组合化学中的绿色固相合成研究概况

综述了组合化学中的绿色固相合成技术概况，讨论了绿色化学，讨论了绿色化学、组合化学、固相合成法、组合化学中的聚合物载体、固相载体上的有机化学反应以及固相合成反应的分析检测方法。     

核磁共振技术在糖类结构解析中的应用

随着人们对糖生物活性的研究和糖生物学的兴起,对糖类结构进行正确解析成为促进糖科学发展的关键之一。核磁共振技术是目前各类有机分子结构解析最重要的工具,其在糖类物质结构解析中发挥着日益重要的作用。本文综述了各类核磁共振技术,包括1HNMR技术、13C NMR技术、2D NMR技术等在糖类结构解析方面的应用,并介绍了微线圈探针技术、超高场NMR技术等的发展对糖NMR解析的改善。     

多肽固相合成法在海洋肽类药物研究与开发中的应用

随着固相多肽合成技术的日趋成熟,海洋肽类药物研究的不断深入,两者结合在药物研究和应用领域前景非常好。现结合多肽固相合成法在芋螺毒素、海葵毒素等的研究与开发中的应用情况,综述多肽固相合成法的原理及其在海洋肽类药物中的应用现状及发展前景。     

抗肝癌药物酪丝亮肽的工艺研究

［摘要］目的 探索一类抗肝癌新药酪丝亮肽的固相合成路线,并与申报的液相合成路线进行优缺点比较. 方法 采用Fmoc/Wang树脂固相合成方法,逐步接肽,然后用裂解液（TFA：Tis:H2O,95.0：2.5：2.5）从树脂切割得到粗品,最后制备液相纯化脱盐,冻干得到产品. 结果 终产品经质谱、磁共振检测确证,纯度为99.5%,产率为82.0%. 结论 Fmoc固相合成方法可以得到与液相合成一致的产品,相比液相路线,该合成方法便捷易操作,生产周期短,产率高,但是成本相对较高.     

Fmoc 策略固相合成磷酰化肽研究进展

蛋白质的磷酰化和去磷酰化对多种生命活动的调节起着关键的作用,磷酰化肽是研究这些生命调节过程中一类非常重要的物质。自 20 世纪 40 年代人类首次成功地合成出磷酰化肽以来,磷酰化肽的研究就引起了化学家和生物学家的广泛关注。由于Fmoc 固相合成策略在多肽的合成中被普遍应用,因此,Fmoc 固相合成策略也已经成为目前磷酰化肽最主要的合成手段。该文对近年来采用 Fmoc 固相合成策略进行磷酰化肽合成的方法（包括整体磷酰化法和磷酰化单体合成法）进行了总结,并对各种合成方法的优缺点进行了讨论。     

新药坎地沙坦酯的核磁共振谱分析

目的 用核磁共振方法鉴定新药坎地沙坦酯的结构。方法 应用HMQC、HMBC等二维核磁共振技术进行测定。结果 对新药坎地沙坦酯的1H—NMR和13C—NMR谱信号进行了全归属。结论 通过二维核磁共振技术确证了新药坎地沙坦酯的结构。     

美国FDA关于合成多肽的指导原则

自从20世纪70年代早期,随着多肽的固相合成及HPLC纯化、分析技术的发展,多肽作为一个潜在的新药,越来越引起人们的兴趣.近年来核磁共振光谱(NMR)、质谱(MS)及合成方法等方面的发展,使得研究者创制与天然多肽在药理作用上有所改变的新化合物成为可能.这些结构修饰后的多肽可以增加与受体的亲和力、增加对受体的选择性、变为拮抗剂、增加对酶降解的抵抗力或改进药代动力学特性.由于以上改进,很多多肽衍生物有可能成为有疗效的药物. 本指导原则仅适用于化学合成的多肽,着力于解决这些化合物所涉及的独特问题.因为合成多肽的制剂与"制剂的生产与控制指导原则”中所涵盖的问题大体一致,所以在此对多肽的制剂不予讨论.作为免疫原使用的多抗原多肽(MAPs)应遵照其他的指导原则.对于此类产品,研制者可与生物制品审评及研究中心(CBER)联系.     

