2-甲基-5-(E)-(邻甲氧基苯亚甲基)环戊酮Mannich碱类化合物的合成及其抗炎活性

目的 设计合成2-甲基-5-（E）-（邻甲氧基苯亚甲基）环戊酮曼尼希碱类化合物，并对其抗炎活性进行初步评价。方法 以N-环戊烯基吗啉、邻甲氧基苯甲醛及多种胺类为原料，经多步反应全成目标化合物，并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果 共合成8个新化合物，经IR，^1H-NMR和MS确证其结构。其中两个化合物的抗炎活性与阿司匹林相当。结论 羧基a位被烷基取代的环戊酮曼尼希碱仍具有较强的抗炎作用。     

2—（E）—（3—甲氧基—4—羟基苯亚甲基）—5—（N—取代胺甲基）环戊酮的合成及其抗炎活性研究

本文合成了15种2－（E）－（3－甲氧基－4－羟基苯亚甲基）环戊酮杂环胺Mannich碱盐酸盐和芒胺Mannich碱，并进行了初步的抗炎活性筛选，所有化 的结构均经波谱分析和元素分析证实，药理试验结果表明；部分化 的对二甲苯致小鼠耳肿胀有较显著的抑制作用；苯胺取代基的变化对芳胺Mannich碱的抗炎活性有显著的影响。     

2-（E）-（3-甲氧基-4-环戊氧基苯基亚甲基）环戊酮衍生物的合成及抗肿瘤活性

目的设计并合成一系列2-（E）-（3-甲氧基-4-环戊氧基苯基亚甲基）环戊酮衍生物，并对其体外抗肿瘤活性进行筛选。方法合成目标化合物并用人肝癌细胞（Bel-7402）和人口腔癌细胞（KB）对化合物的体外抗肿瘤活性进行筛选。结果合成了5个目标化合物，其中3个未见文献报道。化合物的结构经IR、^1H NMR、MS和元素分析确证。初筛结果显示化合物5具有较高的活性，对Bel-7402和KB细胞的IC50值分别为1．62gmol·L^-1和8．04gmol·L^-1,但低于对照药5-氟脲嘧啶。结论2-（E）-（3-甲氧基-4-环戊氧基苯基亚甲基）环戊酮Mannich碱衍生物具有一定抗肿瘤活性。     

(2S,3S,5S)-2,5-二氨基-3-羟基-1,6-二苯基己烷的合成

L-苯丙氨酸用氯苄进行MO-苄基化、氰化、格氏反应、还原制得（2S，3S，5S）-5-氨基-2-二苄胺基-1，6-二苯基-3-己醇，再经钯炭催化脱苄制得抗病毒药洛匹那韦中间体（2S，3S，5S）-2,5-二氨基-3-羟基-1，6-二苯基己烷，总收率约为63％。     

2-(E)-(4-甲基亚苄基)环戊酮曼尼希碱的合成及其抗炎活性研究

目的 合成2－（E）－（4－甲基亚苄基）环戊酮的曼尼希碱及其类似物并研究目标化合物的抗炎作用。方法 以N－环戊烯基吗啉、4－甲基苯甲醛及多种胺类为原料合成目标化合物，并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果 共合成13个新化合物，经IR，^1H-NMR和MS确证其结构；部分化合物对二甲苯致小鼠耳肿胀具有较强的抑制作用。结论 2－（E）－（4－甲基亚苄基）环戊酮曼尼希碱类化合物具有较强的抗炎活性。     

Inhibitory effects of (1E,3E,5E,7E)-5-hydroxy-4-(8-phenyl-1,3,5,7- octatetraenyl)-2(5H)-furanone on proliferation of human malignant tumor cells.

