新型苯胺类苯并咪唑衍生物的合成及其生物活性

目的 设计合成新型苯胺类苯并眯唑衍生物，并评价其对大白鼠胃液分泌和胃酸分泌的作用。方法 以没食子酸、胡椒醛和香草醛为原料，经多步反应合成目标化合物，并通过大白鼠灌胃给药、幽门结扎、测定胃液及和胃酸量，来确定所合成化合物对其胃液和胃酸分泌率的影响。结果 共合成8个新化合物、5个前体及1个对照药物(NC-1300)，经元素分析，IR，^H-NMR和MS确证其结构；其中2个化合物对胃酸分泌抑制作用与NC-l300相当，所有化合物均对胃液分泌无显著影响。在中间体制备中提出了经取代的邻硝基苯甲醛一步催化氢化制备取代的邻氨基苯甲醇的方法及其选择性N，N-二甲基化法。结论 以没食子酸为原料所合成的NC-1300类似物的胃酸分泌抑制作用与NC-1300相当，是强的质子泵抑制剂。     

水杨酸镁铝合成条件的考察

以水杨酸钠，６水氯化镁，６水三氯化铝为原料，经配合反应合成了水杨酸镁铝新型配合物。用均匀设计对其合成条件进行了考察。     

白桦脂酸衍生物的合成修饰及其抗菌活性研究

目的：设计白桦脂酸（BA）的新型衍生物结构，研究其及衍生物的体外抗菌活性。方法：通过Jones氧化反应、Claisen Schmidt缩合反应等得到目标化合物BA-01；采用96孔板的琼脂稀释法测定化合物对5种细菌的最小抑菌浓度（MIC）。结果：合成了一种具有新型结构的BA衍生物，且为首次报道的新化合物，其结构通过¹H NMR，¹³C NMR和MS（ESI）等表征分析确定。体外抗菌活性测试结果表明，目标化合物对3种革兰阳性菌均有显著的抑菌活性，其中对金黄色葡萄球菌的抑菌活性最高，其最小抑菌浓度（MIC）为12.5 μmol·L^-1，与BA相比显著提高。结论：合成修饰的新型结构中C-3位羟基的修饰以及C-2位上苯环的连接对其生物活性具有重要影响，值得进一步深入探究。     

新型肝胆显影剂配体-MEBROFENIN((艹米)溴氨乙酸)及其类似物的合成

通过溴化、成酐、氨解等反应,合成了新型肝胆显影剂配体-莱溴氨乙酸及其四个未见报道的类似物。     

白桦酸及其衍生物的研究进展

对白桦酸衍生物的构效关系及其中的YK-FH312、RPR103611和IC9564等的作用机制及活性进行述评。天然产物白桦酸是有抗HIV和抗肿瘤活性，且具有新型结构和新型作用机制的化合物，其天然来源广泛，半合成方法成熟，是寻找抗HIV和抗肿瘤药物的优秀的先导物。通过对白桦酸的结构修饰，大量白桦酸衍生物已被合成。     

紫杉醇及其相关化合物的研究进展

紫杉醇是近年来研究和开发出的化学结构新颖，作用机理独特的新型抗肿瘤药。本文根据民紫杉醇结构类似的２００多个紫杉烷类二萜化合物，按其骨架特征归纳为五大类，并对每一类的ＮＭＲ谱鉴别特征进行了描述；对紫杉醇的全合成和半合成，紫杉烷基二萜化合物的分析方法和构效关系也作了简要介绍。同时讨论了紫杉醇的来源问题。     

壳聚糖-巯基醋酸偶合物的制备及结构分析

目的制备一种新型生物粘附材料-壳聚糖-巯基醋酸偶合物,并对其结构进行分析。方法以N-羟基丁二酰亚胺(NHS)作催化剂,采用新的合成工艺制备壳聚糖-巯基醋酸偶合物,并测定了偶合物中巯基的含量,同时对偶合物进行了元素分析和红外光谱测定。结果制备得到了巯基含量为1034μmol.g-1的壳聚糖-巯基醋酸偶合物,阐明了该材料的结构特征。结论新的合成工艺可行,材料的结构可用红外光谱来表征。     

