系列新LHRH拮抗剂的合成及其生物活性

本文报道了一系列在5位上含有新非天然氨基酸的促黄体素释放激素(LHRH)拮抗剂的合成及其生物活性。这些拮抗剂绝大多数都能表现出较强的抗排卵活性。以生理盐水为赋型剂,其中有些在1μg剂量下能100％抑制大白鼠排卵。     

壳聚糖微球用于LHRH拮抗剂类似物缓释体系的研究

研究壳聚糖微球对促黄体生成激素释放激素（ＬＨＲＨ）拮抗剂类似物（ＴＸ４６）的吸附与释放，考察了影响吸附与释放的因素，得到了各种不同微球对ＴＸ４６的吸附与释放平衡曲线，为ＬＨＲＨ拮抗剂用于生育控制及其它临床应用提供了初步的实验依据。     

哌嗪嘧啶类CCR4拮抗剂的设计、合成及生物活性

基于对已报道的CCR4拮抗剂的构效关系分析, 设计并合成了一系列哌嗪嘧啶类化合物. 采用细胞趋化抑制实验测试了合成化合物的体外活性, 其中化合物8a的活性优于目前报道的活性最好的化合物BMS-397; 在小鼠鼻炎模型中, 化合物8a以极低的剂量达到了布地奈德(鼻炎临床治疗药物)的治疗效果. 采用毛细管电泳法测得化合物8a与CCR4 N端40肽的结合常数为(3.6179±0.5976)×10⁴ L/mol.     

哒嗪酮类α1-肾上腺素受体拮抗剂的合成和生物活性研究

将苯(氧)乙胺和苯氧烷胺类α1-肾上腺素受体拮抗剂中的苯(氧)乙胺、苯氧烷胺片段引入哒嗪酮类化合物中,设计、合成了30个新的含哒嗪酮环的α1-肾上腺素受体拮抗剂．所有新化合物的结构均经1H NMR,IR,HRMS确证．生物活性测试表明28个目标物对α1-肾上腺素受体有较好的拮抗作用(pA2>6．00),化合物6o,6p,6q,6v,6x,6y,10c,10d的pA2值>7．00．     

替米沙坦及其类似物的合成和生物活性研究

设计合成了替米沙坦及其类似物, 改进了替米沙坦的合成工艺. 用邻苯二胺与相应的有机羧酸缩合, 所得产物苯并咪唑衍生物与4'-溴甲基联苯-2-甲酸甲酯通过N-烷基化得到相应的目标化合物, 合成了替米沙坦和9种未见文献报道的苯并咪唑联苯化合物, 其结构经¹H NMR, IR, MS和元素分析确证. 用体外动脉环的方法, 研究目标化合物的初步体外抗高血压活性, 试验结果表明其中部分化合物具有一定的抗高血压活性.     

AMPA受体拮抗剂NS1209的合成

以5-溴异喹啉为起始原料,经过9步反应合成了AMPA受体拮抗剂——NS1209,总产率37.3％,其结构经1H NMR和MS确证.     

天冬酰胺的环化缩合反应及其在合成拮抗剂与吗啡肽中的应用

天冬酰胺的环化缩合反应及其在合成拮抗剂与吗啡肽中的应用;四氢嘧啶酮;构象;内源性吗啡肽     

N-（取代苯基哌嗪基烷基）酰胺类α_1-受体拮抗剂的设计、合成及生物活性研究

结合苯基哌基类α_1-受体拮抗剂的构效关系和我们应用计算机辅助药物设计 方法所构建的药效团模型,设计并合成了呋喃-2-甲酸{ω-[4-（取代苯基）-1-哌 嗪基]-烷基}酰胺和2-氧代-2H-苯并吡喃-3-羧酸{ω-[4-（取代苯基）-1-哌嗪基]- 烷基}酰胺两类衍生物,其结构经~1H NMR,IR及MS（HRMS）确证。初步生物活性测 试表明,所合成的目标化合物多数具有较好的α_1-受体拮抗剂,良性前列腺增生 。     

Chemistry and Molecular Biology in the Search for New LHRH Antagonists

Hormones—and in particular, the sex hormones—were the first growth factors discovered to be involuntary helpers of cancer. Female breast cancer and male prostate cancer are the best known examples of tumors acknowledged to be hormone-dependent. A look at cancer statistics shows that breast cancer is still the most frequent cancer in women; in men, prostate cancer plays a similarly dominant role with increasing age. Shutting down the main production site of the sex hormones estrogen and testosterone either by removing the ovaries or by castration is a well-known and often effective therapy; however, these procedures can be problematic due to the concomittant psychological stress. Modern hormone therapy for advanced breast cancer and prostate cancer attempts to spare the patient such irreversible operative procedures for as long as possible, by using hormone antagonists, such as the LHRH antagonists, which hinder deployment of the hormone itself and thus its growth-promoting activity.     

