CN1193625A - 用于络合金属离子的多氮大环化合物 - Google Patents
用于络合金属离子的多氮大环化合物 Download PDFInfo
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- CN1193625A CN1193625A CN96122080A CN96122080A CN1193625A CN 1193625 A CN1193625 A CN 1193625A CN 96122080 A CN96122080 A CN 96122080A CN 96122080 A CN96122080 A CN 96122080A CN 1193625 A CN1193625 A CN 1193625A
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
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Abstract
本发明涉及一种新的多氮大环化合物或其盐及其用途。化合物的化学式为(右式),其中X是2,3或P2(s)和q3(s)的结合,而p+q=y;y是3或4;R是(CH2)2P(=O)R1R2;R1是R3或OR3而R3是烷基,环烷基或芳基,R2是H,烷基或而R4是烷基,环烷基或芳基,z是1—3。在一个重要实施方案中,该化合物与金属络合成多氮大环化合物—金属络合物,其化学式为(上式),其中r是2或3且Mc是一种金属离子。
Description
本申请是1989年5月25日向美国申请的序号为07/357193和1988年12月28日申请的序号为07/291053的专利申请的部分续申请,这两个申请在此结合作为参考。而07/291053申请是1987年1月27日申请的007729号申请的部分续申请,而后者又是1984年10月18日申请的序号为662076号申请(已批准,专利号为4639365)的部分续申请。
本发明涉及一系列新的含磷大环螯合物,它们结合一定的生物离子而具有相对的特性。当金属离子占据螯合物的空位时,这些螯合物的31P共振在核磁共振谱(NMR)中漂移到一个新位置,并且这种结合整合物的NMR化学漂移对每个金属离子都不一样。这种性质对于利用31P NMR来监视某些生物阳离子的胞间浓度应是有用的,该阳离子包括如Mg2+、Ca2+和Zn2+。还有几种商业可用的、可测量胞间阳离子浓度的萤光螯合物和可用于NMR目的的含1或2个氟的螯合物。萤光螯合物不可能用于人体研究,而19F螯合物也不可能象本发明的31P螯合物那样用于临床。此外,某些螯合剂结合Gd3+后具有的性质使其成为安全有效的磁共振图的对比剂。
很多的生物体系需要抗磁阳离子,如Ca2+、Mg2+和Zn2+来调节各种反应。Ca2+作为一种胞间信息离子在很多类型细胞中的作用已被很好地确认[1]。实际上对所有包括ATP的生物反应而言Mg2+是一种所需的辅因子,并在较多的各种生物反应的缓冲过程中广泛地起作用[2]。Zn2+被相当紧密地结合在几种酶的活性位置上,它的作用看来似乎包括化学键的极化,以助于键的水解、氧化还原或基团转移反应。然而,在某些细胞如脑细胞中,游离的Zn2+可以起更广泛的作用,并认为游离的Zn2+象存贮颗粒一样被存于神经元中,并在电生理活化期间可以移动[3]。
利用现有测量细胞和充盈器官中游离阳离子浓度的直接方法来评价两价阳离子在细胞功能中的作用是受限制的。目前可用的测量两价阳离子的方法包括基于平衡反应的间接计算[4],离子选择的微电极[5,6],和用金属显色染料的零点测量,该染料既可显微注入细胞[7]又可置于胞外随后溶解在细胞的空间内[8,9]。实际上所有这些方法实质上是侵入型的,且在分析前需损坏样品。与此相反,NMR作为一种非侵入型的工具有显著优点,尤其是测量充盈器官和完整无损的细胞中胞间游离的两价阳离子浓度。