氟苯胺席夫碱及其铜(Ⅱ)、镍(Ⅱ)配合物的合成与抑菌活性研究

目的　开发新型抑菌药物。方法　以水杨醛和对氟苯胺为原料合成含氟Schiff碱及其Cu(Ⅱ)、Ni(Ⅱ)配合物,并进行了初步抑菌活性研究。结果　合成的Schiff碱及其配合物经元素分析、红外光谱等表征其结构组成。结论　抑菌活性试验表明,合成的Schiff碱及其配合物对各供试菌株有明显的抑菌活性,抑菌效果有量效关系,其中Schiff的Cu配合物活性最强,并超过了苯甲酸     

双取代乙二胺金属配合物的合成及抗菌活性

目的 设计合成一系列双取代乙二胺过渡金属配合物并寻找抗菌活性药物。方法以N，N’-双取代乙二胺为配体合成过渡金属配合物，并进行体外抑菌活性筛选。结果合成了6个(Ⅲ1-6)新配合物，其结构经红外光谱、元素分析确证。结论初步抑菌实验表明，合成的配合物对多种菌株有明显的抑制活性，有进一步研究的价值。     

一种新型芳香羧酸钴配合物的合成及晶体结构

目的 合成一种新型芳香羧酸钴配合物并解析其结构.方法 由3,3’,4,4’-联苯四羧酸,1,10-邻菲啉,醋酸钴采用水热法反应,利用X射线单晶衍射对单晶产物进行表征.结果 得到一种新型芳香羧酸钴配合物,表征了其结构.结论 制备了一种新型芳香羧酸钴配合物[Co(H2btc) (phen)(H2O)3](H2 btc=3,3’,4,4’-联苯四羧酸,phen=1,10-邻菲罗啉),为后续的生物活性研究打下基础.     

Photoaffinity labeling of the angiotensin II receptor. 1. Synthesis and biological activities of the labeling peptides.

The synthesis and biological activities of analogues of the peptide hormone angiotensin II (AT) for use in photoaffinity labeling and receptor isolation are described. In the modified sequence of AT, Sar-Arg-Val-Tyr-Val-His-Pro-Phe, the aromatic residues Tyr and Phe have been either singly or simultaneously replaced by L-4'-nitrophenylalanine, L-4'-amino-3',5'-diiodophenylalanine, L-4'-aminophenylalanine, L-4'-diazoniumphenylalanine, and L-4'-azidophenylalanine. The peptides were assembled by solid-phase synthesis and the functional groups in position 4 and/or 8 chemically modified. Radioactivity was introduced by catalytic tritiation of the iodinated peptides to form the photolabeling precursors containing L-4'-amino-3',5'-diiodophenylalanine. On rabbit aorta the AT analogues substituted in position 4 showed poor affinities (0--15%), in position 8 high relative affinities (16--118%), and in position 4 and 8 additive effects of simultaneous substitutions. It is also shown that the new Boc derivative of L-4'-amino-3',5'-diiodophenylalanine can be used in peptide synthesis without side-chain protection.     

Regulation of TRPM2 channels in neutrophil granulocytes by ADP-ribose: a promising pharmacological target

TRPM2 channels play an important role in the activation process of neutrophil granulocytes. One mechanism of TRPM2 channel gating is the binding of intracellular ADP ribose (ADPR) to the Nudix box domain in the C-terminal tail of TRPM2. Intracellular Ca²⁺, although not an activator of TRPM2 by its own, significantly enhances TRPM2 gating by ADPR. Stimulation of neutrophil granulocytes with the chemoattractant peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) induces release of Ca²⁺ ions from intracellular stores which in cooperation with endogenous ADPR levels enable Ca²⁺ influx through TRPM2. Stimulation of the ectoenzyme CD38, a membrane-associated glycohydrolase with ADPR as main product, and uptake of ADPR into the cell may contribute to the effects of fMLP. Inhibition of ADPR production, of uptake and of binding to TRPM2 are all potential pharmacological principles by which a modulation of neutrophil function may become possible in future.This revised version was published online in May 2005 with several corrections to the text     

