化的连接基前体反应，然后纯化连接基/首基中间体，然后与多胺反应。
分析和诊断用途
本发明的双多胺类似物和衍生物还可以用作报道分子和探针，用于分析包括可溶性蛋白在内的其他药学靶分子，可参见PCT/US98/14896，该申请还描述了报道首基的使用和多胺转运试验。
测试多胺转运抑制剂
通过筛选用前述各种方法合成的双多胺化合物，本发明发现有些化合物可有效抑制多胺的转运。“R”值为DFMO或其他多胺合成抑制剂不存在时的测得IC50与DFMO或其他多胺合成抑制剂存在时的测得IC50之比。“R”为1表示多胺转运抑制剂在多胺转合成制剂存在下不引起改变，说明该转运抑制剂不能抑制转运蛋白，或者没有对该转运蛋白的特异性。
如所预计的，多胺合成抑制剂的存者增强了单用本发明双多胺转运抑制剂引起的细胞生长抑制。大幅度的增强说明被测的是优良的转运抑制剂，即具有对多胺转运蛋白的特异性，因为这一增强表明该转运蛋白抑制剂与其他细胞组分没有明显的交叉反应。本发明优选转运抑制剂的“R”约为2以上，但更好的是5、10、50、100、200、300和400。最好，化合物的“R”值大于约500，1000，或10000。由于高“R”值表明不论多胺转运抑制剂还是多胺合成抑制剂都不能单独抑制生长，所以可以认为这两者具有协同作用，这种协同作用的强弱取决于转运抑制剂的特异性和具体所用的合成抑制剂。这样的协同作用很难事先预见，因为各种转运抑制剂的抑制活性强度和特异性程度各不相同。
可以根据本发明多胺转运抑制剂在有无多胺合成抑制剂时的IC50来考虑本发明的“R”值。这样的考虑为可否将转运抑制剂作为活性成分提供了有用的信息。较好的是在多胺合成抑制剂存在下考察“R”值与IC50的关联。这样做是因为，如果IC50过高，该转运抑制剂就不适宜作为活性药物，因为需要很高的浓度才能具有抑制活性。这样的高浓度要求即使在“R”值很高时也不容忽视。因此，本发明的抑制剂在与多胺合成抑制剂联用时的IC50以约100μM或以下为宜，更好的是低于约75、50或25μM。最好的是多胺合成抑制剂存在下IC50低于约10，5，1，0.5，0.1，0.05，甚至0.01μM的化合物。
通过动力学和生物学试验，本发明发明人发现PAT抑制与生长之间存在高度关联性。
药物和治疗组合物
可将本发明的双多胺类似物和衍生物，包括它们的药用盐，配制成药物组合物。本发明含碱性基团的化合物的药用酸加合盐可以用合适的强或中强、无毒有机或无机酸，在碱性胺存在下用已知方法来制备。本发明所述的酸加合盐例如：马来酸盐、富马酸盐、乳酸盐、草酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、酒石酸盐、柠檬酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐和硝酸盐。
如上所述，本发明化合物能够抑制PAT或多胺合成，具有可用于治疗相关疾病—尤其是癌症—的特性。本发明组合物可能本身就具有活性，也可以作为体内能够转化为活性形式的“前药”。
本发明的化合物及其药用盐可以加入常规剂型，例如胶囊、包埋型夹心剂、片剂或注射制剂。可以采用药用的固体或液体载体。还可以配制成定时或延时释放的药物组合物。
本发明化合物宜系统性给药，例如注射为宜。使用中，所述注射可以是任意途径的，例如静脉、皮下、肌内、颅内或腹膜内。注射剂将制成常规剂型，例如溶液或悬浮液，适合在注射前配成溶液或悬浮液的固体剂型，或者是乳液。