最近,氟化的螯合物已被有效地以19FNMR用来测量细胞和充盈器官中胞间游离的Ca2+[10,11]和Mg2+[12,13]。这些螯合物在分离的细胞体系中可适当良好地工作,而用在充盈器官时则遇到意外的界限(line)变宽[13,14]。这些体系的另一缺点是合成这些化合物的路线限制了可能的螯合结构,因此也限制了可设计螯合物的金属离子的选择性。本发明的目的包括合成和开展一系列的三氮和四氮大环膦酸单酯和烷基亚膦酸酯作为31PNMR指示剂来检测生物体系中胞间游离阳离子。
本发明还涉及活体的NMR图,有时称作MRI(磁共振图)。特别涉及一种试剂,它可用来增强这些物体中NMR的对比度。
核磁共振(NMR)作为一种化学分析手段已应用多年了。NMR是种射频谱的类型,它的基础是带电原子核的自旋平行或逆平行于所加磁场而产生的小能量差别。当射频能量施加到样品时,这些自旋原子核改变了自旋状态,正因如此则吸收一些射频能量。在同样的分子内化学环境稍有差别的原子核以稍有不同的能量改变了自旋状态,这就产生了有助于鉴别分子结构的特征吸收或共振。
NMR用于人体检查的时间要更近一些。如计算机轴向断层照象(CAT扫描)的其他方法过去是现在仍然是用来检查人体。然而,由于NMR不使用电离辐射,可以认为它在安全性方面的优点超过CAT。因此在制备人体横截面图象方面NMR是种优越的方法。
NMR扫描获得图象的质量取决于两个性质:各种组织的质子密度和质子松驰速度的差别。组织的质子密度不能轻易改变,而质子松驰速度可通过加入顺磁松驰剂来调节,它通常叫作“对比剂”(contrast agent)。对比剂增大了磁性相似但组织学上不相似的组织之间NMR图象的对比度。
过去常把钆当对比剂用来进行试验,因它有个大磁惯量,可有效地松驰磁性原子核。钆的强顺磁性质归因于它的七个未成对的电子。
钆作为对比剂的一个缺点是它对动物的毒性。对这个问题的一个可能的补求办法是将钆结合成化合物,以化合物通过体内并被排泄而不释放有毒的钆离子。遗憾的是象钆那样的稀土元素并不能与有机分子形成稳定的共价键,所以,这种分子会在体内分解并释出有毒离子。
这就需要一种有效的对比剂能避开前述使用钆时的毒性问题。进面需一种新型更好的对比剂,不管它们包括钆还是其他顺磁金属。
本发明涉及一种新型多氮大环化合物或其盐及其用途。该化合物通式为:
其中x是2,3或P2(s)和q3(s)的结合。这里的p+q=y;y是3或4;R是(CH2)zP(=0)OR′R2,R1是R3或OR3,R3是烷基,环烷基或芳基;R2是H,烷基或
;R4是烷基,环烷基或芳基;(R3和R4在同样分子中可相同或不相同),Z是1-3。
一个优选的烷基是CnH1+2n,这里的n是1-20;优选的环烷基是CnH2m-1,其中m是1-20;优选的芳基是苯基。
其中x是2,3或P2(s)和q3(s)的结合。这里的p+q=y;y是3或4;R是(CH2)zP(=0)OR′R2,R1是R3或OR3,R3是烷基,环烷基或芳基;R2是H,烷基或
;z是1-3;r是2或3;且Me是一金属离子。
y设计表征为象三氮或四氮大环那样的化合物。虽然在许多情况里x有可能为3但优选2。对x的P2(s)和q3(s)之结合当然容易得到,但在多氮大环中众多单元而言p+q之和必是y。
在化合物或其金属络合物的一个优选实施方案中,y是3,p是1且q是2或者p是2而q是1。
在化合物或其金属络合物的另一优选实施方案中y是4,p是1且q是3,p是2且q是2或p是3而q是1,z最佳为1,n优选为2。
在一更佳的实施方案中x是2,y是4,z是1,且R1是R3。
在另一个优选实施方案中x是2,y是3,z是1,R1是OR2且n是2。
Me+r最好是Ca2+,Mg2+,Zn2+或Gd3+。其他特性的两价或三价金属离子,特别是顺磁的镧也可如此被络合。
其中x是2,3或p2(s)和q3(s)的结合且q+p=y;y是3或4;R是(CH2)zP(=0)OR1R2;R1是R3或OR3;R3是烷基,环烷基或芳基。R2是H,烷基或
;R4是烷基、环烷基或芳基;z是1-3;然后测量在31PNMR谱中的漂移,所说的漂移与胞间两价金属浓度成比例关系。在一实施方案中,用本发明化合物的酸酐(即其中R2是
)形式来处理细胞,将其通入细胞,在那里水解成酸的形式(即R2是H)并与胞间金属离子络合。最适合于这种测量的金属通常是钙,镁或锌,优选镁。
