CN101848668A - 用于肿瘤显像和治疗的多模态试剂 - Google Patents
用于肿瘤显像和治疗的多模态试剂 Download PDFInfo
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- CN101848668A CN101848668A CN200880107022A CN200880107022A CN101848668A CN 101848668 A CN101848668 A CN 101848668A CN 200880107022 A CN200880107022 A CN 200880107022A CN 200880107022 A CN200880107022 A CN 200880107022A CN 101848668 A CN101848668 A CN 101848668A
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Abstract
本发明提供了化合物及其用于诊断、显像和/或治疗诸如肿瘤的过度增生组织的方法,所述化合物是由肿瘤细胞表达的整联蛋白的拮抗剂与亲肿瘤性四吡咯光敏剂、荧光染料以及放射性同位素标记的部分中的至少一种的缀合物,其中放射性同位素选自11C、18F、64Cu、124I、99Tc、111In和GdIII。优选地,所述光敏剂是亲肿瘤性四吡咯光敏剂,例如卟啉、二氢卟酚或菌绿素,例如脱镁叶绿酸和焦脱镁叶绿酸。这种缀合物具有极高的亲肿瘤性,并且可被用于通过光吸收来抑制或完全破坏肿瘤。所述整联蛋白通常是αvβ3、α5β1、αvβ5、α4β1或α2β1。优选地,所述拮抗剂是RGD肽或可以合成的另一种拮抗剂,诸如4-{2-(3,4,5,6-四氢嘧啶-2-基氨基)乙基氧基}-苯甲酰基]氨基-2-(S)-氨基乙基-磺酰基氨基基团。这种化合物提供亲肿瘤性和显像能力,因此能够进行选择性的和清晰的肿瘤显像。
Description
发明背景
光动力学治疗(PDT)是以用对准治疗位置的长波长光活化的肿瘤定位光敏剂(PS)为基础的有效的局部疗法。目前的光敏剂具有高的肿瘤选择性,并且可以通过细的柔性光学纤维将光递送到体内的几乎任何位置。
最近发现,四吡咯光敏剂,例如包括二氢卟酚、菌绿素和其它卟啉基衍生物以及包括它们的类似物和衍生物在内的卟啉类,作为光动力学化合物,在诊断和治疗疾病、尤其是某些癌症和其它过度增生疾病诸如黄斑变性中,具有优异的应用。还发现这些化合物在银屑病和乳头状瘤病的治疗中有所应用。
这种衍生物包含这些化合物的二聚体和三聚体。允许的衍生物还包含这些化合物的环变体,条件是,这些化合物的中央十六个边的四个含氮杂环要保持完整。因此,叶绿酸、紫红素、脱镁叶绿酸(pheophorbides)和它们的衍生物被包含在“卟啉、二氢卟酚、和菌绿素以及它们的衍生物和类似物”的范围内。这种衍生物包含这些环状结构上的取代基的变体,例如焦脱镁叶绿酸(pyropheophorbides)。
已经有许多论文涉及这个主题,例如,“Use of the ChlorophyllDerivative Purpurin-18,for Synthesis of Sensitizers for Use inPhotodynamic Therapy”,Lee等人,J.Chem.Soc,1993,(19)2369-77;“Synthesis of New Bacteriochlorins And Their Antitumor Activity”,Pandey等人,Biology and Med.Chem.Letters,1992;“PhotosensitizingProperties of Bacteriochlorophyllin a and Bacteriochlorin a,TwoDerivatives of Bacteriochlorophyll a”,Beems等人,Photochemistry andPhotobiology,1987,v.46,639-643;“Photoradiation Therapy.II.Cure ofAnimal Tumors With Hematoporphyrin and Light”,Dougherty等人,Journal of the National Cancer Institute,July 1975,v.55,115-119;“Photodynamic therapy of C3H mouse mammary carcinoma withhematoporphyrin di-esters as sensitizers”,Evensen等人,Br.J.Cancer,1987,55,483-486;“Substituent Effects in Tetrapyrrole Subunit Reactivityand Pinacol-Pinacolone Rearrangements:VIC-Dihydroxychlorins andVIC-Dihydroxybacteriochlorins”,Pandey等人,Tetrahedron Letters,1992,v.33,7815-7818;“Photodynamic Sensitizers from Chlorophyll:Purpurin-18 and Chlorin p6”,Hoober等人,1988,v.48,579-582;“Structure/Activity Relationships Among Photosensitizers Related toPheophorbides and Bacteriopheophorbides”,Pandey等人,Bioorganic andMedicinal Chemistry Letters,1992,v 2,491-496;“Photodynamic TherapyMechanisms”,Pandey等人,Proceedings Society of Photo-OpticalInstrumentation Engineers(SPIE),1989,v 1065,164-174;和“Fast AtomBombardment Mass Spectral Analyses of Photofrin IIand its SyntheticAnalogs”,Pandey等人,Biomedical and Environmental MassSpectrometry,1990,v.19,405-414。