胸腺素α1的C端活性片段环肽类似物的合成与生物活性评价

用硫酯法合成了一系列Tα1的C端活性片段的环肽类似物, 以提高其活性与稳定性. 用促淋巴细胞增殖法测定了环肽类似物的生物活性, 结果表明, 环肽类似物较好地保留或提高了促淋巴细胞增殖活性.     

长效LHRH拮抗剂的设计、合成和生物活性

根据抗蛋白酶降解的长效肽设计思想, 合成了一系列新型结构的LHRH拮抗剂类似物. 体内生物活性评价结果表明, 所设计的多肽具有比母体肽和阳性对照更长的体内抑制睾酮作用时间和较低的最低有效剂量, 证实了该设计思想的可行性, 并为开发长效LHRH拮抗剂药物提供了新的候选化合物.     

[反]-β-法尼烯类似物的设计、合成与生物活性研究

对[反]-β-法尼烯(EBF)类似物的骨架结构原子进行改造,引入吡虫啉系列活性基团,设计合成了13个结构新颖的EBF类似物,并对其生物活性进行了研究.结果表明,这些化合物对蚜虫具有明显的抑制活性,尤其在低浓度时活性更明显,如质量浓度为25mg/L时,I₁₀和I₁₃对蚜虫的抑制率分别为93.1%和87.1%,远高于同浓度下吡虫啉的抑制率(66.7%).     

促性腺激素释放激素类似物-紫杉醇靶向抗肿瘤缀合物的合成及评价

以促性腺激素释放激素类似物(GnRHa)为靶向配体, 以紫杉醇为抗癌因子, 分别以硫醚键和二硫键为连接臂, 设计合成了2个靶向抗肿瘤缀合物. 研究了缀合物的肿瘤细胞增殖抑制活性和GnRH受体结合活性, 结果表明, 2个缀合物均具有较强的抗肿瘤活性和GnRH受体亲和力; 另外, 血浆稳定性实验结果显示, 以硫醚键偶联的缀合物1在血浆中孵育24 h, 原型保留仍在50%以上, 具有较高的稳定性.     

山竹醇新类似物的合成及其抗肿瘤活性研究

山竹醇具有广泛的生物学活性,例如抗炎、抗肿瘤、抗氧化、诱导细胞凋亡等.通过对山竹醇进行结构修饰,研究其侧链基团对山竹醇活性的影响,以期提高其抗肿瘤活性.以乙酰丙酮为原料,经过Michael加成、Knoevenagel缩合等多步反应,合成了三个未见文献报道的山竹醇类似物,并用噻唑蓝(MTT)法对其进行生物活性研究,分析其构效关系.结果表明,合成的三种新类似物对口腔鳞癌细胞的抑制活性均低于山竹醇,由此可知,C4位置的异戊烯基和C8位置的烯丙基对山竹醇的生物活性起关键作用.     

4—（N—烷基）胺甲基苯丙氨酸的合成

在生物活性肽研究中,通过在肽主链中引入特定结构的氨基酸,得到其活性类似物,可以使人们进一步认识肽结构与生物活性之间的关系,发展高活性、低副作用的肽类药物。蛋白氨基酸的结构都是一定的,不能满足研究工作的需要,所以需要设计合成特定结构的非蛋     

吗啡类生物碱的合成研究进展

吗啡是从鸦片中分离得到的天然产物.因吗啡及其类似物具有独特的结构和有效的生物活性,合成化学家对其合成研究产生了高度的兴趣.按合成吗啡及其类似物的时间顺序分类,对吗啡类生物碱的合成研究进展进行了综述.     

α-氨基膦酸(酯)不对称合成研究进展

α-氨基膦酸作为天然氨基酸的含磷类似物, 具有广泛的生物活性, 详细介绍了使用手性辅助基团诱导和手性催化剂催化两种方法不对称合成光学活性α-氨基膦酸(酯)的最新研究进展.     

茼蒿素类似物的分子多样性2-(Z)-亚苄基-1,6,9-三氧杂螺环 [4,5-癸-3-烯类化 合物的合成

有多种生物活性的茼蒿素类似物是一类具有螺环缩酮烯醚独特结构的化合物。本文报道用糠醇为原料,以我们的呋喃二醇脱水－螺环缩酮化反应为关键反应,合成了一类三氧杂螺环-[4,5]-癸烯的新型茼蒿素类似物。为这类化合物分子多样性开辟了新的途径。     