在一个重要应用中,本发明包括可增强某种物质的磁共振图谱的方法。该方法包括施予该物质一种多氮大环化合物-金属络合物,然后得出该物质的磁共振图,所说的络合物化学式为:
其中x是2,3或p2(s)和q3(s)的结合且p+q=y;y是3或4;R是(CH2)zP(=0)OR1R2;R1是R3或OR3;R3是烷基,环烷基或芳基;R2是H,烷基或
;R4是烷基,环烷基或芳基;z是1-3;r是2或3且Me是顺磁金属(优选钆)。
图1示意说明NOTPME的结构(其中R是CH2CH3且R1是H)。
图2说明2mM的NOTPME(a)和存在等当量Ca2+(b),Mg2+(c)和Zn2+(d)时所得出的电位滴定曲线。
图3表示5mM的NOTPME的31PNMR谱与所添加镁(总数)的函数关系。从底部到顶部Mg2+浓度分别是0,0.5,1.5和3mM。样品构成和光谱参数见方法部分的叙述。
图4表明存在(A)2.05mM ZnCl2和(B)38.5mM CaCl2时5mM NOTPME的31PNMR谱图。样品组成和光谱参数在方法部分中给出。
图5说明5mM NOTPME(a),Ca(NOTPME)(b),Zn(NOTPME)(c)和Mg(NOTPME)(d)的31PNMR化学漂移和PH的依赖关系。
图6显示正常RBCs(a)和负载NOTPME的RBCs(b)的31PNMR谱图。
图7示意说明DOTEP的结构。
图8呈现DOTEP和DOTEP-钙络合物的31PNMR谱图。
图9叙述了钆-DOTA和钆-DOTEP在0.1NHCl中的分解速度。
图10示意说明1,5,9-三氮环十二烷化合物。
图11示意说明1,4,8,12-四氮环十五烷化合物。
图12示意说明1,4,8,11-四氮环十四烷化合物。
实施例1三氮大环化合物
合成1,4,7-三氮环壬烷-N,N′,N″-三(亚甲基磷酸单乙酯)(NOTPME),将其特征化并分析以用作胞间Mg2+和Zn2+离子的31PNMR指示剂。这种螯合物在存在金属离子的31PNMR谱图显示游离螯合物,Mg(NOTPME),Zn(NOTPME)和Ca(NOTPME)的特性共振。通过电势分析法和NMR得到Ca2+和Mg2+络合NOTPME的稳定常数,以及通过电势分析法得其与Zn2+的稳定常数。这种螯合物在生理PH值时对Mg2+的亲合力高于对Ca2+的十倍。对Zn2+的亲合力如此之高使得实际的结合常数不能以NMR来测定。在Mg2+存在下,NOTPME很容易被载入血红细胞。游离螯合物和它的金属络合物的31P化学漂移位于生物体系中对常规含磷代谢产物观察到的很远的下区域(downfield),因而使得能够监测细胞间阳离子浓度和同时发生的细胞力能。原料
从Aldrich化学公司购买1,4,7一三氮环壬烷,多氮甲醛,二乙基亚磷酸盐和活性炭Darco G-60。从Mallickrodt购买MgS-O4,从J.T.Baker购氢氧化钠和苯,从Fisher Scientific买二乙醚。所有化学药剂皆为高纯物,无需进一步纯化。配制标准的ZnCl2,CdCl2,MgCl2和CaCl2溶液。合成NOTPME
将1,4,7-三氮环壬烷(1.91克,14.71mmol)和二乙基亚磷酸盐(7.018克,16.94mmol,过量15%)溶在125ml苯中并回流加热。将无水多聚甲醛(1.727克,30%过量)以小部分加到上述回流混合物中,同时以蒸馏除去苯水共沸混合物。加入多聚甲醛后就是复合体,整个溶液沸腾30分钟,然后蒸发得到黄色粘状油。将该油溶于150ml无水二乙基醚并用无水MgSO4干燥过夜。随着白色沉淀的形成将MgSO4滤掉并丢弃。滤液以活性炭脱色并过滤。再将此滤液真空蒸发得到1,4,7-三氮环壬烷-N,N’,N”-三(亚甲基磷酸二乙酯)(NOTPDE)粘性油。得到纯NOTPDE的产率为96%(9.21克,14.17mmol)并用它来合成NOTPDE(结构见图1)而无需进一步纯化。NOTPDE在CDCl3中的1H NMR数据如下(TMS为零):δ(ppm):1.33(t,18H,-CH3),2.97(s,12H,N-CH2),3.00(d,6H,O-CH2),4.13(P,12H,O-CH2)。