所述固体载体包括：淀粉、乳糖、二水合硫酸钙、石膏粉、蔗糖、滑石、明胶、琼脂、果胶、金合欢胶、硬脂酸镁和硬脂酸。液体载体包括：糖浆、花生油、橄榄油、盐水、水、葡萄糖、甘油等。同样，所述载体或稀释剂可以包含延迟释放的物质，例如甘油一硬脂酸酯或甘油二硬脂酸酯，或是两者与蜡的混合物。如果采用液体载体，该制剂的形式可以是糖浆、酏剂、乳液、软明胶胶囊、包含液体的胶囊、无菌注射液(例如溶液，如安瓿瓶制剂)，或水性或非水性悬浮液。有关药物组和物可参考  Remington’s Pharmaceutical Science，MackPublishingCompany，Easton Pennsylvania(Gennaro，第18版，1990)。
所述药物制剂按照制药工业的常规方法来制备，相关技术包括例如：如果制造片剂，需要混合、造粒和压片；如果制造口服或局部、透皮、阴道内、鼻内、支气管内、颅内、眼内、耳内和直肠给药的非肠胃制剂，则需要适当混合、充装和溶解组分。以上药物组合物可包含少量无毒助剂，例如润湿剂或乳化剂，pH缓冲剂等。
虽然优选的给药途径是系统给药，但本发明药物组合物也可以局部或透皮给药，例如膏药、乳霜或凝胶剂；口服给药；直肠给药；例如栓剂，通过注射或连续输注进行的非肠胃给药；阴道内给药；鼻内给药；支气管内给药；颅内给药；耳内给药；或眼内给药。
就局部给药而言，可将本发明化合物配制在适合局部使用的载体例如油膏或膏药中。活性组份的载体既可以是可喷雾形式的，也可以是不可喷雾形式的。所述不可喷雾形式可以是半固体或固体，其中包含适合局部使用或动力学粘度高于水的载体。合适的制剂包括但不限于：溶液、悬浮液、乳液、乳霜、膏药、粉剂、搽剂、油膏等。根据需要，可以对这些制剂进行消毒，或与防腐剂、稳定剂、湿润剂、缓冲剂或渗透压调节盐等助剂混合。适合非可喷雾局部制剂的优选载体包括膏药基质，例如聚乙二醇-1000(PEG-1000)；HEB乳霜等常规乳霜；凝胶；以及凡士林胶等。
适合局部使用的还有喷雾剂，其中，化合物，最好还有固体或液体惰性载体，被装在一个可挤压的瓶内，或与压缩态挥发性物质—一般为气态推进剂—混合。所述喷雾剂除本发明化合物之外还可包含溶剂、缓冲液、表面活性剂、香精和/或抗氧化剂。
就优选的局部使用而言，尤其是人用，宜将有效量用在目标部位，例如皮肤、粘膜、眼睛等。用量一般约为每次0.001-1g左右，这取决于需要治疗的面积、症状的严重程度和所用局部载体的性质。
本发明组合物可与一种或多种治疗相关疾病或病症的其他化合物联用。就治疗癌症而言，本发明多胺类似物和衍生物可与以下药物联用：抗肿瘤药，例如长春碱等有丝分裂抑制剂；烷基化剂，例如环磷酰胺；叶酸抑制剂，例如甲氨喋啉，pritrexim或三甲曲沙；抗代谢剂，例如5-氟尿嘧啶和胞嘧啶阿拉伯糖苷；嵌入性抗生素，例如阿霉素和博莱霉素；酶或酶抑制剂，例如天冬氨酸酶；拓扑异构酶抑制剂，例如依托泊甘；或生物学反应调节剂，例如干扰素。实际上，本发明还包括本发明多胺类似物和衍生物与各种已知抗癌治疗剂的药物联用的组合物。最好，本发明化合物与多胺合成抑制剂例如DFMO联用。
本发明药物组合物还可以包含一种或多种其他药物，例如抗感染药，具体包括抗细菌药、抗真菌药、抗寄生虫药、抗病毒药和抗球虫药。
本发明典型的单剂量约为每kg体重1ng至10g，以约0.01mg至1g为佳，以约0.1mg至100mg为最优。就局部给药而言，剂量范围约为0.01-20％所述化合物，推荐1-5％。优选口服剂量为每日约1-500mg。然而，以上只是建议剂量，因为个体治疗的可变因素很多，实际剂量可能与以上推荐剂量有较大差异，但这是本领域普通技术人员能够确定的。