低组胺释放副作用的GnRH拮抗剂的设计合成及活性评价

根据肽类组胺释放剂具有多个碱性氨基酸的结构特点, 将具有羧基结构的基团引入促性腺激素释放激素(GnRH)的不同位置, 合成了一系列新的GnRH类似物, 并进行了大鼠体内抑制睾酮释放的生物活性评价及大鼠腹腔肥大细胞中的促组胺释放副作用评价. 结果表明, 某些带有酸性基团的GnRH类似物不仅组胺释放副作用大大降低, 而且保留了原有的生物活性. 该结果为研发具有低组胺释放副作用的安全型GnRH拮抗剂药物提供了新的构效关系信息.     

Synthesis of a β-turn mimetic suitable for incorporation in the peptide hormone LHRH

LHRH is a decapeptide hormone which plays a central role in neuroendocrinology. Conformational studies have suggested that LHRH may adopt a β-turn involving residues 5-8 when bound to its receptor. A β-turn mimetic with side chains corresponding to those of a Tyr-Gly-Leu-Orn tetrapeptide has therefore been synthesized for incorporation at positions 5-8 in LHRH. In the turn mimetic, residues i and i+1 are connected by a ψ[CH₂O] isostere instead of an amide bond, while a covalent ethylene bridge replaces the hydrogen bond which is often found between residues i and i+3 in β-turns. The turn mimetic was assembled from three types of building blocks: an azido aldehyde, an Fmoc protected amino acid and a protected dipeptide amine.     

Synthesis and Anti-HIV Activity of a Novel Series of Isoquinoline-Based CXCR4 Antagonists

An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium mobilization assays, respectively. In addition, the anti-HIV activity of all analogues was determined. All compounds showed excellent activity, with compound 24c being the most promising one, since it displayed consistently low nanomolar activity in the various assays.     

Synthesis of Hydantoin Androgen Receptor Antagonists and Study on Their Antagonistic Activity

Hydroxymethylthiohydantoin, hydroxymethylthiohydantoin, and hydantoin, containing a pyridine group, were synthesized to study their androgen receptor antagonistic activities. Among them, compounds 6a/6c/7g/19a/19b exhibited excellent androgen receptor antagonistic activity, which was consistent with or even superior to enzalutamide. In addition, compounds 19a and 19b exhibited better antiproliferative activity than enzalutamide in prostate cancer cells. The results show that compound 19a has great potential as a new AR antagonist.     

Determination of the configuration of histrelin,and LHRH analog,by chiral capillary gas chromatography

Summary Summary The assigned chirality at each center of the synthetic nonapeptide histrelin (L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-N^im-benzyl-histidyl-L-leucyl-L-arginyl-L-proline-ethylamide) was verified using chiral gas chromatography. The procedure involved acid hydrolysis of histrelin to the constituent amino acids, derivatization as the N-pentafluoropropionyl/isopropyl esters and the analysis of the mixture using a commercially available 25m chiral capillary column (Chirasil-L-Val). There was no significant difference in the retention time of the amino acids obtained from the hydrolysate mixture when compared to the appropriate standards. Additionally, the hydrolysate was spiked with the D and L amino acids to prove the identity of closely eluting peaks. Luteinizing hormone-releasing hormone     

新型含吡唑环的N-甲氧基氨基甲酸甲酯类化合物的设计、合成及生物活性

以苯(吡啶)乙/丙酮类化合物为原料, 经酯化、环化和缩合三步制得新型含吡唑环的N-甲氧基氨基甲酸甲酯类化合物3a~3r, 化合物及其中间体的化学结构经红外光谱、核磁共振谱及元素分析确认. 生物活性结果表明, 化合物3在400 mg/L下分别对水稻稻瘟病、黄瓜霜霉病和小麦白粉病具有很好的防治效果. 对水稻稻瘟病, R₁为甲基或甲氧基取代的苯基时活性最好; 对于黄瓜霜霉病和小麦白粉病, R₁为苯基或甲基取代苯基的化合物杀菌活性优于其它化合物, R₂为甲基的化合物杀菌活性优于R₂为氢的化合物.     

Novel Method for Synthesis of Diarylpyrazole Derivatives as Cannabinoid CB_1 Receptor Antagonists

A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The react...     

Rational Design and Synthesis of AT1R Antagonists

Hypertension is one of the most common diseases nowadays and is still the major cause of premature death despite of the continuous discovery of novel therapeutics. The discovery of the Renin Angiotensin System (RAS) unveiled a path to develop efficient drugs to fruitfully combat hypertension. Several compounds that prevent the Angiotensin II hormone from binding and activating the AT1R, named sartans, have been developed. Herein, we report a comprehensive review of the synthetic paths followed for the development of different sartans since the discovery of the first sartan, Losartan.     

长链烷基氨基苯并冠醚的合成

采用４′－氨基苯并－１５－冠－５与长链卤代烷反应，合成了一系列Ｎ－单长链烷基取代及Ｎ，Ｎ－双长链烷基取代的氨基苯并－１５－冠－５。通过１ＨＮＭＲ、ＩＲ、ＭＳ、ＵＶ和元素分析证明了产物的结构