这些论文被并入本文作为现有技术用于参考。
在这个领域中关于这些光动力学化合物已经在世界范围申请了许多专利并获得授权。例如可以提及以下美国专利:4,649,151、4,866,168、4,889,129、4,932,934、4,968,715、5,002,962、5,015,463、5,028,621、5,145,863、5,198,460、5,225,433、5,314,905、5,459,159、5,498,710、和5,591,847,所述专利被并入本文作为参考。
这些化合物中的一种“Photofrin”已经在美国、加拿大和日本获得批准。这些化合物中的其它化合物也已得到至少受限的批准,例如用于治疗黄斑变性的BPD,以及处于临床试验阶段或正被考虑进行这种试验的其它化合物。
如本文中使用的,术语“卟啉、二氢卟酚和菌绿素”如上所述意在包含它们的衍生物和类似物,并如通过被作为背景技术用于参考的前述论文和专利所描述和举例说明的。
已经发现这种化合物具有优先累积在肿瘤中而不是累积在大多数正常细胞和器官中(除了肝脏和脾之外)的卓越特征。此外,许多的这些肿瘤可以被杀死,因为所述化合物被光活化而变得具有肿瘤毒性。
这种化合物优先被吸收进癌细胞中,并在暴露于它们的近红外(NIR)吸收的优先波长吸光度的光下时破坏癌细胞。另外的这种化合物发射波长比优先吸收波长更长的辐射,使得光渗透组织几厘米。因此,有可能通过测量漫射光传播来检测和量化表面下组织中的光敏剂浓度。
然而,对于小的、体积大的、或埋藏的病变来说,难以检测恶性肿瘤和/或难以正确地放置光学纤维来照明整个肿瘤。因此,利用高选择性的光学和放射性核素肿瘤显像、实现肿瘤可视化、光学纤维的图像引导放置、和随后光动力学破坏病变的导引治疗方法对于癌症的诊断和治疗而言将是极其有用的。
光学显像是一个飞快发展的领域。光学造影剂可以以高灵敏度提供平面图像和X射线断层图像。对于小型动物而言,平面图像就足够了,但是荧光图像的光学X射线断层重建正在变得可行。
大部分的卟啉基光敏剂(PS)发荧光,并且这些卟啉的体内荧光性质已被一些研究者加以利用,用于检测肺、膀胱和各种其它位置中的早期癌症,以及用于引导治疗用的活化光。然而,PS不是用于肿瘤检测或治疗导引的最佳的荧光团:(1)它们具有比花青染料更弱的荧光。它们具有小的斯托克斯频移,使得难以将荧光与激发光分开。
具有NIR激发波长和发光波长的荧光花青染料可以具有高的量子产率和激发系数,以及适合的斯托克斯频移。它们具有高的消光系数和适合的斯托克斯频移。我们已决定可以使用与光敏剂结合的这种化合物作为“双功能试剂”(即,肿瘤显像和光照疗法)。参见例如,待决的PCT专利申请PCT/US05/24782。
正电子发射断层显像(PET)已被主要用于显像和试验生物化学过程和循环功能(circular function)。然而,越来越多地使用放射性标记的肽配体来靶向恶性肿瘤。可利用的同位素标记物包含11C(t1/2=20.4min)、18F(t1/2=110min)、64Cu(t1/2=12.8h和124I(t1/2=4.2天)。对于靶向光敏剂,可能希望长的循环时间,因为这样可以增加试剂向肿瘤内的递送。我们已证明,I-124标记的光敏剂可用于PET显像和PDT。参见例如,2006年2月14日提交的待决的美国专利申请11/353,626。
整联蛋白是在由细胞表面介导的信号转导中起重要作用的异源二聚体跨膜粘附受体。已经识别了由18个α亚单位和8个β亚单位组装的至少24种不同的整联蛋白受体。αvβ3、α5β1、αvβ5、α4β1、α2β1是已知的由肿瘤细胞表达的整联蛋白。作为本发明的一个实例,使用整联蛋白αvβ3来举例说明本发明,其结合于RGD肽,RGD肽是包含RGD序列[精氨酸(Arg)-甘氨酸(Gly)-门冬氨酸(Asp)三氨基酸序列]的小肽。应该理解,可以使用包含RGD序列的更长的序列(例如,多达10个或更多个氨基酸的序列),并且所有这种肽在本文中都被称为RGD肽。作为非肽拮抗剂或配体的实例,使用包含4-{2-(3,4,5,6-四氢嘧啶-2-基氨基)乙基氧基}-苯甲酰基]氨基-2-(S)-氨基乙基磺酰基氨基(THPAB)基团的化合物。我们最初集中于特异性受体,即整联蛋白αvβ3,作为由肿瘤细胞表达的这种整联蛋白的实例。已知整联蛋白αvβ3在肿瘤细胞有高水平表达并且其结合于RGD肽。
使用T-Coffee和ClustalW多重序列比对程序,对得自不同生物体(人、鼠、牛、鸡、蛙、斑马鱼(zebrafish))的整联蛋白αv亚单位进行的序列分析显示它们高度保守,特别是在哺乳动物中。从对得自不同生物体(人、小鼠、大鼠、鸡、蛙、斑马鱼)的整联蛋白β3亚单位的序列分析也观察到相似的结果。明显地观察到所涉及配体结合残基的严格保守。