治疗疾病的有效量可用已被认可的体外系统或特定病症的体内动物模型来测定。如果是癌症，已有许多业内认可的多种人类癌症模型。可用标准方法和多种人或动物肿瘤细胞系培养物检测化合物对肿瘤细胞的生长抑制。此类方法中许多—包括动物模型—可参考Geran，R.I.等，“筛选抗动物肿瘤的化合物和天然产物的方法和其他生物学系统(第三版)”，癌症化学治疗报道，第3部，3：1-112。
合成方法
合成本发明用于制备双多胺的多胺类似物和衍生物的方法，包括平行文库的合成以及组合方法，都可参考PCT/US98/14896。
此外，本发明提供了可方便制得双多胺的合成方法(见图3A和3B，以及以下实施例)。简而言之，该方法用tBoc保护的多胺衍生物作为起始物，将其连接成为双多胺。然后，用离子交换层析纯化这些双多胺产物。通过洗脱回收产物，然后还可以进行去保护。
以上大致描述了本发明，通过以下实施例将更易于理解本发明。这些实施例仅用于说明而非限定本发明的范围，除非特别申明。
                       实施例I
             在转运和生长试验中筛选多胺类似物
图2( 3-98)概括了许多潜在PAT转运抑制剂对MDA细胞PAT和生长的作用。比值“R”是单用多胺时的IC50与多胺类似物与ODC抑制剂联用时的IC50之比。该“R”值体现了多胺类似物与ODC抑制剂之间的相对“协同作用”水平。在生长试验条件下，单用ODC抑制剂没有表现出抑制作用。
                      实施例II
                Ki的测定和结构-活性关联性
可在细胞培养物内评价本发明双多胺类似物和衍生物抑制MDA细胞亚精胺吸收的能力。Joro蜘蛛毒素JSTx-3购自Calbiochem；1-萘基乙酰基精胺购自RBI。脱氧精胍菌素由Paul Gladstone赠与。测定了图16中双多胺类似物的Ki，并显示了测得值。
                       实施例III
                 DFMO加亚精胺的抗MDA细胞IC50
本发明发明了一种细胞试验，1μM亚精胺存在下，它突出了氨基酸/精胺酰胺与ODC抑制剂DFMO联合时的效力。该试验中，单用DFMO没有发现抑制作用，因为即使多胺的生物合成被抑制，细胞仍能利用加入培养基的亚精胺。可见，任何一种被测类似物或衍生物对外加亚精胺吸收的抑制都可因缺少多胺而引起明显的生长抑制。
图16显示了某些去保护双多胺的试验结果。
                       实施例IV
                        双多胺的合成
合成双多胺的底物可用一种分两该部分的方法来制备：合成连接基和合成单保护多胺。
制备所例举的连接基是用4-硝基苯酚将相应的酰氯转化为对硝基苯基活化酯。见图4。图18例举了此类活化酯。所述酯通过EtOH/CH2Cl2(10-30％EtOH)重结晶纯化，并在高度真空中干燥。
可用本领域熟知的方法保护多胺。例如，用1.5小时，向精胺的二噁烷/水加NaOH(1eq)溶液中缓慢加入二叔丁基二碳酸酯(1eq)，生成单保护的精胺(3当量(eq))。见图5。搅拌24小时后，蒸发溶剂，用Bio-Rex阳离子交换树脂柱(45×2.5cm)纯化所得化合物。
双多胺的合成可按图3A所示的反应方案进行，其中，由对硝基苯基活化酯与被保护的精胺反应。
例如，一烧瓶中装有2.2当量N1-tBoc-精胺的10ml甲醇溶液，向其中边搅拌边滴加1当量4-硝基苯基酯溶于5ml DMF和10ml MeOH所成的溶液，历时3小时或通宵。
第二当量的4-硝基苯基酯可以固体形式加入，同时搅拌3小时。蒸发溶剂，高度真空去除DMF。先将粗制产物溶于水，并用Bio-Rex阳离子交换树脂柱(45×2.5cm)纯化。