头孢菌素类抗生素的核磁共振波谱特征

目的阐述头孢菌素类抗生素的核磁共振波谱特征。方法应用1H-1H COSY、HMQC,HMBC等二维核磁共振技术对头孢噻吩钠等8个头孢菌素类抗生素进行了测试。结果在对8个头孢菌素类抗生素的1H NMR1、3C NMR信号进行全归属的基础上,对1H NMR谱偶合裂分、偶合常数及1H NMR1、3C NMR谱中取代基对化学位移的影响进行了分析,总结了头孢菌素类抗生素核磁共振波谱的特征。结论头孢菌素类抗生素母核的1H NMR和13C NMR谱有明显特征,取代基的变化对质子和碳的化学位移影响有一定规律。     

青霉属生物中分离出的抗真菌四肽的固相合成

目的以固相合成法合成抗真菌四肽D-Phe-Val-D-Val-Tyr-OH。方法采用固相合成法通过4步反应顺利获得目标四肽,所得化合物的结构通过MS、1H NMR等光谱确证。结果合成得到了抗真菌四肽D-Phe-Val-D-Val-Tyr-OH,总收率为47.0%。结论合成方法具有可行性,操作简便、总收率高,目标化合物可用于抗真菌药物研究。     

固相合成胸腺五肽的制备高效液相纯化工艺研究

目的研究F-moc法固相合成胸腺五肽的纯化方法。方法采用制备高效液相色谱法对固相合成胸腺五肽进行纯化。结果与结论建立了适用于工业化生产的纯化工艺条件,纯化后精肽收率达到62.42%,纯度达到99.25%,并采用质谱法对纯化所得精肽进行了结构鉴定。     

Enzyme-assisted synthesis and structural characterization of pure benzodiazepine glucuronide epimers

The three hydroxybenzodiazepines oxazepam, temazepam, and lorazepam used for their anxiolytic, sedative, and anticonvulsant properties are metabolized by glucuronidation, which is the predominant pathway in the clearance mechanism of exogenous and endogenous substances during phase II metabolism. The aim of this study was the synthesis of benzodiazepine-O-glucuronides as analytical reference substances. All benzodiazepines are prescribed clinically as racemic formulations. The resulting conjugates from the coupling reactions with glucuronic acid are epimeric pairs of glucuronides. Due to the importance of stereochemical factors in drug disposition it is necessary to separate the diastereomeric forms after synthesis. An enzyme-assisted synthesis was developed and optimized by using microsomal UGT from fresh swine liver to receive multimilligram amounts of the benzodiazepine glucuronides, which were not accessible by standard synthetic procedures, like the Koenigs–Knorr- and Williamson-ether-synthesis. Swine liver microsomes were prepared by homogenization and differential centrifugation of liver tissue. In the presence of liver microsomes the benzodiazepines and cofactor UDPGA were incubated for 24 h. After incubation the microsomes were removed by protein precipitation and the residual benzodiazepines by liquid–liquid extraction (dichloromethane). The epimeric pairs of benzodiazepine glucuronides were separated by preparative high performance liquid chromatography (HPLC) followed by solid phase extraction (SPE) to obtain the pure benzodiazepine glucuronide epimers. The synthesis products were characterized by mass spectroscopy and nuclear magnetic resonance (NMR) spectroscopy.     

Identification and analysis of drugs in the solid state by 13C CPMAS NMR: suxamethonium chloride and hydrocortisonum (Corhydron)

Cross-polarization (CP) magic angle spinning (MAS) 13C NMR spectroscopy has become a routine tool in pharmacy, employed to identify and characterize drugs in the solid phase. 13C CPMAS NMR spectra were recorded for solid hydrocortisone 21-hemisuccinate and suxamethonium chloride. White crystalline substances, such as these two drugs, can be easily distinguished; and solid-state 13NMR spectra of remarkably good quality are obtained in less than half an hour. 13C CPMAS chemical shifts for solid suxamethonium chloride and hydrocortisone sodium hemisuccinate are given, as well as cross-polarization kinetic parameters for suxamethonium chloride.     