对于整联蛋白的三维结构,可在PDB获得几种晶体结构。对于整联蛋白β3亚单位,有整联蛋白β3-Talin嵌合体复合物(1MK7,1MK9)的晶体结构、整联蛋白β3胞质结构域的NMR结构(1S4X)、以及整联蛋白αIIbβ3受体晶体(ITXV,1TY3,1TY5,1TY6,1TY7,ITYE)和NMR(1M8O)结构。对于整联蛋白αvβ3系统,可获得整联蛋白αvβ3的胞外域(1JV2)以及其与MN2+的复合物(IMlX)和与RGD配体的复合物(1L5G)的结构。另外,已经报道了在αvβ3受体的情况中的β亚单位结构的氨基末端PSI(神经丛蛋白(plexin)-信号素-整联蛋白)结构域(1U8C)。我们进行了整联蛋白αvβ3和αIIbβ3的整体结构的成对比较。其清楚地显示出离子结合残基的保守。
仔细地考查了整联蛋白αvβ3RGD肽复合物的晶体结构。RGD肽结合在αv和β3亚单位的接触面处,其中涉及3个Mn阳离子的相互作用的复杂网状结构在RGD Asp残基的识别中起重要作用(参见图1和图2)。
整联蛋白是同时具有粘附功能和信号转导功能的主要的细胞膜受体团体。它们通过与周围的胞外基质相互作用而影响赘生性细胞的行为,参与肿瘤形成。其表达的增加与肿瘤的增加的恶度有关。据报道,αvβ3在结肠癌、肺癌、胰腺癌和乳癌中有显著的过度表达,与没有发生转移的患者的肿瘤相比,发生转移的患者的肿瘤中的整联蛋白表达水平显著更高。
以下参考文献被并入本文作为现有技术用于参考。
1.Yihui Chen、Amy Gryshuk、Samuel Achilefu、TymishOhulchansky、William Potter、Tuoxiu Zhong、Janet Morgan、BrittonChance、Paras N.Prasad、Barbara W.Henderson、Allan Oseroff和Ravindra K.Pandey,A Novel Approach to a Bifunctional Photosentizerfor Tumor Imaging and Phototherapy.Bioconjugate Chemistry,2005,16,1264-1274。
2.Suresh K.Pandey、Amy L.Gryshuk、Munawwar Sajjad、XiangZheng、Yihui Chen、Mohei M.Abouzeid、Janet Morgan、IvanCharamisinau、Hani A.Nabi、Allan Oseroff和Ravindra K.Pandey,Multiomodality Agents for Tumor Imaging(PET,Fluorescence)andPhotodynamic Therapy:A Possible See and Treat Approach.J.Med.Chem.2005,48,6286-6295。
3.Xiaoyuan C.等人,Integrin αvβ3-Targeted Imaging of LungCancer.Neoplasia,2005,7,271-279。Yihui Chen、Amy Gryshuk、SamuelAchilefu、Tymish Ohulchansky、William Potter、Tuoxiu Zhong、JanetMorgan、Britton Chance、Paras N.Prasad、Barbara W.Henderson、AllanOseroff和Ravindra K.Pandey,A Novel Approach to a BifunctionalPhotosentizer for Tumor Imaging and Phototherapy.BioconjugateChemistry,2005,16,1264-1274.
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附图说明
图1示出了整联蛋白RGD肽复合物的晶体结构。扁平箭头指示β链和α螺旋的柱体。白色指示αv亚单位和卟啉、二氢卟酚或菌绿素,例如脱镁叶绿酸和焦脱镁叶绿酸,灰色指示β3亚单位。整联蛋白RGD肽(Arg-Gly-Asp-D-Phe-N-甲基缬氨酸)位于球棒图中示出的αv和β3亚单位之间。位于RGD肽附近的锰离子显示为球。
图2示出了Asp如何与得自β3亚单位的残基以及嵌入在β3亚单位中的Mn离子相互作用。具体地,中间的Mn离子直接与Asp侧链(COO-)基团配位。接着,这个Mn离子被Ser 121、Ser 123和Glu 220配位。这些残基又与另外两个Mn离子配位,所述另外两个Mn离子与得自β3亚单位的其它残基形成另外的配位。RGD肽的Asp侧链还与Asn 215直接相互作用。涉及3个Mn离子的相互作用的这种网状结构似乎是非常重要的稳定因素。
发明简述
本发明涉及化合物及其用于诊断、显像和/或治疗过度增生组织的方法,所述化合物是由肿瘤细胞表达的整联蛋白的拮抗剂与荧光染料或亲肿瘤性(tumor avid)四吡咯光敏剂中的至少一种的缀合物,其可与元素X复合,其中X是选自Zn、In、Ga、Al或Cu的金属、或放射性同位素标记的部分,其中放射性同位素选自11C、18F、64Cu、124I、99Tc、111In和GdIII,所述过度增生组织诸如肿瘤和其它生长不受控制的组织,例如在黄斑变性中发现的那些。
在优选的实施方案中,所述化合物是与由肿瘤细胞表达的整联蛋白的拮抗剂缀合的亲肿瘤性四吡咯光敏剂化合物。这种化合物具有极高的亲肿瘤性,并且可用于通过光吸收来抑制或完全破坏肿瘤。所述四吡咯光敏剂通常是卟啉、二氢卟酚或菌绿素,包括脱镁叶绿酸和焦脱镁叶绿酸,以及整联蛋白通常是αvβ3、α5β1、αvβ5、α4β1、或α2β1整联蛋白。
