5,12-二苯基-7,14-二甲基-1,4,8,11-四氮杂环十四烷-N,N″-二乙酸及其镧系配合物的合成和表征

多氮杂大环的配位化学一直是人们感兴趣的领域。近年来,人们努力把支链配位基团引入大环中,以便得到同时具有相对刚性和动力学稳定性的大环结构单元和具有相对柔性和动力学活性的开链结构单元的新型配体。我们曾通过简单的立体化学选择合成得到一系列部分N-乙酸取代六甲基四氮杂大环。本文报道新的大环配体c-meso-meso-5,12-二苯基-7,14-二甲基-1,4,8,11-四氮杂环十四烷-N,N″-二乙酸(H_2L~3及其镧系配合物的合成和表征。     

1,4,7,10-四氮杂环十二院的合成研究

多氮杂环化合物及其衍生物近年来愈来愈显示出其重要而广泛的用途,譬如：可作为人体内结石的清除药物［‘·’j,作为MnSOD的模拟物可抑制心肌缺血性再灌注引起的损伤［’j,且具有抗爱滋病活性等;尤其是在制造磁共振成像（MRI）、X射线CT、超声成像等医学影像技术的造影剂以及恶性肿瘤的放射性治疗药物方面［‘－’‘,多氨杂环烷烃特别是1,4,7,10一四氮染环十二烷（Cyclen,环楞胺）及其衍生物显示出极其重要的应用价值．多氨杂环烷烃及其衍生物可因具体情况有不同的合成方法,环楞胺最初由乙二胶二乙酸氯与乙二胺在高度稀释条…     

大环多胺脂质体介导的核酸转染

以大环多胺为亲水部分构建的脂质体可以有效用于核酸转染。大环多胺中带正电荷的氮原子可通过静电吸引和氢键等方式与核酸(DNA/RNA)结合。当前用于构建脂质体并进行核酸转染的大环多胺主要涉及到1,4,7-三氮杂环壬烷(tacn)、1,4,7,10-四氮杂环十二烷(cyclen)、1,4,8,11-四氮杂环十四烷(cyclam)等类型,其中基于cyclen的脂质体研究较多。亲水的大环多胺头部、疏水基团尾部及连接基团的结构对脂质体的转染效率有很大影响。一些大环多胺的金属配合物除了可以作为基因转染载体,在标记、示踪等方面也有特殊作用。本文综述了基于大环多胺的两亲性分子在核酸载体方面的应用,对其构效关系进行了讨论,并对相关领域的发展做了展望。     

杂氮硅三环成环反应的研究

本文报导了与硅原子直接相连的有机基团(R)对杂氮硅三环成环速率的影响。利用气相色谱检测成环反应的产物之一——乙醇的生成速率和数量,并同与硅相连的R基团对成环反应速率的影响作比较。实验结果表明五种杂氮硅三环成环速度顺序为Cl_2CH—>ClCH_2—>ClCH_2CH_2CH_2—>CH_2=CH—>CH_3—,这与理论推断相符。     

含氮大环化合物的研究

总结十五年来在氮杂冠醚和大环多胺的合成和性质研究方面的主要成果：氮杂冠醚和大环多胺合成的方法学研究,氮杂冠醚和大环多胺的NMR研究,含氮杂冠醚结构单元的吲哚啉螺苯并吡喃类信息接受体的合成和性质研究,桥连环糊精二聚体的分子识别研究。     

双大环多胺Zn(Ⅱ)配合物及其与DNA作用的溴乙锭荧光探针

以1,4,7,10-四氮杂环十二烷(Cyclen)为原料合成的一种新型双大环多胺配体及其双核Zn2+配合物,其结构用1H NMR、质谱和元素分析等测试技术进行了表征。 以溴乙锭(EB)为探针,用荧光光谱法研究了双环多胺配体及其Zn(Ⅱ)配合物与小牛胸腺DNA的作用,当cComplex 6/cDNA=0.51时,DNA/EB体系的荧光强度降低至原来的47.3%,表明双大环配合物是以嵌入方式与小牛胸腺DNA结合。 化合物对DNA/EB体系的荧光猝灭顺序为：双大环多胺双核Zn(Ⅱ)配合物＞双大环多胺配体＞四氮杂环多胺Zn(Ⅱ)配合物＞四氮杂环多胺。     