将9.20克(14.15mmol)NOTPDE与2.50克NaOH(在9ml水中)混和,2小时后将整个反应混合物沸腾,直至得到清液(大约5分钟)。溶液冷却到室温并让它静置过夜。用带有粗孔级滤盘的压力过滤漏斗从粘性母液中滤出形成的晶体。用冷无水乙醇将晶体洗涤一次,再用无水乙醇-二乙醚(1∶1)混合物洗涤三次,最后用二乙醚洗涤。把Na2NOTPME晶体在干燥氮气流中于25℃干燥2小时。于50℃将NOTPME真空(10mmHg)干燥5小时除去微量的水和乙醇。而后得到纯的NOTPME白色晶体,极易吸潮,易溶于水并颇溶于氯纺。纯NOTPME的产率是40.8%(3.24克,5.77mmol)。
1H NMR(参照位于4.90ppm的D2O、HDO峰),δ(ppm):1.23(t,9H,-CH3),2.54(s,宽峰,6H,p-CH2),2.79(2,宽峰,12H,N-CH2,3.91(P,6H,o-CH2)。NMR测量
在JEOL FX-200型NMR能谱仪上用10mm探头室温操作得到1H NMR数据。用通用电子公司GN-500型NMR能谱仪对NOTPME和其络合物溶液进行研究。对31P探测时将10mm宽带探头拧到202.4MHg。到85%的H3PO4作外标测量NOTPME和其络合物的漂移。探头温度精确到±0.5℃。
以NMR进行KD测定所用的NOTPME样品的构成为115mM的KCl,20mM的NaCl和10mM的HEPES,用Tris碱(氨基丁三醇)将其缓冲,PH为7.4。变化Mg2+,Ca2+或Zn2+的浓度(通常0.5-10mM)加到样品中,得到所导致的31PNMR谱图。使用GE软件以将各峰积分的方式测定共振面积。电位测量
25℃下使用Corning离子分析仪(250型)和MetrohmDorsimat自动滴定管(Brinkman仪器公司)进行电位滴定。按照Irving等人〔15〕建议的方法从所测PH值得到氢离子浓度。将Na3NOTPME溶于0.1M四甲基铵氯化物中,用HCl调节PH到低值并用0.098M的KOH来滴定。以针对邻苯二甲酸氢钾的电位滴定方式将KOH标样并在氮气氛下贮存。在同样的盐溶液中分别测定氢离子活度系数和Kw。以电位滴定金属和配位体之比为1∶1的溶液方式测定Zn(NOTPME),Mg(NOTPME)和Ca(NOTPME)的稳定常数。所有的滴定中,样品用环己烷薄层遮盖以排除CO2。
质子化作用常数(KHiL)和稳定常数(KML和KMHL)由下面等式限定:
KHiL=[HiL]/{[Hi-L][H+]} (1)
KML=[ML]/{[M][L]} (2)
KMHL=[MHL]/{[ML][H+]} (3)在IBM PC上用单形非线性算法运算电位数据得到质子化作用和稳定常数。NOTPME的红血细胞载荷
取新鲜的全血放入抗凝结化的试管中在3000g离心机上分离6分钟,以除去血沉棕黄色层。然后在5mM磷酸盐缓冲盐水(PH=7.4)中将RBC5洗涤三次。将存在于50%红血细胞中的RBC5悬浮在负荷介质(loading medium)中,该介质含有120mMNaCl,5mM MgCl2,10mM pH为7.4的HEPES,10mM葡萄糖和10mM NOTPME,然后于37℃培育12小时。负荷过程中没有观察到RBC5的溶解。离心分离RBC5,弃掉上清液。在以等渗压介质悬浮前用PH=7.4的磷酸盐缓冲盐水将RBC5洗涤两次。质子化作用研究
图2说明25℃时NOTPME在0.1M四甲铵氯化物中的电位滴定曲线。从这些数据可得三个质子化作用常数(PK1=11.8,pK2=3.65,pK3=1.4)。还测量了NOTPME的31PNMR谱图随PH而变化的函数关系(数据未示出),从这些数据得到的质子化作用常数通常与电位得到的那些相一致。在多氮环中磷的漂移对氮的质子化作用非常敏感,类似于母体NOTP磷酸盐所观察到的那样〔17〕。第一个双质子化作用(logK=11.8,3.65)导致了31P漂移到低频,这和双环氮的质子化作用相一致〔17〕。这表明在NOTP与NOTPME相比较时第一个氮的质子化作用十分类似(分别是logK1=12.1与11.8相比较),而第二个氮的质子化作用引人注目的不同(logK2=9.4与3.65相比较)。这些pK2的差别反映了磷酸盐与磷酸盐单酯侧链形成内部氢结合质子化氮能力方面的差别,这就与下面的结论相一致,即,NOTP(质子化作用常数在6.0-7.5之间)中膦酸酯氧的碱性大大超过了NOTPME(质子化作用常数低于1.4)中膦酸酯氧的碱性。NOTPME的31PNMR谱展示单个共振覆盖了整个PH范围,表明在所有质子化的种类中的快速转变。络合研究
