Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 31): 2-Heteroaryl Derivatives

A range of 14 derivatives of flavone-8-acetic acid (FAA) with a heterocyclic substituent in place of the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. Some of the compounds, notably 2c, d and s , showed significant in vivo activity and these require further studies in order to evaluate their potential for development.     

Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 1: 6-Methyl Derivatives

A range of 17 derivatives of flavone-8-acetic acid (FAA) with a 6-methyl substituent have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. While many of the compounds show activity comparable to FAA in vitro, this essentially disappears in vivo, possibly due to degradation before the compounds can reach the tumour site.     

3—取代—4—氧—3H—咪唑并[5,1—d][1,2,3,5]四嗪—8—羧酸衍生物的合成及其抗癌活性研究

根据咪唑四嗪酮类抗癌药物构效关系研究结果,以替莫唑胺和米托唑胺为先导化合物,设计合成了10个3－取代－4－氧－3H－咪唑并[5,1-d][1,2,3,5]四嗪－8－羧酸及其衍生物,以4－氨基咪唑－5－甲酰胺盐酸盐为起始原料,经酰化,重氮化环合得到咪唑四嗪酮环,再经3位和8位官能团转化,得到目标化合物,其中5个目标化合物未见文献报道,其结构均经红外光谱,核磁共振氢谱和元素分析等数据证实,经体外抗癌活性筛选,3个化合物表现出良好的抗癌活性。     

Amino Acid Derivatives,Part 4: Synthesis and Anti‐HIV Activity of New Naphthalene Derivatives

A new series of 2‐(naphthalen‐2‐yloxy)‐N‐[(aryl‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐triazol‐3‐yl)methyl] acetamides 5a–f was synthesized from naphthalene‐derived glycine derivative 2 via the hydrazinoacetamide analogs 4a–f . Alternatively, treatment of 4a with H₂SO₄ afforded 2‐(naphthalen‐2‐yloxy)‐N‐((5‐(phenylamino)‐1,3,4‐thiadiazol‐2‐yl)methyl) acetamide 6a . Alkylation or sulphonylation of 5a afforded the S‐alkylated derivatives 7 and 8 , respectively. Interestingly, treatment of 3 with methoxide ion gave the triazine derivative 9 . The synthesized compounds have been screened for their inhibitory activity against HIV‐1 and HIV‐2 in MT‐4 cells. However, 7 was found to be the potent inhibitor in vitro for the replication of HIV‐1 (EC₅₀ = 0.20 μg/mL), suggesting a new lead in the development of an antiviral agent.     

Synthesis and Antimicrobial Activity of New 1-Benzylbenzimidazolium Chlorides

1-Benzylbenzimidazole reacts with chloromethylalkyl ethers or sulfides or chloromethylcycloalkyl ethers to produce 3-alkoxy-methyl-1-benzylbenzimidazolium or 3-alkylthiomethyl-1-benzylbenzimidazolium or 1-benzyl-3-cycloalkoxymethylbenzimidazolium chlorides in very good yields. All the 1-benzylbenzimidazolium chlorides showed antimicrobial activity. The relationship between chemical structure and antimicrobial activity was analyzed by quantitative structure-activity relationships (QSAR).     

Anthracene-1,4,9,10-tetraone Derivatives: Synthesis and Antitumor Activity

A series of 2-alkylated anthracene-1,4,9,10-tetraone (ATO) derivatives were synthesized, and their antitumor action in ICR mice bearing S-180 cells and antiproliferative activity against L1210 cells were evaluated. Overall, the introduction of an alkyl group (C₁–C₈) at C-2 enhanced the antiproliferative activity. Among 2-(1-hydroxyalkyl)- or 2-(1-acetoxyalkyl)-ATO derivatives, four compounds possessing alkyl chain of an intermediate size (C₄–C₆) gave T/C values of > 300%. Acetylation at 1′-OH failed to cause an enhancement in the antitumor action, in contrast to a remarkable increase in antiproliferative activity. Although there was no direct relationship between antiproliferative activity and antitumor action, the compounds with lower antiproliferative activity tended to show higher antitumor activity. Further study shows that the antiproliferative activity of ATO derivatives may be explained properly neither by redox cycling nor arylating capacity.     