基于大环多胺的新型线型聚合物的合成及与DNA相互作用的研究

设计合成了一种新型线形大环聚合多胺（POGEC）,该聚合物可通过1,3-丙二醇二缩水甘油基醚和1,7-二（二乙氧磷酰基）-1,4,7,10-四氮杂环十二烷反应得到．琼脂糖凝胶电泳和电子扫描光谱（SEM）显示POGEC与DNA有很强的结合能力．当生理浓度的氯化钠溶液加入到已经形成的POGEC／DNA复合物中,DNA可被有效释放．通过荧光光谱测量了POGEC与DNA的结合能力及紧缩能力．圆二色光谱表明POGEC的强结合力并未改变DNA的构象．     

含萘磺酰基大环多胺与Cu(II)和DNA作用的荧光性能研究

以1,4,7,10-四氮杂环十二烷(Cyclen)为原料,合成了含有萘磺酰基的大环多胺,其结构经1H NMR、MS、元素分析等表征。用荧光光谱法测定了大环多胺与Cu(II)在不同pH下的配位情况,研究了大环多胺激发和发射波长,配体浓度与吸光度的线性关系;Cu(II)、小牛胸腺嘧啶DNA对大环多胺荧光性能的影响。     

含吡啶环氮(王)冠的合成

本文报道了新的含吡啶环的氮(王)冠的合成。以活泼双功能团化合物2,6-二(溴四基)-吡啶和N-对甲苯磺酰基取代的多乙撑基多胺(二乙撑三胺,三乙撑四胺)二钠盐直接缩合成环,得到含吡啶环的氮(王)冠化合物:3,6,9-三对甲苯磺酰基-3,6,9,15-四氮双环[9.3.1]十五环-1(15),11,13-三烯(A)和3,6,9,12-四对甲苯磺酰基-3,6,9,12,18-五氮双环[12.3.1]十八环-1(18),14,16-三烯(B)。(A)和(B)经用30%的HBr-CH_3COOH溶液处理,得到3,6,9,15-四氮双环[9.3.1]十五环-1(15),11,13-三烯(C)和3,6,9,12,18-五氮双环[12.3.1]十八环-1(18),14,16-三烯(D)。以上化合物均经元素分析、IR和1~H NMR.等鉴定。这种直接缩合的方法,具有反应条件温和、设备简单、操作简便等优点。     

氮杂大环钕配合物[Nd(L)(CH~3CN)(CF~3sO~3)~3]的合成和结构

本文报道了三价钕与氮杂大环(简称L)配合物的合成和晶体结构.配合物组成为[Nd(L)-(CH~3CN)(CF~3SO~3)~3],晶体属三斜晶系,空间群PI.a=0.8738(2),b=1.2870(3),c=1.2900(3)nm,a=85.63(2),β=87.25(2),γ=9785302)°;最终偏差因子R=0.0370,R~w=0.0385,配合物中钕为8配位,其配位多面体为扭曲的四方反棱柱体.     

Gd(III) chelates as NMR probes of protein-protein interactions. Case study: rubredoxin and cytochrome c3

Two cyclen-derived Gd probes, [Gd-DOTAM](3+) and [Gd-DOTP](5-) (DOTAM = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetamide; DOTP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonate)), were assessed as paramagnetic relaxation enhancement (PRE)-inducing probes for characterization of protein-protein interactions. Two proteins, Desulfovibrio gigas rubredoxin and Desulfovibrio gigas cytochrome c(3), were used as model partners. In a (1)H NMR titration it was shown that [Gd-DOTP](5-) binds to cytochrome c(3) near heme IV, causing pronounced PREs, characterized by line width broadenings of the heme methyl resonances at ratios as low as 0.08. A K(d) of 23 ± 1 μM was calculated based on chemical shift perturbation of selected heme methyl resonances belonging to three different heme groups, caused by allosteric effects upon [Gd-DOTP](5-) binding to cytochrome c(3) at a molar ratio of 2. The other probe, [Gd-DOTAM](3+), caused PREs on a well-defined patch near the metal center of rubredoxin (especially the patch constituted by residues D19-G23 and W37-S45, which broaden beyond detection). This effect was partially reversed for some resonances (C6-Y11, in particular) when cytochrome c(3) was added to this system. Both probes were successful in causing reversible PREs at the partner binding site, thus showing to be good probes to identify partners' binding sites and since the interaction is reversible to structurally characterize protein complexes by better defining the complex interface.     