新型光活性多羟基氮杂核苷类似物的合成

研究开发新的抗癌、抗病毒药物的有效途径之一是设计、合成以及生物活性评价新型结构的核苷类似物。根据核苷结构的特点,核苷类似物的研究包括碱基改造和糖基改造两个方面。现已报道的糖基结构改造的核苷类似物基本分为含氧杂环、碳环、其它杂环(如:含氮杂环,含硫杂环等)以及无环类似物等⁽¹⁾。由于可利用天然单糖作为原料,获得光活性的含多个手性碳的含氧杂环核苷类似物相对较容易;而其它杂环的光活性核苷类似物,则因涉及至少两个手性碳原子的引入,合成难度增加。本文首次报道了用光活性的苹果酸和酒石酸为起始原料,成功地合成了光活性多羟基氮杂核苷类似物(Ⅰ,Ⅱ)。     

含有络合功能基的非天然氨基酸的设计、合成及在生物活性肽中的应用

设计合成了一类侧链带有络合基团的非天然氨基酸, 即侧链带有N,N-二羧甲基氨甲基、N,N-二酰胺甲基氨甲基和N,N-二羟乙基氨甲基的苯丙氨酸衍生物, 并将这类非天然氨基酸用于促性腺激素释放激素(LHRH)类似物的固相合成. 高效液相色谱分析结果表明, 粗肽的纯度较好, 易于纯化; 用电喷雾质谱测定了多肽的分子量. 这些非天然氨基酸可作为其它肽类药物合成的构建单元.     

Synthesis of tetrazole analogues of amino acids using Fmoc chemistry: isolation of amino free tetrazoles and their incorporation into peptides

An efficient synthesis of tetrazole analogues of amino acids starting from N^α-Fmoc amino acid in a three-step protocol is reported. The free amino tetrazoles were obtained in good yields and with excellent purity after removal of the Fmoc group. The synthesis of analogues of aspartic and glutamic acids in which the 5-tetrazolyl moiety is inserted at the β/γ carboxyl group starting from Fmoc-Asn and Fmoc-Gln and the incorporation of these tetrazoles into peptides are also described.     

Expansion of repertoire of modified DNAs prepared by PCR using KOD Dash DNA polymerase

Thymidine analogues bearing a variety of functional groups at the C5-position via an amino-linker arm were prepared and the substrate activity for PCR using thermophilic KOD Dash DNA polymerase was examined. The enzyme accepted the thymidine analogues bearing pyridine, imidazole, biotin, a cationic-charged guanidinium, a cationic-charged amino, mercaptopyridyl and phenanthrolne groups at the C5-position, forming the corresponding PCR product. However, a thymidine analogue bearing a carboxyl group at the C5-position was a poor substrate and the corresponding PCR products could not be obtained. The thymidine analogue bearing a mercapto group was also a poor substrate for the enzyme, because it dimerized by disulfide linkage under PCR conditions. The enzyme hardly accepts the thymidine analogues with a negatively-charged carboxyl group or a bulky group as a substrate. KOD Dash DNA polymerase, having a broader substrate specificity than any other DNA polymerase, will expand the variety of modified DNAs that can be prepared by PCR.     

Structural studies of C-amidated amino acids and peptides: crystal structures of Z-Gly-Phe-NH2, Tyr-Lys-NH2, and Asp-Phe-NH2

As part of the series investigating the structural features of C-terminal amidated amino acids and peptides, three crystal structures of Z-Gly-Phe-NH2, Tyr-Lys-NH2, and Asp-Phe-NH2 were analyzed by the X-ray diffraction method, and their molecular conformations and intermolecular interactions were investigated. Although the respective dipeptides exhibited an energetically allowable torsion angle concerning each backbone or side chain, the observed extended (Z-Gly-Phe-NH2, Asp-Phe-NH2) and folded (Tyr-Lys-NH2) conformations were considerably different from those of the corresponding unamidated peptides, due to the conformational flexibility of the respective dipeptides. The comparison between the crystal packings of the amidated and unamidated dipeptides indicated that the C-terminal amides tend to associate with the same neighboring group through hydrogen bonds, in which both the amide NH and O=C groups participate, while the unamidated peptides prefer a linear molecular connection, where both or either of the two carboxyl oxygens participate in the hydrogen bond formation. The difference in hydrogen bonding ability between the C-terminal amide and carboxyl groups has been considered to be based on the structural data of the related peptides analyzed so far.     

Antioxidant activity of peptide-based angiotensin converting enzyme inhibitors

Angiotensin converting enzyme (ACE) inhibitors are important for the treatment of hypertension as they can decrease the formation of vasopressor hormone angiotensin II (Ang II) and elevate the levels of vasodilating hormone bradykinin. It is observed that bradykinin contains a Ser-Pro-Phe motif near the site of hydrolysis. The selenium analogues of captopril represent a novel class of ACE inhibitors as they also exhibit significant antioxidant activity. In this study, several di- and tripeptides containing selenocysteine and cysteine residues at the N-terminal were synthesized. Hydrolysis of angiotensin I (Ang I) to Ang II by ACE was studied in the presence of these peptides. It is observed that the introduction of L-Phe to Sec-Pro and Cys-Pro peptides significantly increases the ACE inhibitory activity. On the other hand, the introduction of L-Val or L-Ala decreases the inhibitory potency of the parent compounds. The presence of an L-Pro moiety in captopril analogues appears to be important for ACE inhibition as the replacement of L-Pro by L-piperidine 2-carboxylic acid decreases the ACE inhibition. The synthetic peptides were also tested for their ability to scavenge peroxynitrite (PN) and to exhibit glutathione peroxidase (GPx)-like activity. All the selenium-containing peptides exhibited good PN-scavenging and GPx activities.     