Nuclear Magnetic Resonance and Infrared Spectroscopic Analysis of Nedocromil Hydrates

Purpose. Nedocromil sodium (NS), which is used in the treatment ofreversible obstructive airway diseases, such as asthma, has been foundto exist in the following solid phases: the heptahemihydrate, thetrihydrate, a monohydrate, an amorphous phase, which contains variableamounts of water, and a recently discovered methanol + water (MW)solvate. Our aim was to apply ¹³C solid-state nuclear magneticresonance (NMR) spectroscopy and solid-state Fourier transform infrared(FTIR) spectroscopy to the study of specific interactions in the varioussolid forms of NS. Methods. The ¹³ solid-state NMR and FTIR spectra of the varioussolid forms of NS were obtained and were related to the crystalstructures of NS, the conformations of the nedocromil anion, and theinteractions of the water molecules in these crystals. Results. The ¹³C solid-state NMR spectrum is sensitive to theconformation of the nedocromil anion, while the solid-state FTIR spectrumis sensitive to interactions of water molecules in the solid state. In NSmonohydrate, for which the crystal structure has not yet been solved,and in the amorphous phase, the information about the conformationsof the nedocromil anion and the interactions of the water moleculesare deduced from the ¹³C solid-state NMR spectra and solid-state FTIRspectra, respectively. Conclusions. ¹³C solid-state NMR spectroscopy and solid-state FTIRspectroscopy are shown to be powerful complementary tools forprobing the chemical environment of molecules in the solid state,specifically the conformation of the nedocromil anion and the interactions ofwater-molecules, respectively.     

Solid phase extraction chromatography and NMR spectroscopy (SPEC-NMR) for the rapid identification of drug metabolites in urine

The use of solid phase extraction onto disposable columns containing a C18 bonded silica gel provides a rapid and simple procedure for the removal of interfering endogenous components from urine samples containing drug metabolites prior to detection and identification by (1)H NMR spectroscopy. In addition, these columns can be used to retain and concentrate the compounds of interest, thus improving the effective sensitivity of the NMR detection method. Using simple step gradients chromatographic separations can be performed, and metabolites may be rapidly fractionated. This approach (solid phase extraction chromatography with NMR or SPEC-NMR) utilises the multiparametric metabolite detection facility of a Fourier transform NMR spectrometer to monitor a chromatographic separation, as such it has some of the beneficial properties of a directly linked liquid chromatography-NMR system without any of the disadvantages. Applications of the SPEC-NMR method in the investigation of drug metabolism are illustrated here by reference to excretion studies on the drugs ibuprofen, paracetamol, aspirin, oxpentifylline and naproxen.     

In-line monitoring of partial and overall solid concentration during solvent-mediated phase transition using Raman spectroscopy

A calibration strategy for the continuous monitoring of solvent-mediated phase transition was developed using in situ Raman spectroscopy. Citric acid which exhibits enantiotropy during its anhydrous/monohydrate phase transition was selected as a model organic product. Using 25 samples in suspension, specific calibration of the spectral data was obtained for estimating in-line both the overall solid concentration in suspension and the composition of the solid phase. In addition to such key-measurements, reliable estimates of supersaturation were computed in-line from the mass balance of the solute. In order to validate the technique, anhydrous to monohydrate phase transition experiments were performed in suspensions at 15 degrees C and the kinetic process involved was monitored. Despite the use of various solid concentrations and reactor configurations, both the reproducibility and the reliability of the in situ Raman measurements are shown to be satisfactory.     

Feglymycin, a novel inhibitor of the replication of the human immunodeficiency virus. Fermentation, isolation and structure elucidation.

The novel peptide feglymycin has been isolated from cultures of Streptomyces sp. DSM 11171 by solid phase extraction, size exclusion chromatography and repeated reversed-phase chromatography. The molecular weight was found to be 1900.90 g/mol and the molecular formula is C95H97Nl3O30. Feglymycin contains 13 amino acids of which four are 3-hydroxyphenylglycine and five are 3,5-dihydroxyphenylglycine residues. The structure of the linear peptide has been determined by 1H and 13C NMR spectroscopy. The sequence was confirmed by the observed mass spectroscopic fragmentation pattern. As well as having weak antibacterial activity, feglymycin inhibits the replication of the human immunodeficiency virus (HIV) in vitro.     