手术导航用荧光探针

荧光成像技术因具有操作简便、分辨率高、安全性好且可实时成像等优势,在术中导航中具有广阔的应用前景。虽然目前还没有靶向荧光探针在临床上得到批准,但已经有相当一部分荧光探针进入了临床试验阶段。最早进入临床试验的是一些偶联肿瘤靶向配体的荧光染料,例如近红外菁染料(IRDye800CW)标记的肿瘤特异抗体,叶酸标记的异硫氰酸荧光素(EC17)等。近来,结构更复杂的荧光探针如酶反应激活型探针和PET/荧光双模态探针也逐步进入临床试验。本文依据近年来手术导航用荧光探针的最新研究进展,分别就受体介导的靶向荧光探针、可激活型靶向荧光探针、近红外二区(NIR-Ⅱ)荧光探针、多模态荧光探针和诊疗一体化探针进行了分类讨论,重点对正在进行临床研究及具有临床转化前景的荧光探针的分子设计原理进行了分析与总结,并对手术导航用荧光探针未来的发展进行了展望。     

New Cyclopendant Organophosphorus Ligands

Abstract

New cyclopendant orgsnophosphorus neutral ligands were synthesized from cyclic polyamines. N,N′,N″-Tris-(diphenylphosphorylmethyl) 1,4,7-triazacyclononane(I) was obtained by the reaction of triazacyclononane with diphenylphosphine oxide and formaldehyde. Interaction of 1,4,7,10-tetraazacyclododecane with diphenylvinyl-phosphine oxide N,N′,N″,N?-tetra(β-diphenylphosphorylethyl)-1,4,7,10-tetraazacyclododecane(II) was obtained.     

Near-infrared fluorescent probes: a next-generation tool for protein-labeling applications

The development of near-infrared (NIR) fluorescent probes over the past few decades has changed the way that biomolecules are imaged, and thus represents one of the most rapidly progressing areas of research. Presently, NIR fluorescent probes are routinely used to visualize and understand intracellular activities. The ability to penetrate tissues deeply, reduced photodamage to living organisms, and a high signal-to-noise ratio characterize NIR fluorescent probes as efficient next-generation tools for elucidating various biological events. The coupling of self-labeling protein tags with synthetic fluorescent probes is one of the most promising research areas in chemical biology. Indeed, at present, protein-labeling techniques are not only used to monitor the dynamics and localization of proteins but also play a more diverse role in imaging applications. For instance, one of the dominant technologies employed in the visualization of protein activity and regulation is based on protein tags and their associated NIR fluorescent probes. In this mini-review, we will discuss the development of several NIR fluorescent probes used for various protein-tag systems.

This minireview describes the development of NIR chemical probes for various protein-tag systems.     

Bis-azamacrocyclic anthracene as a fluorescent chemosensor for cations in aqueous solution

A bis-azamacrocyclic anthracene (L2), which has two a 12-membered cyclic tetraamine (cyclen) connected through a 9,10-dimethylanthracene spacer, has been synthesized as a new fluorescent chemosensor for detection of pH and metal cations in aqueous solution (cyclen = 1,4,7,10-tetraazacyclododecane, L2 = 9,10-bis(1,4,7,10-tetraazacyclododecane-1-ylmethyl)anthracene). The fluorescence response of L2 has been studied in comparison to that of the previously reported monoazamacrocyclic anthracene (L1 = 1-(9-anthrylmethyl)-1,4,7,10-tetraazacyclododecane). Plots of the fluorescence intensity of L2 against pH demonstrate a sigmoidal curve with pKa 7.4, which is lower than that of L1 (8.3). Potentiometric titration reveals that the increase in the L2 fluorescence requires protonation of both cyclen rings, thus resulting in the lower pKa value. L2 demonstrates impressive fluorescence response against metal cations. At basic pH, upon addition of Zn2+ or Cd2+, L1 leads to an increase in the fluorescence intensity with a 1:1 metal-intensity response. L2, however, shows a 2:1 response to Zn2+, while showing a 1:1 response to Cd2+. At neutral pH, L1 fluorescence decreases upon addition of Zn2+ or Cd2+ because of a formation of metal-anthracene pi complex. L2, however, still demonstrates a Zn2+-induced increase in intensity with a 2:1 response, while no change in intensity is observed upon Cd2+ addition. The obtained findings suggest potential utilities of L2 as a new type fluorescent chemosensor for the detection of cations in aqueous solution.     