在优选实施方案中,所述拮抗剂是RGD肽或可以合成的另一种拮抗剂,诸如4-{2-(3,4,5,6-四氢嘧啶-2-基氨基)乙基氧基}-苯甲酰基]氨基-2-(S)-氨基乙基-磺酰基氨基基团。整联蛋白最通常是αvβ3。
拮抗剂可以与显像化合物诸如荧光染料或包含元素X的结构结合,其中X是选自Zn、In、Ga、Al或Cu的金属、或放射性同位素标记的部分,其中放射性同位素选自11C、18F、64Cu、124I、99Tc、111In。这种化合物提供亲肿瘤性和显像能力,因此能够进行选择性的和清晰的肿瘤显像。
本发明的目的包括:
1.用于制备αvβ3靶特异性光敏剂的有效的合成方法。
(a)与RGD缀合的光敏剂
(b)与整联蛋白拮抗剂缀合的光敏剂。
2.包含和不含RGD肽的多模态试剂(光敏剂-花青染料缀合物)。
3.靶特异性PET/荧光显像剂。
发明详述
如前讨论的,本发明涉及化合物及其用于诊断、显像和/或治疗过度增生组织的方法,所述化合物是由肿瘤细胞表达的整联蛋白的拮抗剂与荧光染料或亲肿瘤性四吡咯光敏剂中的至少一种的缀合物,其可与元素X复合,其中X是选自Zn、In、Ga、Al或Cu的金属、或放射性同位素标记的部分,其中放射性同位素选自11C、18F、64Cu、124I、99Tc、111In和GdIII,所述过度增生组织是诸如肿瘤和其它生长不受控制的组织,例如在黄斑变性中发现的那些。
在存在有四吡咯光敏剂的情况中,其通常为如下结构式:
及其与X的复合物;及其多核素(polynuclide)复合物,其中:
其中R9=-OR10,其中R10为1-8个碳原子的低级烷基、-(CH2-O)nCH3、-(CH2)2CO2CH3、-(CH2)2CONH亚苯基CH2DTPA、-CH2CH2CONH(CONH亚苯基CH2DTPA)2、-CH2R11或或荧光染料部分;R2、R2a、R3、R3a、R4、R5、R5a、R7和R7a独立地为氢、低级烷基或被取代的低级烷基,或者相邻碳原子上的两个R2、R2a、R3、R3a、R5、R5a、R7和R7a基团可合起来形成共价键,或者同一碳原子上的两个R2、R2a、R3、R3a、R5、R5a、R7和R7a基团可形成连接于二价侧基的双键;R2和R3可合起来形成包含氧、氮或硫的5元或6元杂环;R6为-CH2-、-NR11-或共价键;R8为-(CH2)2CO2CH3、-(CH2)2CONH亚苯基CH2DTPA、-CH2CH2CONH(CONH亚苯基CH2DTPA)2、-CH2R11或其中R11为-CH2CONH-RGD-Phe-Lys、-CH2NHCO-RGD-Phe-Lys、荧光染料部分或-CH2CONHCH2CH2SO2NHCH(CO2)CH2NHCO苯基OCH2CH2NH环CNH(CH2)3N;条件是该化合物包含至少一种整联蛋白拮抗剂,所述整联蛋白拮抗剂选自-CH2CONH-RGD-Phe-Lys、-CH2NHCO-RGD-Phe-Lys和-CH2CONHCH2CH2SO2NHCH(CO2)CH2NHCO苯基OCH2CH2NH环CNH(CH2)3N,其中X是选自Zn、In、Ga、Al或Cu的金属或放射性同位素标记的部分,其中放射性同位素选自11C、18F、64Cu、124I、99Tc、111In和GdIII。
与X的复合物可以简单地通过将化合物与X的盐诸如氯化物一起加热而容易地制备。该复合物会形成为如果存在的DTPA部分的螯合物、或在四吡咯结构内在胺结构的氮原子之间的螯合物、或两种情况都有。这种结构的实例是:
M=2H,或
M=In、Cu、Ga(包含或不含放射性同位素)
和
M=2H,或
M=In、Cu、Ga(包含或不含放射性同位素)
其中,X=M。
在其中荧光染料与整联蛋白拮抗剂(经常为配体)缀合的情况中,荧光染料可以是引起缀合物优先在800-约900nm发射(荧光)的任何无毒的染料,例如靛青染料。这种染料通常具有通过共轭双键、芳香族碳环、共振杂环、或其组合的中间共振结构连接在一起的至少两个共振的环状结构(经常是发色团)。
这种染料的实例包括双吲哚染料,其中两个吲哚或经过修饰的吲哚环结构在它们的32和21碳原子处分别由前述的中间共振结构连接在一起。这种染料通常被称为三碳菁(tricarboclyanine)染料。这种染料几乎总是具有至少一个,且通常具有至少两个亲水性取代基,使得染料具有水溶性。这种水溶性促进了该结构进入生物体及其细胞结构中,并由于在脂肪组织中的储存减少和从系统的快速清除而减少了毒性的可能性。中间共振结构通常包含多个双键碳原子,所述双键碳原子通常是共轭双键并且还可以包含不饱和的羧基环(carboxylic rings)或杂环。这种环使得能够与卟啉或其它结构缀合,而不显著地妨碍该中间结构的共振。优选的染料是吲哚菁绿。
在将放射性同位素与整联蛋白拮抗剂合并时,该放射性同位素可以通过共价键或半离子键而化学结合于该化合物,或者可被螯合进该化合物中。在这种情况中,该化合物经常包括已知的螯合结构诸如DTPA。
172(175-N-叔丁基-亚乙基-二酰胺基-)焦脱镁叶绿酸-a 2的制备。
反应路线1
根据文献方法从螺旋藻(spirolina algae)得到焦脱镁叶绿酸-a羧酸1(200mg)。将其溶解于无水二氯甲烷(DCM)(5ml)中,在氮气下向该溶液中依次添加三乙胺(0.3ml)、Boc-保护的二乙胺(66.6ul)和BOP(146mg),在排空(2-3次)之后,将反应混合物在N2下在室温搅拌过夜。将反应混合物浓缩并在二氧化硅上进行色谱纯化(洗脱剂:含4%甲醇的二氯甲烷)并分离得到期望的化合物2作为主要产物。收率90%。NMR(AMX400):(CDCl3,δppm):9.35,9.15和8.50(都是单峰,1H,环间的H);7.80(m,IH CH=CH2);6.25,6.1(都是双峰,1H,CH-CH2);5.22(dd,2H,-CH2环外的环);4.41(q,1H,18H);4.28(d,1H,17H);3.75(q,2H,CH2-CH3);3.62,3.4,3.25(都是单峰,3H,环的-CH3),2.8-2.0(几个多重峰,CH2-CH2-CO-NH-CH2-CH2-NH),1.2(s,9H,Boc)。