图2还显示了存在一种两价的Mg2+,Ca2+或Zn2+时NOTPME的电位滴定数据。由这些数据得到的Mg(NOTPME),Ca(NOTPME)和Zn(NOTPME)的稳定常数概括在表I中。
表I
NOTPME与Ca2+,Mg2+和Zn2+络合的稳定常数。 金属离子 KD(在25°x) KD(在37℃) logKML
Ca2+ 50mM 47.62mM 5.1
Mg2+ 5.77mM 4.66mM 6.3
Zn2+ (10-11M)4 — 15.4KD值由NMR数据得到而1ogK值在25℃以电位测定。KD值由热力学值(logKML=15.4)来建立,同时要考虑配位体的pK值和pH=7.4时的质子浓度。
与Mg2+或Ca2+相比,Zn2+和NOTPME形成的络合物要稳定的多。大大地反映出Zn2+比其他离子Mg2+和Ca2+有更强的形成M2+-N键的倾向。Mg(NOTPME)和Ca(NOTPME)两者分别与其NOTP络合物相比,稳定性要弱一些[18],再次反映出膦酸酯侧链配位体更为酸性。然而,NOTPME和NOTE一样,金属越小,与之形成的络合物越稳定,Mg2+小于Ca2+则Mg2+的更稳定。这反映出在这两者情况下三氮环壬烷大环的尺寸选择性。
图3演示了含5mMNOTPME溶液的31PNMR谱对添加的Mg2+的函数关系。该谱图表示出结合Mg2+的NOTPME是慢慢地与“游离”NOTPME互换的。图4表明存在2.05mMZn2+和38.5mM Ca2+时5mM NOTPME的31PNMR谱图。正如予料的基于电位滴定测定稳定常数的情况,这种溶液与含Mg2+的等效溶液相比存在更多的Zn(NOTPME)。令人感兴趣的是Mg2+和Zn2+结合NOTPME的化学漂移十分不同,确实,在含有两者金属离子的混合物中能够得到Zn(NOTPME)和Mg(NOTPME)的特征共振。正如予料的那样,Ca2+结合得更弱一些,在加入32mM的Ca2+后仅仅能分辨出Ca(NOTPME)的特征共振。Ca(NOTPME)的化学漂移(22.1ppm)也不同于Mg(NOTPME)(23.5ppm)和Zn(NOTPME)(23.1)所形成的。这也许反映出Ca2+比Mg2+或Zn2+有较大的尺寸,它不适于进入环壬烷内腔。
通过积分和估算其浓度可得相符于游离和结合金属NOTPME的共振面积。以Mg2+和Ca2+络合物于25℃的NMR获得KD值分别是5.77mM和50mM.和氟化的螯合物MF-APTRA相比较,其他人所报导的〔12〕对Mg2+的KD是1mM,对Ca2+是12μm。
表1也显示出NMR在37℃得到的Mg(NOTPME)和Ca(NOTPME)的KD。显然,37℃时Mg(NOTPME)和Ca(NOTPME)在稳定度方面的差别等级维持不变。这就可以确定在生理温度下NOTPME对Mg2+的亲合力高于Ca2+。从NMR数据不能得到Zn(NOTPME)的KD,因为在所有的真实测量条件下滴定的Zn2+完全与NOTPME相结合。
图5呈现出Ca2+,Mg2+和Zn2+的NOTPME络合物的31PNMR化学漂移与PH为6-10之间的函数关系。在金属离子和配位体为1∶1的溶液中,可见到的Zn(NOTPME)共振特性覆盖了这个PH范围,Mg(NOTPME)的特征共振仅在PH为6.4以上时才能检测出,而Ca(NOTPME)的特征则只有PH在7.8以上时才看得见。这些差别清楚地说明:在生理PH(大约7.4)时NOTPME对Mg2+的选择性大于对Ca2+的。如上所示,结合金属类的化学漂移实际上在上面PH值范围内与PH值无关。人体红细胞中胞间游离Mg2+浓度的测定
图6说明应用NOTPME检测RBC5中胞间游离的Mg2+。首先通过在含有含5mMMgCl2的NOTPME负荷介质中于37℃将RBC5培育12小时而制备载有NOTPME的RBC5(图6b)。负荷介质中无MgCl2时则不能观察到NOTPME载入了RBC5中。图6a示出了对比的RBC5。