Small-molecule fluorescent probes for imaging gaseous signaling molecules: current progress and future implications

Endogenous gaseous signaling molecules including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H₂S) have been demonstrated to perform significant physiological and pharmacological functions and are associated with various diseases in biological systems. In order to obtain a deeper insight into their roles and mechanisms of action, it is desirable to develop novel techniques for effectively detecting gaseous signaling molecules. Small-molecule fluorescent probes have been proven to be a powerful approach for the detection and imaging of biological messengers by virtue of their non-invasiveness, high selectivity, and real-time in situ detection capability. Based on the intrinsic properties of gaseous signaling molecules, numerous fluorescent probes have been constructed to satisfy various demands. In this perspective, we summarize the recent advances in the field of fluorescent probes for the detection of NO, CO and H₂S and illustrate the design strategies and application examples of these probes. Moreover, we also emphasize the challenges and development directions of gasotransmitter-responsive fluorescent probes, hoping to provide a general implication for future research.

This perspective article aims to introduce the design principles and recognition strategies of small-molecule fluorescent probes which are applied for the detection of gas signaling molecules including NO, CO and H₂S in biological systems.     

Fluorescent probes for detection of biothiols based on “aromatic nucleophilic substitution-rearrangement” mechanism

“Aromatic nucleophilic substitution-rearrangement (SNAr-rearrangement)” mechanism provided a powerful tool to design fluorescent probes for the discrimination between biothiols.     

Synthese de coordinats macrocycliques polyazotes comportant une fonction amine secondaire discriminee

A synthetic scheme is elaborated to prepare two polyaza-macrocycles in which one nitrogen atom is distinct from the others. Thus, (tri-N-methyl)-1,4,7,10-tetraazacyclododecane and (tetra-N-methyl)-1,4,7,10,13-pentaazacyclopentadecane were synthesised. Through acylation and alkylation reactions, the remaining secondary nitrogen site allows further modifications of the ligand structures and leads to new cyclic polyamines bearing lateral functionalities. Several complexes between the ligands and transition metals (Cu, Co, Ni, Rh) are also described     

Fluorescent probes for detection of biothiols based on “aromatic nucleophilic substitution-rearrangement” mechanism

Biothiols, including cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) play important roles in physiological processes, and the detection of thiol using fluorescent probes has attracted attention due to their high sensitivity and selectively and invasive on-time imaging. However, the similar structures and reactivity of these biothiols present great challenges for selective detection. This review focused on the the “aromatic nucleophilic substitution-rearrangement (S_NAr-rearrangement) mechanism”, which provided a powerful tool to design fluorescent probes for the discrimination between biothiols. We classify the fluorescent probes according to types of fluorophores, such as difluoroboron dipyrromethene (BODIPY), nitrobenzoxadiazole (NBD), cyanine, pyronin, naphthalimide, coumarin, and so on. We hope this review will inspire exploration of new fluorescent probes for biothiols and other relevant analytes.     

Tetraphenylethene based zinc complexes as fluorescent chemosensors for pyrophosphate sensing

We described a serious of zinc complexes that exhibit characteristic fluorescence responses toward pyrophosphate(PPi) and adenosine triphosphate(ATP) in aqueous media. These novel probes exploited tetraphenylethene(TPE) as fluorophore and macrocycle-polyamine(including 1,4,7,10-tetraazacyclododecane and 1,4,7-triazacyclononane) Zn(II) complexes as binding group. These ‘‘OFF–ON' type probes exhibited promising selectivity and sensitivity to PPi and ATP via a restriction of intramolecular rotation(RIR) mechanism. The detection limit for PPi was found within nmol/L range.