METHIONINE ENKEPHALIN AND ISOSTERIC ANALOGUES I. Synthesis on a Phenolic Resin Support†

An efficient synthesis of methionine enkephalin using a phenolic resin support is described. Analogues modified at their C-termini, such as peptide acids, amides, methyl esters and compounds formed by their reduction, were prepared conveniently from common peptide phenyl ester resins. The resin was used in the synthesis of complex isosterically modified analogues designed to investigate the role the peptide backbone plays in receptor interaction. Free hexapeptide phenyl ester resins underwent intramolecular aminolysis liberating the corresponding cyclic peptides.     

Structure-activity relationships of dermorphin tetrapeptides carrying a ketomethylene linkage

The synthesis and in vitro pharmacological tests of 5 ketomethylene tetrapeptide analogues of the opioid heptapeptide dermorphin H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 are described in this study. The substitution of the original Phe-Gly peptide bond (-CO-NH-) by the ketomethylene linkage (-CO-CH2-) provided analogues with reduced opioid activity.     

Structural study of the N-terminal segment of neuropeptide tyrosine

A series of analogues of neuropeptide tyrosine (NPY) was synthesized by solid-phase peptide synthesis using BOP as a coupling reagent for the complete synthesis. A structure-activity study of the N-terminal portion of the molecule was performed with the analogues obtained by the successive replacement of the first 10 amino acids by the residue L-alanine. NPY and its analogues [Ala1-10]hNPY were tested for their potency on rat vas deferens and for their affinity to central nervous system receptors on a rat brain membrane preparation. The results suggest that the hypothetical polyproline type II helix structure of the N-terminal segment is involved in both potency and affinity. Indeed, the substitution by L-Ala of proline residues in position 2, 5, or 8 showed important losses of activity and affinity. The more important losses were observed with the replacement of Pro-5 or Pro-8. A critical loss of potency of hNPY was also observed after the substitution of the Tyr-1 residue by L-Ala, thus confirming the important role played by this residue for the full expression of the biological activity of NPY.     

Novel sst5-selective somatostatin dicarba-analogues: synthesis and conformation-affinity relationships

We describe synthesis, conformational studies, and binding to the five somatostatin receptors (sst 1-5) of a few analogues of the cyclic octapeptide octreotide (1), where the disulfide bridge was replaced by a dicarba group. These analogues were prepared by on-resin RCM of linear hepta-peptides containing two allylglycine residues; first- and second-generation Grubbs catalyst efficiencies were compared. The C=C bridge was hydrogenated via two different methods. Binding experiments showed that two analogues had good affinity and high selectivity for the sst5 receptor. Three-dimensional structures of the active analogues were determined by (1)H NMR spectroscopy. Conformation-affinity relationships confirmed the importance of D-Phe(2) orientation for sst2 affinity. Moreover, helical propensities well correlates with the peptide sst5 affinity. The presence of the bulky aromatic side chain of Tyr(Bzl)(10) favored the formation of a 3(10)-helix and enhanced the sst5 selectivity suppressing the sst2 affinity. Finally, a new pharmacophore model for the sst5 was developed.     