如同在体内研究,在RBC5中观察到两个相应于游离和Mg2+结合的NOTPME的共振情况。用下面公式估算RBC5中胞间游离的Mg2+浓度:
[Mg2+]=KD[MgNOTPME]/[NOTPME]在该特殊实例中得到的胞间游离Mg2+浓度为1.71mM。因为RBC5中胞间游离Mg2+的含量范围通常在0.2-O.3mM之间[12,19,20],所以该实验观察到胞间游离Mg2+的高浓度一定是Mg2+以和NOTPME的络合物形式输运的结果。于悬浮介质中外加两价阳离子的离子载体A23187后,则观察到胞间游离Mg2+浓度增大(至1.90mM)(未出数据)。这些结果表明NOTPME可很容易地检测出完整细胞中游离Mg2+含量的微小变化。
第一个质子化作用常数非常高的数值以及所需三氮环的构造和尺寸,可强烈影响NOTPME络合物的形成特性。使用常规电位滴定方法可以研究NOTPME与Zn2+,Mg2+及Ca2+络合物,这个事实表明溶液中形成络合物相当快。表I所见,Zn2+比Mg2+或Ca2+两者与NOTPME形成更稳定的络合物。对三氮环壬烷三乙酸酯络合物(即NOTA)与这些金属离子络合时也观察到同一倾向;报导的logK值分别是:Zn(NOTA)18.3;Mg(NOTA),9.69;及Ca(NOTA)是8.92〔21〕。因此,羧酸酯与所有三种金属离子形成更稳定的络合物也许是由于羧酸酯氧配位体的碱度大于膦酸盐氧配位体的。母体膦酸盐NOTP在其与Zn2+,M2+和Ca2+的金属络合能力方面也显示同一倾向,但在此情况中,所得给合物的稳定常数与相应的NOTPME或NOTA的数值都要高出几个数量级。报导的logK值对Zn(NOTP)4-,Mg(NOTP)4-和Ca(NOTP)4-分别是24.9,11.0和6.4〔18〕。因为NOTP中氮和膦酸盐氧比NOTPE中的那些碱性更强,则与这些金属离子所得的稳定常数也都大。其倾向依然保持为Zn2+>>Mg2+>Ca2+。
生物体系中测量胞间Mg2+方面,NOTPME有几个优于氟化络合物如BAPTA和APTRA的优点。这些优点包括:(a)容易合成,(b)对Mg2+的亲合力大于对Ca2+的,(c)对于结合的和游离的配位体共振没有明显的互换影响,以及(d)因可以同时测量细胞力能,该螯合物中三个磁性等效的31P核能提供对生物组织有亲合力的NMR核。NOTPME在生理PH方面展示对Mg2+优于对Ca2+的显著选择性有个大优点,即在生物体系中监测Mg2+而不受Ca2+的影响。强调下面这点很重要,即NOTPME及其与镁络合物的共振并不与组织内含磷代谢物的相重叠。因此,在用31PNMR测量胞间游离镁的改变以及各种生理事件期间代谢物的改变方面,NOTPME提供了万能手段。在许多生物体系中,生理PH处KDMg(NOTPME)对测量胞间Mg2+方面落入所需要的范围,虽然这点是偶然的,却可证明能够精细调节NOTPME对Mg2+的亲合力,其方法是改变膦酸盐氧上的烷基取代基,或者将一个烷基加在膦酸盐基团连接三氮环所连的碳原子上。
实施例2四氮大环化合物DOTEP的合成
图7显示的DOTEP制备如下。将2ml二氯乙基膦慢慢地与冰混和,生成相应的乙次膦酸。暖到室温后加入390mg的1,4,7,10-四氮环十二烷的盐酸盐(亚环基四盐酸)(Parrish化学公司,Ogden,Utah),在氮气氛下将混合物加热至沸。将溶在10m16MHCl中的含157mg多聚甲醛溶液以0.5nl/hr的速度加入混合物中,同时继续进行回流。将最终混合物另外回流4小时,然后冷却到室温。真空下浓缩溶液成粘状油,用6ml水再溶解,放进Dowex50W×4(氢形式)型阳离子交换柱(床容积7.5ml)。用水将交换柱洗涤到中性,再用60ml 0.66MHCl洗脱产物。含有DOTEP的馏分被结合,将其蒸发,用无水乙醇再溶解后蒸发成白色固体。在无水乙醚中分散该固体,过滤,氮气下予干燥后于60-70℃真空干燥得白色非常吸潮的固体(360mg,产率44%)。该固体要封在安瓿内贮存。元素分析和电位滴定表明它是DOTEP·2H2O。DOTEP的应用A.Ca(DOTEP)作[Ca2+]游离的31PNMR指示剂