2-(1-咪唑基)乙酸的新法合成

唑来膦酸 ( zoledronic acid)可用于治疗由肿瘤引起的高血钙症和恶性骨转移瘤。自 2 0 0 1年在日本和欧洲获准上市后 ,现已在全球 40多个国家上市。近期临床试验结果表明本品还具有良好的抗骨质疏松作用。2 - ( 1 -咪唑基 )乙酸 ( 1 )是制备唑来膦酸的关键中间体 ,其合成已有多     

Synthesis and antitumour activity of new derivatives of flavone-8-acetic acid (FAA). Part 4: Variation of the basic structure

A range of 11 derivatives of flavone-8-acetic acid (FAA) in which the structure has been substantially altered in different ways have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. The generally poor activity observed shows that the basic structure cannot be altered much without destroying the activity.     

Research on Antifungal and Antimycobacterial Agents. Synthesis and Activity of 4-Alkylthiopyridine-2-carbothioamides

A series of 4-alkylthiopyridine-2-carbothioamides have been prepared and evaluated in vitro for antimicrobial activity. Chemical structures have been demonstrated by IR and ¹H NMR data and by elemental analysis. The antimycobacterial activity of these compounds against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium, and Mycobacterium fortuitum, and the antifungal activity against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Trichophyton mentagrophytes, Aspergillus fumigatus, and Absidia corymbifera were determined by the MIC values. Compounds 3 exhibit good antimycobacterial activity compared to isoniazide. A moderate antifungal activity was observed against T. mentagrophytes. Activity is influenced by hydrophobicity of the alkyl group.     

Synthesis and Antifungal Activities of Myristic Acid Analogs

Myristic acid analogs that are putative inhibitors of N-myristoyl-transferase were tested in vitro for activity against yeasts (Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans) and filamentous fungi (Aspergillus niger). Several (±)-2-halotetradecanoic acids including (±)-2-bromotetradecanoic acid ( 14c ) exhibited potent activity against C. albicans (MIC = 39 μM). C. neoformans (MIC = 20 μM), S. cerevisiae (MIC = 10 μM), and A. niger (MIC < 42 μM) in RPMI 1640 media. Improved synthetic methods have been developed for the synthesis of 12-fluorododecanoic acid ( 12a ) and 12-chlorododecanoic acid ( 12c ). Three novel fatty acids, 12-chloro-4-oxadodecanoic acid ( 8a ), 12-phenoxydodecanoic acid ( 12i ), and 11-(4-iodophenoxy)undecanoic acid ( 13d ) were also synthesized and tested.     

阿魏酸衍生物的合成及其抗肿瘤活性研究

目的 设计、合成了一系列含有喹唑啉结构的阿魏酸衍生物，并对其抗肿瘤活性进行研究。方法 基于拼接原理，将阿魏酸与喹唑啉进行结合，并对喹唑啉6位进行修饰得到目标化合物，采用CCK-8法测试目标化合物对肺癌细胞A549的抗肿瘤活性，利用分子对接技术对目标化合物与表皮生长因子受体的结合模式进行模拟。结果 目标化合物的结构经HRMS(ESI)、¹H-NMR进行确证；体外抗肿瘤活性结果表明化合物11d、11f、12d和12g的IC₅₀低于阳性药吉非替尼，11c的IC₅₀值与吉非替尼相当。结论 化合物11d(IC₅₀=3.09 μmol·L^-1)对肺癌细胞A549抗肿瘤活性较强，值得深入研究。     

(E)-4-芳酰氧基苯基丙烯酸类衍生物的合成及抑癌活性(英文)

本文报道了 18个 (E) 4 芳酰氧基苯基丙烯酸类衍生物的设计与合成。其中 17个化合物未见文献报道。所有目标物的化学结构经元素分析、红外光谱和核磁共振氢谱确证。初步体外抑癌试验结果表明 ,在 0 3μmol·L- 1 浓度下化合物 3e、3f、3g、3h、3k、4h和 4j对小鼠艾氏腹水癌 (EAC)呈现显著抑制作用。     

(E)-4-酰氧基苯基丙烯酸类衍生物的合成及抑癌活性

报道了18个(E)-4-酰氧基苯基丙烯酸类衍生物的设计与合成。其中17个化合物未见文献报道。所有目标物的化学结构经元素分析、红外光谱和核磁共振氢谱确证。初步体外抑癌试验结果表明,化合物3e、3f、3g、3h、3k、4h和4j在0.3μmol·L-1浓度下对小鼠艾氏腹水癌(EAC)呈现显著抑制作用。     