Solid phase synthesis of a fully active analogue of cholecystokinin using the acid-stable Boc-Phe (p-CH2) SO3H as a substitute for Boc-Tyr(SO3H) in CCK8

Substitution of the -OSO₃H group in the sulfated-tyrosine by the non-hydrolyzable -CH₂SO₃H group was the first described modification of the sulfate ester that does not affect CCK₈ activity. In addition to its capacity to mimic the sulfated tyrosine residue, the amino acid Phe(p-CH₂SO₃Na) was shown to be stable in acidic media, including HF containing mixtures. The synthesis of Boc-Phe(p-CH₂SO₃Na)-OH in racemic and resolved forms and its introduction into the sequence of CCK₈ by solid phase using standard Boc/benzyl synthesis conditions and BOP as coupling reagent is now reported. The two CCK₈ analogues containing the l - or the d -Phe(p-CH₂SO₃Na) residue, obtained in satisfactory yields, were separated by HPLC and the stereochemistry of Phe(p-CH₂SO₃Na) residue in each peptide was established by NMR spectroscopy and confirmed by a separate solid phase synthesis in which the pure l isomer was used. Both CCK₈ analogues displayed high affinities for peripheral and central receptors (KI ～ 1 nm ) and proved to be full agonists in the stimulation of pancreatic amylase secretion. The ?stabilized-CCK₈ peptide”, easily prepared by solid phase, could replace the native peptide in biochemical and pharmacological studies. Moreover the modified amino acid Phe (p-CH₂SO₃Na) could also be used in solid phase synthesis to prepare a wide variety of CCK analogues and more generally, peptides analogues containing the acid-labile O-sulfated tyrosine.     

Sobrerol enantiomers and racemates: solid-state spectroscopy, thermal behavior, and phase diagrams

The characterization of the solid state of sobrerol enantiomers and racemates has been accomplished by a number of techniques on solid phase such as thermal analysis (DSC) and spectroscopy (IR, 13C NMR, and X-ray diffraction both on powders and on single crystal). Experimental and theoretical binary phase diagrams of cis- and trans-sobrerol enantiomers and their mixtures have been drawn and are discussed. Thermal analysis allowed, moreover, the detection of cis racemate polymorphism. Finally, the quantitative analysis of the cis racemate as an impurity of the trans racemate by means of microcalorimetric determinations is reported.     

An NMR compatible model for solid tumour

An NMR model for the study of drug interactions with solid tumour is described. It is based on the use of packed cells in a simple medium. The system is capable of dealing with cellular biochemistry at a molecular level through experiments conducted in a homogeneous field by ¹H spin-echo NMR spectroscopy. However, through a simple imaging technique, it is also possible to introduce a spatial element into the chemistry of the packed cells. The use of these complementary NMR methods are illustrated by the action of the cytotoxic agent doxorubicin on cellular glycolysis. A pattern of signals observed in a homogeneous field experiment following oxidative stress are duplicated in the imaging experiment to illustrate the toxins' ability to penetrate the model tumour.     

Prediction of designer drugs: synthesis and spectroscopic analysis of synthetic cannabinoid analogues of 1H‐indol‐3‐yl(2,2,3,3‐tetramethylcyclopropyl)methanone and 1H‐indol‐3‐yl(adamantan‐1‐yl)methanone

In this work, emergence patterns of synthetic cannabinoids were utilized in an attempt to predict those that may appear on the drug market in the future. Based on this information, two base structures of the synthetic cannabinoid analogues – (1H‐indol‐3‐yl(2,2,3,3‐tetramethylcyclopropyl)methanone and 1H‐indol‐3‐yl(adamantan‐1‐yl)methanone) – together with three substituents – butyl, 4‐fluorobutyl and ethyl tetrahydropyran – were selected for synthesis. This resulted in a total of six synthetic cannabinoid analogues that to the authors’ knowledge have not yet appeared on the drug market. Spectroscopic data, including nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier transform infrared (FTIR) spectroscopy (solid and gas phase), are presented for the synthesized analogues and some additional related cannabinoids. In this context, the suitability of the employed techniques for the identification of unknowns is discussed and the use of GC‐FTIR as a secondary complementary technique to GC‐MS is addressed. Examples of compounds that are difficult to differentiate by their mass spectra, but can be distinguished based upon their gas phase FTIR spectra are presented. Conversely, structural homologues where mass spectra are more powerful than gas phase FTIR spectra for unambiguous assignments are also exemplified. This work further emphasizes that a combination of several techniques is the key to success in structural elucidations. Copyright © 2015 John Wiley & Sons, Ltd.