图9所示31P的谱图是含大约1mMCa2+和3mMDOTEP于生理PH时水溶液所得的。显然,游离的和结合形式的DOTEP的31P共振具有各自清楚的化学漂移,两者与组织内观察到的正常代谢物的31P共振都不重叠。这表明以制备合适的水解酯方式将DOTEP载入细胞时,使用简单的关系式使细胞内俘获的NOTEP直接给出[Ca2+]游离的测量,
[Ca2+]游离=KD·[Ca(DOTEP)]/[DOTEP]游离这里的KD=11μM(此时PH=7.4)。
上面报导的PH=7.4时KD的值是用31PNMR和PH电位滴定所测定的(31PNMR测量游离和结合的积分在含有已知量的[Ca2+]总和和]DOTEP]总和溶液中是PH的函数)。这个KD值表明DOTEP用来测量[Ca2+]游离可覆盖的范围大约为1-50μM。B.Gd(DOTEP)作MRI对比剂
DOTEP可与Gd3+形成稳定络合物(logK大约等于16)。所得络合物有个有利的水质子松驰度(R=5.1S-1mM-1),且络合物有许多相同的动力学优点,如图10的数据所示的Gd(DOTA)。在该实验中,Gd(DOTEP)和Gd(DOTA)溶在0.1MHCl中,它们分解成游离Gd3+和游离配位体并随后进行水松驰测量。如示,两种络合物在强酸中分解的半存留期(half-lives)对Gd(DOTA)大约是110小时,对Gd(DOTEP)是30小时。这表明在PH为7.4时两个络合物的分解速度比这(大约106小时)要大几个数量级,因而用于人体是十分安全的。
实施例3 多氮大环N-烷基膦酸盐或膦酸酐NOTPME-AC的合成
[NOTPME-AC是1,4,7-三氮环壬烷-N,N′N”-三(亚甲基膦酸单乙酯乙酸酐)
将NOTPME三钠盐(178.63mg,0.318mM)溶在4.0ml无水氯仿中(新从过量P4O10中蒸馏的),加入120毫升乙酰氯。溶液在密闭容器中于室温搅拌24小时。然后在干燥氮气氛下将溶液蒸发成黄色的非常粘的油。向该油加无水乙醚,滤出NOTPME-AC(以氯化钠加合物形式沉淀),在干燥氮气下于35原子上。
实施例2四氮大环化合物DOTEP的合成
图7显示的DOTEP制备如下。将2ml二氯乙基膦慢慢地与冰混和,生成相应的乙次膦酸。暖到室温后加入390mg的1,4,7,10-四氮环十二烷的盐酸盐(亚环基四盐酸)(Parrish化学公司,Ogden,Utah),在氮气氛下将混合物加热至沸。将溶在10m16M HCl中的含157mg多聚甲醛溶液以0.5ml/hr的速度加入混合物中,同时继续进行回流。将最终混合物另外回流4小时,然后冷却到室温。真空下浓缩溶液成粘状油,用6ml水再溶解,放进Dowex50W×4(氢形式)型阳离子交换柱(床容积7.5ml)。用水将交换柱洗涤到中性,再用60ml 0.66M HCl洗脱产物。含有DOTEP的馏分被结合,将其蒸发,用无水乙醇再溶解后蒸发成白色固体。在无水乙醚中分散该固体,过滤,氮气下予干燥后于60-70℃真空干燥得白色非常吸潮的固体(360mg,产率44%)。该固体要封在安瓿内贮存。元素分析和电位滴定表明它是DOTEP·2H2O。DOTEP的应用A.Ca(DOTEP)作[Ca2+]游离的31P NMR指示剂
图9所示31P的谱图是含大约1mMCa2+和3mMDOTEP于生理PH时水溶液所得的。显然,游离的和结合形式的DOTEP的31P共振具有各自清楚的化学漂移,两者与组织内观察到的正常代谢物的31P共振都不重叠。这表明以制备合适的水解酯方式将DOTEP载入细胞时,使用简单的关系式使细胞内俘获的NOTEP直接给出[Ca2+]游离的测量,新鲜的全血放入抗凝试管中,在3000g条件下离心分离3分钟,除去血沉棕黄色层。然后将(离心机)甩密的血红细胞用PH=7.4的磷酸盐生理盐水5mM洗涤三次。在含有负荷介质的NOTPME衍生物中悬浮50%压积细胞的血红细胞。负荷介质含有130mM NaCl,5mMNOTPME衍生物(苯甲酰基或乙酰基衍生物),1mM腺嘌呤,10mM葡萄糖和10mM HEPES,PH=7.4。上述负荷介质中的红细胞于25℃培育1小时。在负荷步骤期间没有观察到血红细胞的溶解。用NOTPME衍生物载荷1小时后,离心分离红细胞悬浮液并丢弃上清液。在以等渗压的盐水悬浮前将红细胞用PH=7.4的5mM磷酸盐生理盐水洗涤两次,以用于NMR测量。31PNMR测量表明这些NOTPME的衍生物已载入红细胞内并水解成NOTPME。NMR测量后将样品离心分离,分析上清液中残留NOTPME。在NMR测量的历时期间内没有观察到残留的NOTPME。因此,十分清楚,这些NOTPME衍生物进入了红细胞,并已水解成NOTPME留存在红细胞内。