焦脱镁叶绿酸-环(Lys-Arg-Gly-Asp-L-Phe)缀合物的制备。
反应路线2
将焦脱镁叶绿酸2用90%的三氟乙酸(TFA)处理,以除去Boc基团,在旋转蒸发器上除去TFA并将3高真空干燥用于进一步反应。将3(15mg)溶解于无水DCM中,在N2下向该溶液中添加环(Lys-Arg-Gly-Asp-L-Phe)(20mg)和EDCI(12mg)。将反应混合物在N2下在室温搅拌过夜。将反应混合物浓缩并在制备性二氧化硅板上进行色谱纯化(洗脱剂:含10%甲醇的二氯甲烷)。将分离的化合物进一步用90%TFA/DCM处理3-4小时,以得到期望的焦脱镁叶绿酸4。旋转蒸发除掉TFA并将化合物进一步在HPLC上纯化,使用C-18柱(洗脱剂:从含90%MeOH的水到100%MeOH的梯度,流速0.5ml/min)。产量为10mg。质谱:m/z=1161(M+H)+
中-紫红素酰亚胺(meso-Purpurinimide)6的制备。
反应路线3
将中-紫红素酰亚胺(60mg)和Boc-保护的二乙胺(2.24g)溶解于最少量的DCM中并将反应混合物在N2下室温搅拌48小时。UV-VIS显示吸光度从685nm完全位移到651nm。向这个反应混合物中添加新制备的重氮甲烷(200-400mg)并通过TLC(含5%MeOH的DCM)监控反应。在10分钟后,UV-VIS显示在651nm处的峰完全消失,和在695nm处的产物峰。立即将反应混合物用含2%乙酸的水洗涤,然后用水洗涤(x3),将化合物用Na2SO4干燥,浓缩并在二氧化硅上进行色谱纯化(洗脱剂:含2-3%甲醇的二氯甲烷),将分离的化合物进一步用90%TFA/DCM处理3-4小时,旋转蒸发除掉TFA,得到期望的化合物6作为主要产物。收率90%。NMR(AMX400):9.54(s,1H,10H);9.16(s,1H,5H);8.4(s,1H,20H);5.34(m,1H,17H),4.67(m,2H,N-CH2),4.34(q,1H,18H),3.78,3.58,3.23,3.15(都是3H,分别为12CH3,172 CH3,2CH3,7CH3),3.74(q,2H,8′CH2),3.605(CH 2 -CH3),2.71(m,1H,1x172H),2.402(m,2H,2x171H),2.0(m,1H,172H),1.76(d,3H,18CH3),1.7-1.64(8H,82CH2-CH 3 ,3CH2-CH 3 ,N-CH2-CH 2 -NH2),0.11-.1(2H,都是单峰,-NH)。
中-紫红素酰亚胺-环(Cys-Arg-Gly-Asp-L-Phe)缀合物8的制备。
反应路线4
将中-紫红素酰亚胺6(17mg)溶解于无水DCM,在N2下向该溶液中添加环(Lys-Arg-Gly-Asp-L-Phe)(20m g)和EDCI(12mg)。将反应混合物在N2下在室温搅拌过夜。将反应混合物浓缩并在制备性二氧化硅板上进行色谱纯化(洗脱剂:含10%甲醇的二氯甲烷)。将分离的化合物进一步用90%TFA/DCM处理3-4小时,以得到中-紫红素酰亚胺-环(Lys-Arg-Gly-Asp-L-Phe)缀合物8。旋转蒸发除去TFA并将化合物高真空干燥。产量为19mg。质谱:m/z=1207(M+H)+。
焦脱镁叶绿酸-环(Lys-Arg-Gly-Asp-D-Phe)缀合物8的制备。
反应路线5
根据文献方法从螺旋藻得到焦脱镁叶绿酸-a羧酸7(200mg)。将7(14mg)溶解于无水DCM,在N2下向该溶液中添加环(Lys-Arg-Gly-Asp-D-Phe)(20mg)、EDCI(12mg)和DMAP(12mg),将反应混合物在N2下在室温搅拌过夜。将反应混合物浓缩并在制备性二氧化硅板上进行色谱纯化(洗脱剂:含10%甲醇的二氯甲烷)。将分离的化合物进一步用90%TFA/DCM处理3-4小时,并将固体产物用MeOH洗涤,得到期望的焦脱镁叶绿酸-环(Lys-Arg-Gly-Asp-D-Phe)缀合物8,旋转蒸发除去TFA并将化合物真空干燥。产量为10mg。质谱:m/z=1119.6(M+H)+。
中-紫红素酰亚胺-甘氨酸酯10的制备
反应路线6
将58mg的紫红素-18溶解于最少量的甲苯中,向该溶液中添加甘氨酸-叔丁基酯盐酸盐和10-15滴的三乙胺,使反应在N2下回流,在3小时之后,UV-VIS显示起始原料的在696nm处的峰完全消失,并出现在705nm处的新峰,将反应混合物浓缩并在二氧化硅上进行色谱纯化(洗脱剂:含2%甲醇的二氯甲烷),并分离得到期望的中-紫红素酰亚胺-甘氨酸酯10作为主要产物。收率为90%。NMR(AMX400):9.64(s,1H,10H),9.39(s,1H,15H),8.58(s,1H,20H),7.84(d,1H,3CH-CH2),6.16(d,1H,3CH=CH2),5.4(m,1H,17H),4.46(m,2H,N-CH2-CH 2 -CO2H),4.31(q,1H,18H),3.84(s,3H,7CH3);2.68和2.39(都是m,1H+2H,2x 171H);1.99(m,1H,1X172H);1.74(d,3H,18CH3),1.64(t,3H,82 CH3);0.07和-0.16(都是宽峰,1H,2NH)。