或者，可以选用50％MeOH/水作为溶剂来提高双多胺的溶解度。所述化合物可用0至1-2N的NH4OH梯度来洗脱。汇集所需组分，蒸发去除溶剂，于是得到双多胺。
如图18所示，本发明将N1-tBoc-精胺与8种对硝基苯基酯偶联，其中包括琥珀酰(n＝2)连接的双精氨。本发明用Bio-Rex阳离子交换层析纯化了其中6种化合物。粗制产物一般是薄层层析(TLC)上两点的混合物。这两点的迁移率都高于N1-tBoc-精胺，其中之一接近溶剂前沿，另一则比N1-tBoc-精胺高，但具体情况取决于对硝基苯酯。
通常，n越大，该点的迁移率越高。当n＝10时(即十二烷二酰基衍生物)，两点的迁移位置非常接近，都靠近溶剂前沿。纯化大n值的化合物一般采用0至1或1.5N的NH4OH梯度进行洗脱。
但有一个例外，即琥珀酰衍生物，它由TLC上的4种反应产物构成。本发明用50％的MeOH/水代替纯水作为溶剂，成功地纯化了该衍生物。
为了去除N1-tBoc-保护基，可在以上反应条件下加入5ml 3M HCl，然后搅拌1小时。
本发明完成了tBoc保护的双多胺的1H和13C NMR谱，但对ORI 1268仅完成了1H NMR谱。类似的，还测得了去保护终产物ORI 1236、1288、1290的1H和13C NMR谱。还完成了ORI 1288和1290的质谱。
                        实施例V
                    双多胺对多胺转运抑制
所测的大多数精氨二聚体都具有很好的转运抑制Ki，即75nM以下。ORI 1236的Ki为22nM，是最强的抑制剂。该值可与ORI 1090的Ki(对MDA细胞约为10-22nM)相比。只有ORI 1275的Ki高于100nM(219nM)。生长抑制试验的结果与以上结果相应。所有化合物都与DFMO具有协同作用，IC50等于或低于10μM。最强的生长抑制剂是ORI 1288，其后依次是ORI1286＞1236＞1289＞1290＞1275＞1299。
在理论之外，似乎相连精氨二聚体越短，则其效力越强。因为类似物之间的活性没有更显著的差异，所以这表明转运蛋白的多胺结合位点对于脂族连接基的长度具有相当大的耐受性。这还支持以下发现，即PTI抑制剂—例如1202和1090—连接基的长度可以允许一定的误差。这些双多胺分子与转运蛋白相互作用的方式可能与ORI 1202和1090相同。
本发明发现，ORI 1236与DFMO联用的最大生长抑制低于ORI 1202/DFMO对照。这表明ORI 1236具有部分多胺缺乏挽救能力。其次，ORI 1236被发现部分DFMO挽救。除ORI 1287之外的所有其他双多胺的最大生长抑制都低于ORI1202/DFMO对照。对ORI 1236和1290重新进行了测定，只有ORI 1290表现出挽救作用。
不论前文是否特别声明，对于所引用的参考文献，本发明均作了全面的参考。
根据以上对本发明的充分论述，本领域技术人员可以发现，根据本发明的构思，在本发明的范围内，无需过多的试验，即可用多种等效参数、浓度和条件来实施本发明。
虽然以上结合具体实施方式对本发明进行了描述，但不难看出还存在进一步修改的可能。本申请应涵盖基于本发明原理的所有改变、用途或修改，这包括虽不同于以上具体所述，但属于本发明所属领域已知或常规操作范围之内的改换，该原则同样适用于后文权利要求范围内的必要技术特征。

Claims (30)

1.一种结合分子的多胺结合位点并且/或抑制多胺转运的多胺类似物或衍生物，它是双多胺。
2.根据权利要求1所述的类似物或衍生物，所述的双多胺包含至少一个N1-单取代多胺，该单取代多胺是N1-单取代腐胺、亚精胺或精胺。