A butenolide compound (1E,3E,5E,7E)-5-hydroxy-4-(8-phenyl-1,3,5,7- octatetraenyl)-2(5H)-furanone (KNK-41), was shown to have strong anti-tumor activity. KNK-41 inhibited the proliferation of various kinds of human malignant tumor cells, such as HeLa (cervical carcinoma), HGC-27 (gastric cancer), PANC-1 (pancreatic cancer) and GOTO (neuroblastoma). Flow cytometric analysis indicated that KNK-41 caused an arrest in G0/G1 phase of the cell cycle. However, it scarcely affected DNA synthesis and the level of c-myc mRNA. These results suggest that the growth-inhibitory effect of KNK-41 is the result of G0/G1 arrest and not of the suppression of DNA synthesis and/or c-myc expression.     

Mass spectroscopic characterization of protein modification by 4-hydroxy-2-(E)-nonenal and 4-oxo-2-(E)-nonenal

The modification of proteins by 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) was investigated using mass spectroscopic approaches. Electrospray ionization MS analysis of HNE- and ONE-treated myoglobin and apomyoglobin revealed that the latter more "open" protein structure resulted in more extensive modification. Reductive methylation of Lys residues halved the extent of modification, implicating the importance of adduction of HNE and ONE to both His and Lys residues. HPLC-MS/MS analysis of tryptic and chymotryptic peptides of HNE- or ONE-adducted apomyoglobin was aided by the knowledge of structures previously elucidated through model reactions. In the case of HNE, the adducts detected were the HNE-His Michael adduct (on H24, H36, H64, and H113), its dehydrated form (on H36), and the HNE-Lys pyrrole adduct (on K16, K42, K45, K145, and K147). In the case of the more reactive ONE, the adducts detected were the ONE-His Michael adduct (on H24), the ONE-Lys pyrrolinone adduct (on K16 and K145), and the ONE-His-Lys pyrrole cross-link (linking K16 to H24 in the C(5) peptide). Although previous analyses of tryptic peptides yielded findings about the nature of His modification, the current chymotryptic peptide analysis produced the first structural characterization of Lys modification on intact proteins by HNE and ONE using mass spectrometry.     

2-(E)-(4-环戊氧基-3-甲氧基苯亚甲基)环戊酮芳胺 Mannich 碱类化合物的合成及抗肿瘤活性

目的设计合成一系列2-(E)-(4-环戊氧基-3-甲氧基苯亚甲基)环戊酮Mannich碱类化合物,并对其抗肿瘤活性进行体外试验.方法以环戊酮为原料,经Stock反应、Williamson反应、Mannich反应和芳胺交换反应合成目标化合物.结果合成12个未见文献报道的新化合物,化合物的结构经1H-NMR、IR和元素分析确证.用人肝癌细胞(Bel-7402)、人口腔癌细胞(KB)进行体外抗肿瘤活性试验.初步体外活性筛选结果显示,化合物Ⅰ9具有较高的活性,对Bel-7402和KB细胞的IC50值分别为0.98、2.19 μmol*L-1,但低于阳性对照药氟脲嘧啶.结论在苯亚甲基环戊酮2位侧链氨基连接的苯环的2、3、4位引入供电子基,或者在对位引入,可提高化合物活性,但在对位引入诱导效应的卤素原子,其活性下降.     

Synthesis and antimicrobial activity of 1-(4-hydroxyphenyl)-4-acyl-5-aryl-3-hydroxy-3-pyrrolin-2-ones

The reaction of methyl esters of acylpyruvic acids, 4-aminophenols, and aromatic aldehydes leads to the formation of 1-(4-hydroxyphenyl)-4-acyl-5-aryl-3-hydroxy-3-pyrrolin-2-ones. The proposed structures of the synthesized compounds were confirmed by IR and PMR spectroscopy. The antibacterial activity of some of the newly synthesized compounds was studied.     