中-紫红素酰亚胺-甘氨酸-环(Lys-Arg-Gly-Asp-D-Phe)缀合物12的制备。
反应路线7
将中-紫红素酰亚胺-甘氨酸酯10(17mg)溶解于无水DCM,在N2下向该溶液中添加环(Lys-Arg-Gly-Asp-D-Phe)(20mg)、EDCI(12mg)和DMAP(12mg),将反应混合物在N2下在室温搅拌过夜。将反应混合物浓缩并将固体粉末用MeOH洗涤。将分离的化合物进一步用90%TFA/DCM处理3-4小时,得到期望的中-紫红素酰亚胺-甘氨酸-环(Lys-Arg-Gly-Asp-D-Phe)缀合物12,旋转蒸发除去TFA,用MeOH洗涤并真空干燥。产量为20mg。质谱:m/z=1220(M+H)+。
单-I-Cypate的制备。
反应路线8
将Cypate 13(260mg,0.4mM)溶解于无水DMF(10-15ml)中,在N2下向该溶液中添加间-I-苄胺(92mg,0.4mM)、EDCI(92mg,0.48mM)和HoBt(64.75mg,0.48mM),将反应混合物在N2下在室温搅拌过夜。在过夜反应之后,高真空除去DMF,并将反应混合物用盐水(x3)和水(x3)洗涤,用Na2SO4干燥并浓缩。在Si柱上进行纯化,使用MeOH/DCM作为洗脱剂。产量为57mg(17%)。质谱:m/z=839(M+H)+。NMR(AMX400):7.25-8.03(m,16H,芳香族),6.28-6.80(m,4H,-CH),2.47-3.0(m,10H,CH2),1.88(s,12H,CH3)。
单-I-Cypate-环(Lys-Arg-Gly-Asp-D-Phe)缀合物16的制备。
反应路线9
将单-I-Cypate(30mg)溶解于无水DCM,在N2下向该溶液中添加环(Lys-Arg-Gly-Asp-D-Phe)(20mg)、EDCI(12mg)和DMAP(12mg),将反应混合物在N2下在室温搅拌过夜。在过夜搅拌之后,将反应混合物浓缩并在制备性二氧化硅板上进行色谱纯化(洗脱剂:含13%甲醇的二氯甲烷)。将分离的化合物进一步用90%TFA/DCM处理3-4小时,并进一步在HPLC(Waters,Delta 600,带有996光二极管矩阵检测器)上分析和纯化油状的产物。分析柱:Waters Symm-C-81,4.6x150mm,5μ;半制备柱:Waters Symm-C-18,7.8x150mm,7μ;使用乙腈/水作为洗脱剂(梯度:从30%到100%ACN),得到期望的单-I-Cypate-环(Lys-Arg-Gly-Asp-D-Phe)缀合物16,产量为24mg。质谱:m/z=1424(M+H)+。
焦-IA(甲基酯)(19):
在氮气气氛下向3-[4-{2-(3,4,5,6-四氢嘧啶-2-基氨基)乙基氧基}-苯甲酰基]氨基-2-(S)-氨基乙基磺酰基氨基丙酸甲酯(17)(47mg,0.1mmol)和焦羧酸(pyrocarboxylic acid)(18)(60mg,0.11mmol)在无水DMF(5.0mL)中的溶液添加PyBOP(65mg,0.12mmol)和无水三乙胺(0.3mL),将得到的反应混合物在室温下搅拌过夜。然后将反应混合物旋转蒸发到干燥并在纯化粗反应混合物后得到期望的产物(19),所述纯化首先在制备性二氧化硅TLC板上进行(洗脱剂:含10%MeOH的CH2Cl2)、随后用短的二氧化硅柱进行(洗脱剂:含8%MeOH的CH2Cl2)。产量为50mg(50%)。
1H-NMR(含10%CD3OD的CDCl3;400MHz):δ9.39,9.28和8.56(都是单峰,1H,环间的-H);7.95(dd,J=11.4,18.2,1H,3-乙烯基);7.73(d,J=8.8,2H,ArH);6.84(d,J=8.8,2H,ArK);6.28(d,J=17.6,1H,3-乙烯基);6.18(d,J=11.6,1H,3-乙烯基);5.26(d,J=20,1H,132-CH2);5.06(d,J=20,1H,132-CH2);4.51(m,1H,18-H);4.30-4.20(m,2H,CH和17-H);4.00(t,J=5.0,2H,OCH2);3.85(m,1H,CONHCH 2 );3.67(s,3H,环CH3);3.62(m,2H,8-CH 2 CH3);3.60(m,1H,CONHCH 2 );3.58(s,3H,OCH3);3.42(t,J=5.0,2H,SO2 CH 2 );3.38(s,3H,环CH3);3.37-3.31(m,6H,3x NHCH 2 );3.19(s,3H,环CH3);3.14(m,2H,3x NCH2);2.66,2.45,2.28,2.20(都是多重峰,4H,171和172-H);1.93(t,J=5.6,2H,CH2);1.80(d,J=7.2,3H,18-CH3);1.68(t,J=7.8,3H,8-CH2CH 3 )。C52H62N10O8S的质谱:986.45(计算值);986.6(实测值,M+)。
焦-整联蛋白拮抗剂-IA(20):