实施例4 予言合成同属的多氮大环N-烷基膦酸
盐,多氮大环N-烷基膦类或其酸酐
有机合成化学领域内技术人员可将实施例1,2和3的步骤很容易地适用于各种适宜的稳定的多氮大环化合物。适宜的多氮大环化合物包括下列三氮和四氮大环化合物,并在Aldrich化学公司(Milwaukee,Wisconsin)有售:
1,5,9-三氮环十二烷(见图10);
1,4,8,12-四氮环十五烷(见图11);和
1,4,8,11-四氮环十四烷(见图12)。
下列引证文献此处结合参照,引证缘由不言而喻。
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Claims (1)
1.一种合成1,4,7-三氮环壬烷-N,N′,N″-三(亚甲基磷酸单乙酯)(NOTPME)的方法,该方法包括下列步骤:
(1)使1,4,7-三氮环壬烷、亚磷酸二乙酯和无水多聚甲醛反应形成1,4,7-三氮环壬烷-N,N′,N″-三(亚甲基磷酸二乙酯);
(2)使该产物与氢氧化钠反应直至产生清液,然后结晶得到1,4,7-三氮环壬烷-N,N′,N″-三(亚甲基磷酸单乙酯)。
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JP3334717B2 (ja) | 2002-10-15 |
MX9102116A (es) | 1992-06-01 |
AU654987B2 (en) | 1994-12-01 |
IL100073A0 (en) | 1992-08-18 |
NO931793L (no) | 1993-05-18 |
IE914001A1 (en) | 1992-05-20 |
ZA919127B (en) | 1993-05-18 |
NZ240626A (en) | 1994-11-25 |
HK88897A (en) | 1997-06-27 |
JPH06502645A (ja) | 1994-03-24 |
ES2093816T3 (es) | 1997-01-01 |
NO307380B1 (no) | 2000-03-27 |
ATE144522T1 (de) | 1996-11-15 |
WO1992008725A1 (en) | 1992-05-29 |
PT99556A (pt) | 1992-10-30 |
CA2095615C (en) | 2003-07-08 |
FI932231A0 (fi) | 1993-05-17 |
CN1036717C (zh) | 1997-12-17 |
HUT64768A (en) | 1994-02-28 |
CN1066073A (zh) | 1992-11-11 |
NO931793D0 (no) | 1993-05-18 |
PT99556B (pt) | 1999-04-30 |
US5342606A (en) | 1994-08-30 |
CA2095615A1 (en) | 1992-05-20 |
SG48154A1 (en) | 1998-04-17 |
DE69122881T2 (de) | 1997-04-03 |
HU9301431D0 (en) | 1993-12-28 |
FI932231A (fi) | 1993-05-17 |
IL100073A (en) | 1997-11-20 |
DE69122881D1 (de) | 1996-11-28 |
AU9077091A (en) | 1992-06-11 |
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