3.根据权利要求2所述的类似物或衍生物，所述的N1-单取代包括一个酰胺键。
4.根据权利要求2所述的类似物或衍生物，所述的N1-单取代包括一个磺酰胺键。
5.根据权利要求2所述的类似物或衍生物，所述的N1-单取代包括一个胺。
6.根据权利要求3所述的类似物或衍生物，所述的N1-单取代还包括一个连接基部分。
7.根据权利要求3所述的类似物或衍生物，所述的N1-单取代还包括一个氨基烷基部分。
8.根据权利要求3所述的类似物或衍生物，所述的N1-单取代还包括一个氨基酸首基或其衍生物。
9.根据权利要求8所述的类似物或衍生物，所述的氨基酸首基是被保护的天然氨基酸或非天然氨基酸。
10.根据权利要求1所述的多胺类似物或衍生物，它选自图16所列举的化合物。
11.根据权利要求1所述的多胺类似物或衍生物，它选自图17所列举的化合物。
12.根据权利要求4所述的类似物或衍生物，所述的N1-单取代多胺选自图9h所列举的化合物。
13.根据权利要求3所述的类似物或衍生物，所述的N1-单取代多胺选自图9a-9c所列举的化合物。
14.根据权利要求8所述的类似物或衍生物，所述的N1-单取代多胺选自图9d-9g所列举的化合物。
15.根据权利要求11所述的类似物或衍生物，所述的N1-单取代多胺选自图9a-9f所列举的化合物。
16.根据权利要求1所述的类似物或衍生物，它还包含一个反应性部分，该部分能够与靶分子的亲核位点形成共价键。
17.根据权利要求16所述的类似物或衍生物，所述的靶分子是蛋白质或核酸。
18.根据权利要求16所述的类似物或衍生物，所述的靶分子是细胞受体或其他细胞表面分子。
19.一种用于治疗需要抑制多胺转运的疾病或病症的组合物，它包含：
根据前述权利要求中任一项所述的多胺类似物或衍生物，和
药用赋形剂。
20.一种用于治疗需要抑制多胺转运和合成的疾病或病症的组合物，它包含权利要求19所述的组合物和多胺合成抑制剂。
21.根据权利要求20所述的组合物，所述多胺合成抑制剂是二氟甲基鸟氨酸，即DFMO。
22.根据权利要求20所述的组合物，它还包含一种或多种已知用于治疗所述疾病或病症的其他药物。
23.一种治疗与细胞恶性增殖相关并且/或可通过抑制多胺转运来治疗的疾病或病症的方法，它包括给予治疗有效量的权利要求1-18中任一项所述的多胺类似物或衍生物。
24.根据权利要求23所述的方法，所述的恶性细胞增殖与免疫系统细胞、脉管neontima细胞、肿瘤细胞的增殖或恶性血管生成相关。
25.根据权利要求23所述的方法，所述疾病或病症是癌症或血管成形术后损伤。
26.一种治疗与细胞恶性增殖相关并且/或可通过抑制多胺转运和合成来治疗的疾病或病症的方法，它包括给予治疗有效量的权利要求1-18中任一项所述的多胺类似物或衍生物和多胺合成抑制剂。
27.根据权利要求26所述的方法，所述的多胺合成抑制剂是二氟甲基鸟氨酸，即DFMO。
28.根据权利要求26所述的方法，还包括一种或多种已知用于治疗所述疾病或病症的其他药物。
29.根据权利要求23-28中任一项所述的方法，其给药途径为口服、非肠胃、局部、透皮、阴道内、鼻内、支气管内、颅内、眼内、耳内、直肠或注射给药。
30.根据权利要求29所述的方法，所述的注射是静脉、皮下、肌内、颅内或腹膜内注射。
CNA018105106A 2000-05-31 2001-05-31 可作为治疗剂和诊断剂的新多胺类似物 Pending CN1512982A (zh)

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