在氩气气氛下向焦-IA(甲基酯)(19)(40mg)在无水THF(10mL)中的溶液添加LiOH(80mg,在5+4mL的H2O+MeOH中)溶液并将反应混合物搅拌45分钟。然后将反应小心地用阳离子交换树脂中和。将树脂滤出并将反应混合物旋转蒸发到干燥。没有进行纯化产物的进一步尝试。产量为35mg(90%)。1H-NMR(含25%CD3OD的CDCl3;400MHz):δ9.39,9.28和8.56(都是单峰,1H,环间的-H);7.95(dd,J=11.4,18.2,1H,3-乙烯基);7.73(d,J=8.8,2H,ArH);6.84(d,J=8.8,2H,ArH);6.28(d,J=17.6,1H,3-乙烯基);6.18(d,J=11.6,1H,3-乙烯基);5.26(d,J=20,1H,132-CH2);5.06(d,J=20,1H,132-CH2);4.51(m,1H,18-H);4.30-4.20(m,2H,CH和17-H);4.00(t,J=5.0,2H,OCH2);3.85(m,1H,CONHCH 2 );3.67(s,3H,环CH3);3.62(m,2H,8-CH 2 CH3);3.60(m,1H,CONHCH 2 );3.42(t,J=5.0,2H,SO2CH 2 );3.38(s,3H,环CH3);3.37-3.31(m,6H,3xNHCH 2 );3.19(s,3H,环CH3);3.14(m,2H,3x NCH2);2.66,2.45,2.28,2.20(都是多重峰4H,171和172-H);1.93(t,J=5.6,2H,CH2);1.80(d,J=7.2,3H,18-CH3);1.68(t,J=7.8,3H,8-CH2CH 3 )。C52H62N10O8S的质谱:972.4(计算值);972.6(实测值,M+)。
紫红素酰亚胺-Gly-IA(甲基酯)(22):
在氮气气氛下向3-[4-{2-(3,4,5,6-四氢嘧啶-2-基氨基)乙基氧基}-苯甲酰基]氨基-2-(S)-氨基乙基磺酰基氨基丙酸甲酯(17)(20mg,0.04mmol)和甘氨酸紫红素酰亚胺(21)(20mg,0.03mmol)在无水DMF(3.0mL)中的溶液中添加PyBOP(20mg,0.04mmol)和无水三乙胺(0.1mL)并将得到的反应混合物在室温下搅拌过夜。然后将反应混合物旋转蒸发至干燥并在纯化粗的反应混合物之后得到期望的产物(22),所述纯化首先用制备性二氧化硅TLC板(洗脱剂:含10%MeOH的CH2Cl2),随后用短的二氧化硅柱(洗脱剂:含8%MeOH的CH2Cl2)。产量为15mg(45%)。
1H-NMR(含10%CD3OD的CDCl3;400MHz):δ9.07,8.94和8.58(都是单峰,1H,环间的-H);7.82(dd,J=11.4,18.2,1H,3-乙烯基);7.70(d,J=8.8,2H,ArH);6.75(d,J=8.8,2H,ArH);6.26(d,J=17.6,1H,3-乙烯基);6.16(d,J=11.6,1H,3-乙烯基);5.25(d,J=7.2,1H,17-H);5.10(dd,J=8.6,16.0,2H,NCH2);4.42(dd,J=4.4,7.6,1H,CH);4.35(q,J=6.8,1H,18-H);3.89(m,2H,OCH2);3.85(m,1H,CONHCH 2 );3.80(m,2H,NHCH 2 );3.72,3.52,3.36,3.33和2.85(都是单峰,都是3H,3x环CH3和2x OCH3);3.67(m,1H,CONHCH 2 );3.35(m,4H,2x NHCH 2 );3.26(m,4H,8-CH 2 CH3和SO2CH 2 );3.15(m,2H,NCH2);3.62(m,2H,8-CH 2 CH3);2.68,2.38,1.98(都是多重峰4H,171和172-H);1.83(t,J=5.6,2H,CH2);1.80(d,J=7.2,3H,18-CH3);1.41(t,J=7.8,3H,8-CH2CH 3 )。C55H65N11O11S的质谱:1087.46(计算值);1087.8(实测值,M+)。
紫红素酰亚胺-Gly-IA(23):
反应路线10
在氩气气氛下向紫红素酰亚胺-Gly-IA(甲基酯)(22)(15mg)在无水THF(7mL)中的溶液中添加LiOH(30mg,在4+3mL的H2O+MeOH中)溶液并将反应混合物搅拌45分钟。然后将反应小心地用阳离子交换树脂中和。将树脂滤出并将反应混合物旋转蒸发到干燥。没有进行纯化产物的进一步尝试。产量为12mg(85%)。
1H-NMR(含25%CD3OD的CDCl3;400MHz):δ9.07,8.94和8.58(都是单峰,1H,环间的-H);7.82(dd,J=11.4,18.2,1H,3-乙烯基);7.70(d,J=8.8,2H,ArH);6.75(d,J=8.8,2H,ArH);6.26(d,J=17.6,1H,3-乙烯基);6.16(d,J=11.6,1H,3-乙烯基);5.25(d,J=7.2,1H,17-H);5.10(dd,J=8.6,16.0,2H,NCH2);4.42(dd,J=4.4,7.6,1H,CH);4.35(q,J=6.8,1H,18-H);3.89(m,2H,OCH2);3.85(m,1H,CONHCH 2 );3.80(m,2H,NHCH 2 );3.36,3.33和2.85(都是单峰,都是3H,3x环CH3);3.67(m,1H,CONHCH 2 );3.35(m,4H,2x NHCH 2 );3.26(m,4H,8-CH 2 CH3和SO2CH 2 );3.15(m,2H,NCH2);3.62(m,2H,8-CH 2 CH3);2.68,2.38,1.98(都是多重峰,4H,171和172-H);1.83(t,J=5.6,2H,CH2);1.80(d,J=7.2,3H,18-CH3);1.41(t,J=7.8,3H,8-CH2CH 3 )。C55H65N11O11S的质谱:1059.43(计算值);1059.8(实测值,M+)。
Claims (12)
1.化合物,包括由肿瘤细胞表达的整联蛋白的拮抗剂与亲肿瘤性四吡咯光敏剂、荧光染料以及元素X中的至少一种的缀合物,其中X是含金属的部分或放射性同位素标记的部分,所述金属选自Zn、In、Ga、Al或Cu,所述放射性同位素选自11C、18F、64Cu、124I、99Tc、111In和GdIII。