Synthesis and biological activities of photoaffinity labeling analogues of substance P

Substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH2, SP) is an undecapeptide with important properties as a neurotransmitter and with other functions. No specific antagonists and no long-acting analogues of this peptide hormone are known to date. In order to reach these goals, analogues of SP have been prepared which contain potential affinity, as well as photoaffinity labeling functions, suitable for irreversible attachment to SP receptors. We report here the synthesis of SP analogues which have the Phe residues in positions 7 or 8 replaced with (4'-NO2)Phe, (4'-NH2)Phe, (4'-N2+)Phe, and (4'-N3)Phe. Some of these peptides are used for photoaffinity labeling studies using various bioassays. The synthesis of the (NO2)Phe-containing peptide was carried out on solid phase using Nle instead of Met and the Boc strategy up to residue 4; the remaining amino acids were added using an Fmoc strategy. The protected undecapetide was cleaved by ammonolysis, purified by chromatography on silica gel with chloroform/methanol and deprotected afterwards. The amino, diazonium, and azido peptides were obtained in this sequence by chemical modification of the nitro peptides. On guinea pig ileum the modified peptides in position 8 had close to maximal activity, whereas modifications in position 7 produced some reduced activity, especially the nitro modification. No diazonium peptide produced any irreversible effects on guinea pig ileum. Photoinactivation studies were carried out on strips of guniea pig trachea, but no irreversible effects have been observed, neither permanent stimulation nor permanent inactivation. The biological activities and effects are discussed in view of the molecular properties of the synthesized analogues.     

High affinity conformationally constrained nociceptin/orphanin FQ(1-13) amide analogues

A series of cyclic analogues with a lactam linkage were prepared by solid phase peptide synthesis to explore possible biologically active conformation(s) of nociceptin/orphanin FQ (N/OFQ). cyclo[D-Asp(7),Lys(10)]- and cyclo[Asp (6),Lys(10)]N/OFQ(1-13)NH2 exhibit high affinity (Ki = 0.27 and 0.34 nM, respectively) and high potency in the GTPgammaS assay (EC 50 = 1.6 and 4.1 nM, respectively) at human nociceptin/orphanin FQ peptide (NOP) receptors. These analogues exhibit 2- to 3-fold higher affinity and 2- to 5-fold higher potency than the parent peptide.     

Structure-activity relationship studies of phenanthridine-based Bcl-XL inhibitors

Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X L and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC 50 values.     

Cyclic disulfide analogues of the complement component C3a Synthesis and conformational investigations

The flexible C-terminal region of the anaphylatoxic peptide C3a was reported to contain the receptor binding site. To elucidate the receptor binding conformation of the C-terminus, as well as to examine a synthetic approach to potential C3a-antagonists, 26 cyclic disulfide bridged C3a analogues were synthesized. Solid phase peptide synthesis was performed on different polymeric supports by individual peptide synthesis, with Fmoc strategy, and simultaneous multiple peptide synthesis, using Boc and Fmoc strategies. Both strategies gave open-chain peptides in comparable yields. Syntheses using the Boc strategy employed the HF-labile 4(methoxy)benzyl group (Mob) for β-thiol protection of cysteine; in contrast, the TFA-stable protecting groups, acetamidomethyl (Acm) and trityl (Trt), were chosen for syntheses employing Fmoc strategy. Ring closure reactions by iodine oxidation were carried out starting from protected (Acm/Acm, Trt/Acm) or unprotected dithiols. The resulting cyclic C3a analogues were characterized by HPLC, amino acid analysis, and FAB-MS. Conformational investigations using CD spectroscopy and theoretical structural investigations by means of molecular dynamics calculations revealed that slight variations in sequence result in pronounced conformational consequences. The potential of cyclic C3a analogues to activate or to desensitize guinea pig platelets, a standard test system for biological activities of anaphylatoxic peptides like C3a, revealed relatively low activities for cyclic peptides (<0.1% C3a activity). N-terminal acylation with cationic, arginine-rich sequences like YRRGR- led to amplified biological effects. Three of the synthesized peptides, namely CAALCLAR (P1), YRRGR°CGGLCLAR (P5) and YRRGRAhx°CGGLCLAR (P8), point in the direction of C3a antagonists.