新型抗肿瘤药物埃坡霉素的研究

综述了近年来大环内酯类抗肿瘤药埃坡霉素的研究进展。简要介绍了其作用机制、药理活性和临床疗效，重点对埃坡霉素的构效关系以及若干种全合成策略，如大环内酯化合成、烯烃转化／stiue偶合等方法进行了分析和介绍。     

Synthesis of Isosteric Triterpenoid Derivatives and Antifungal Activity

Dermatomycoses are among the most widespread and common superficial and cutaneous fungal infections in humans. There is an urgent need to develop efficient and non‐toxic antimycotic agents with a specific spectrum of activity. Triterpenes have been demonstrated to exhibit a wide range of biological activities, including antifungal activities. In this study, through hemisynthesis, we aimed to obtain triterpene‐isosteric molecules from betulinic and ursolic acids to improve the antifungal activity and spectrum of action of these compounds. Six compounds were resynthesized and tested against eleven mucocutaneous and cutaneous mycotic agents. The results of the susceptibility assays were expressed as the minimal inhibitory concentration (MIC). The MIC values of the piperazinyl derivatives of ursolic and betulinic acids that were active against pathogenic yeasts were in the range of 16–32 μg/mL and 4–16 μg/mL, respectively, whereas fungicidal effects were observed at concentrations ranging from 16 to 128 μg/mL and 8 to 128 μg/mL, respectively. The piperazinyl derivative of betulinic acid exhibited an antifungal profile similar to that of terbinafine and was the most effective derivative against dermatophytes. This strategy led to a promising candidate for the development of a new antifungal agent.     

Design,Synthesis, and Preliminary Activity Evaluation of Novel Pyrimidine Derivatives as Acid Pump Antagonists

Acid-related diseases of the upper gastrointestinal tract, especially gastroesophageal reflux disease (GERD), remain a widespread problem worldwide. In this paper, we reported the design, synthesis, and preliminary gastric antisecretory activity evaluation of novel pyrimidine derivatives as acid pump antagonists. The gastric antisecretory activity assay results showed that all compounds displayed potent gastric antisecretory activity when gastric secretion was stimulated by histamine. The most potent compound 5g exhibited even similar gastric antisecretory activity compared with the control revaprazan, and the relative inhibition rate was 93.0%, which was worthy of further investigation.     

4—肉桂酰阿魏酸苯酚酯衍生物的合成及其抗炎活性

选择对环氧酶／５－脂氧酶和氧自由基具有抑制作用的苯乙烯酚作为先导物，设计合成了１２个４－肉桂酰阿魏酸苯酚酯目标物，其中８个化合物未见文献报道。经药理初筛结果表明，目标物（７ｇ）对角叉菜胶致大鼠足趾肿胀，二甲苯致小鼠耳廓肿胀和棉球致大鼠肉芽组织增殖有显著抑制作用。     

Synthesis of Novel Aminopropylguanidine Derivatives with Potential Antihypertensive Activity

Pharmaceutical Research -     

Synthesis and In Vitro Antioxidant Activity of New 3-Substituted-2-Oxindole Derivatives

A series of new 1,3-dihydro-3-hydroxy-3-(2-phenyl-2-oxoethyl)-2H-indol-2-ones (1a-g) and 1,3-dihydro-3-(2-phenyl-2-oxoethylidene)-2H-indol-2-ones (2a-g) were synthesised by Knoevenagel condensation of substituted indole-2,3-diones (isatins) with various acetophenones. The synthesised compounds were characterised by their physical data, elemental, IR, ¹H NMR, ¹³C NMR and mass spectral analyses and their in vitro antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay. These compounds showed moderate to good antioxidant activities as compared with the standard, ascorbic acid. The antioxidant potential of 3-hydroxy-3-substituted oxindoles (1a-g) increased in a concentration-dependent manner from 10 to 500 μg/ml with 5-fluoro and 5-methyl analogues showing maximum activity. Of 3-aroyl methylene indol-2-ones (2a-g), majority of compounds with halogen substitution at position 5 of isatin ring exhibited good antioxidant activity within a concentration range of 5-100 μg/ml and the maximum activity was observed at 20 and 25 μg/ml concentrations. Thus, our study provides evidence that some newly synthesised isatin derivatives exhibit substantial antioxidant activity at low concentrations.