2.权利要求1的化合物,包括与由肿瘤细胞表达的整联蛋白的拮抗剂缀合的亲肿瘤性四吡咯光敏剂化合物。
3.权利要求1的化合物,其中光敏剂是卟啉、二氢卟酚或菌绿素,包括脱镁叶绿酸和焦脱镁叶绿酸。
4.权利要求2的化合物,其中整联蛋白是αvβ3、α5β1、αvβ5、α4β1或α2β1整联蛋白。
5.权利要求3的化合物,其中整联蛋白是αvβ3、α5β1、αvβ5、α4β1或α2β1整联蛋白。
6.权利要求2的化合物,其中拮抗剂是RGD肽。
7.权利要求2的化合物,其中拮抗剂包括4-{2-(3,4,5,6-四氢嘧啶-2-基氨基)乙基氧基}-苯甲酰基]氨基-2-(S)-氨基乙基-磺酰基氨基基团。
8.权利要求6的化合物,其中整联蛋白是αvβ3。
9.权利要求7的化合物,其中整联蛋白是αvβ3。
10.权利要求1的化合物,具有以下结构式:
及其与X的复合物、及其多核素复合物,其中
R1为-CH=CH2、-CH2CH3、-CHO、-COOH、或
其中R9=-OR10,其中R10为1-8个碳原子的低级烷基、-(CH2-O)nCH3、-(CH2)2CO2CH3、-(CH2)2CONH亚苯基CH2DTPA、-CH2CH2CONH(CONH亚苯基CH2DTPA)2、-CH2R11或或荧光染料部分;R2、R2a、R3、R3a、R4、R5、R5a、R7和R7a独立地为氢、低级烷基或被取代的低级烷基,或者相邻碳原子上的两个R2、R2a、R3、R3a、R5、R5a、R7和R7a基团可合起来形成共价键,或者同一碳原子上的两个R2、R2a、R3、R3a、R5、R5a、R7和R7a基团可形成连接于二价侧基的双键;R2和R3可合起来形成包含氧、氮或硫的5元或6元杂环;R6为-CH2-、-NR11-或共价键;R8为-(CH2)2CO2CH3、-(CH2)2CONH亚苯基CH2DTPA、-CH2CH2CONH(CONH亚苯基CH2DTPA)2、-CH2R11或其中R11为-CH2CONH-RGD-Phe-Lys、-CH2NHCO-RGD-Phe-Lys、荧光染料部分或-CH2CONHCH2CH2SO2NHCH(CO2)CH2NHCO苯基OCH2CH2NH环CNH(CH2)3N;条件是该化合物包含至少一种整联蛋白拮抗剂,所述整联蛋白拮抗剂选自-CH2CONH-RGD-Phe-Lys、-CH2NHCO-RGD-Phe-Lys和-CH2CONHCH2CH2SO2NHCH(CO2)CH2NHCO苯基OCH2CH2NH环CNH(CH2)3N,其中X是选自Zn、In、Ga、Al或Cu的金属或放射性同位素标记的部分,其中放射性同位素选自11C、18F、64Cu、124I、99Tc、111In和GdIII。
11.权利要求1的化合物,包括由肿瘤细胞表达的整联蛋白的拮抗剂与荧光染料的缀合物。
12.权利要求1的化合物,其中荧光染料是靛青染料。
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US8609837B2 (en) * | 2010-07-06 | 2013-12-17 | Health Research, Inc. | Metallation enhancements in tumor-imaging and PDT therapy |
WO2012103328A1 (en) * | 2011-01-26 | 2012-08-02 | The Methodist Hospital Research Institute | Labeled, non- peptidic multivalent integrin alpha -v - beta - 3 antagonists, compositions containing them and their use |
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US4968715A (en) * | 1988-07-06 | 1990-11-06 | Health Research, Inc. | Use of purified hematoporphyrin trimers in photodynamic therapy |
US5198460A (en) * | 1988-07-20 | 1993-03-30 | Health Research Inc. | Pyropheophorbides and their use in photodynamic therapy |
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US6566517B2 (en) * | 2001-06-06 | 2003-05-20 | Brookhaven Science Associates, Llc | Metalloporphyrins and their uses as imageable tumor-targeting agents for radiation therapy |
US20060198783A1 (en) * | 2005-02-25 | 2006-09-07 | Health Research, Inc., Roswell Park Cancer Institute Division | Porphyrin-based compounds for tumor imaging and photodynamic therapy |
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