Binding sites of [Ru(bpy)2(H2O)2](BF4)2 with sulfur- and histidine-containing peptides studied by electrospray ionization mass spectrometry and tandem mass spectrometry

The composition and binding sites of cis-[Ru(II)(bpy)2]2+-bound sulfur-containing peptides of Met-Arg-Phe-Ala, glutathione and oxidized glutathione, and also histidine-containing peptide of oxidized insulin B chain, were investigated by electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS). The composition of Ru(II)-containing peptides was precisely determined by ESI-MS, zoom scan and simulation of isotope distribution patterns. MS/MS analysis shows that, in sulfur-containing peptides, the Ru(II) complex prefers to anchor to a carboxyl group, although some other potential binding sites of thiol, thioether and N-terminal amino groups present in these peptides, and in oxidized insulin B chain, Ru(II) first anchors to His10, then either to the hydroxyl group of Thr27 or to the carboxyl group of Ala30. Its secondary structure and microenvironment surrounding the potential binding sites may affect the binding ability of cis-[Ru(II)(bpy)2]2+ to oxidized insulin B chain.     

酶促合成肽的研究 II: 含羧基侧链氨基酸的肽的酶促合成

用嗜热菌酶酶促合成了一系列含门冬氨酸、谷氨酸的肽. 实验证明, 缩合反应中羧基组份中的门冬氨酸β-羧基或谷氨酸γ-羧基毋需保护. 同时也研究了邻近氨基酸残基对缩合反应的影响.     

A new strategy utilizing electrospray ionization-quadrupole ion trap mass spectrometry for the qualitative determination of GnRH peptides

Numerous forms of the neurotransmitter GnRH have been discovered in vertebrates and invertebrates. Methods used for identification of these peptides are laborious and often require the application of multiple, confirmatory techniques. In this study, we investigate whether HPLC-MS/MS and de novo sequencing techniques applied to whole peptide analysis can provide a simpler approach to GnRH characterization. Experiments were performed with six GnRH forms (chicken I, chicken II, lamprey III, mammalian, salmon and seabream) to determine whether MS/MS spectra would be dominated by proline-directed fragmentation to the detriment of obtaining sufficient fragmentation for sequencing. While the expected b8 fragment was prominent, sufficient ion series were obtained for the six GnRH peptides to provide sequence identification. On the basis of the patterns observed for six model peptides, similar fragmentation patterns are expected for other GnRH forms. To confirm the applicability of the method, extracts from Sprague-Dawley rat brains were examined. These experiments confirm the presence of mammalian GnRH and a posttranslationally modified form of mammalian GnRH, hydroxyproline9 GnRH, in Sprague-Dawley rat brains and demonstrate that ESI-MS/MS techniques provide a valuable addition to existing qualitative methods.     

Investigating natural rubber composition with Fourier Transform Infrared (FT-IR) spectroscopy: A rapid and non-destructive method to determine both protein and lipid contents simultaneously

A large panel of Natural Rubber (NR) samples was characterized using Fourier Transform Infrared (FT-IR) spectroscopy in Attenuated Total Reflection (ATR) configuration. Specific vibrational bands were attributed to some non-isoprene compounds naturally present in NR composition. A rapid and non-destructive method was developed to investigate some specific functional groups contained in lipids (ester and carboxyl groups) and proteins (amides). Ester and carboxyl groups were quantified using calibration curves developed from synthetic cis-1,4-polyisoprene mixtures with either methyl stearate or stearic acid. Amide groups of proteins and peptides were found to be directly quantifiable from NR FT-IR spectra. The clonal origin and processing were found to influence the non-isoprene composition of NR. Significant correlations were found between FT-IR results and conventional chemical analyses: nitrogen content for proteins and total lipid extract.     

Neues Verfahren zur Bestimmung der endständigen Carboxylgruppen von Peptiden

A new and simple method for the determination of the C-terminal groups of peptides is proposed. The carboxyl groups are converted into the corresponding peptide-triazines by treating with dimethylbiguanide. These derivatives are then hydrolysed by Streptomyces griseus protease and the amino-acid derivatives in the hydrolysate are identified by thin-layer or paper chromatography.