Synthesis and biological activity of 4-acyl-5-aryl-3-hydroxy-1-(2-hydroxyethylaminoethyl)-3-pyrrolin-2-ones

A series of 4-acyl-5-aryl-3-hydroxy-1-(2-hydroxyethylaminoethyl)-3-pyrrolin-2-ones (I) and their hydrochlorides (II) were synthesized via reactions of methyl esters of acylpyruvic acids with a mixture of aromatic aldehyde and N-hydroxyethylethylenediamine. The antibacterial activity of compounds I and the influence of compounds I and II on blood coagulation were studied. All compounds demonstrate pronounced anticoagulant or hemostatic action. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 9, pp. 22–25, September, 2007.     

5'-Monophosphate-activated protein kinase (AMPK) improves autophagic activity in diabetes and diabetic complications

Diabetes mellitus (DM), an endocrine disorder, will be one of the leading causes of death world-wide in about two decades. Cellular injuries and disorders of energy metabolism are two key factors in the pathogenesis of diabetes, which also become the important causes for the process of diabetic complications. AMPK is a key enzyme in maintaining metabolic homeostasis and has been implicated in the activation of autophagy in distinct tissues. An increasing number of researchers have confirmed that autophagy is a potential factor to affect or induce diabetes and its complications nowadays, which could remove cytotoxic proteins and dysfunctional organelles. This review will summarize the regulation of autophagy and AMPK in diabetes and its complications, and explore how AMPK stimulates autophagy in different diabetic syndromes. A deeper understanding of the regulation and activity of AMPK in autophagy would enhance its development as a promising therapeutic target for diabetes treatment.Abbreviations: ACC, carboxylase; AdipoR, adiponectin receptors; ADP, adenosine diphosphate; AMP, adenosine monophosphate; AMPK, 5′-monophosphate-activated protein kinase; ATP, adenosine triphosphate; CaMKK, Ca²⁺ calmodulin-dependent protein kinase kinase; DEPTOR, DEP domain-containing mTOR-interacting protein; DM, Diabetes mellitus; DN, Diabetic nephropathy; ERK, extracellular signal-regulated kinase; FoxO, forkhead box class O; GFRs, glomerular filtration rates; IKK, IκB kinase; JLDG, Jinlida granule; JNK, janus kinase; LC3, light chain 3; LKB1, liver kinase B1; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin (mTOR) complex 1; PKC, protein kinase C; PRAS40, proline-rich Akt substrate 40 kDa; RAPTOR, regulator associated protein of mTOR; SOGA, suppressor of glucose form autophagy; SQSTM1, sequestosome 1; STZ, streptozotocin; TSC, tuberous sclerosis complex; ULK1, Unc-51-like kinase 1; VPS34, vacuolar protein-sorting 34KEY WORDS: Diabetes, Autophagy, AMP-activated protein kinases, Diabetic complications     

Antinociceptive activity of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone, on nociception-induced models in mice

Abstract: This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6‐bis‐(4‐hydroxy‐3‐methoxybenzylidene)cyclohexanone (BHMC), using chemical‐ and thermal‐induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose‐related inhibition in the acetic acid‐induced abdominal constriction test in mice with an ID₅₀ of 0.15 (0.13–0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin‐induced paw licking test with an ID₅₀ of 0.35 (0.27–0.46) mg/kg and 0.07 (0.06–0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot‐plate test. Moreover, the antinociceptive effect of the BHMC in the formalin‐induced paw licking test and the hot‐plate test was antagonized by pre‐treatment with the non‐selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID₅₀ of 0.66 (0.41–1.07) mg/kg and 0.42 (0.38–0.51) mg/kg, respectively. Finally, it was also shown that BHMC‐induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of various inflammatory mediators.     

Sensitivity of different resistant tumour cell lines to the two novel compounds (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene

The inhibition of cell proliferation by methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) has been studied in vitro against four cell lines selected for their resistance to doxorubicin, cisplatin, taxol and 5-fluorouracil. In previous experiments both compounds showed good in vitro antiproliferative, cytotoxic and pro-apoptotic activities against cell lines of different histologic origin. The results of the experiments presented here suggest that 1-Naph-NMCB is able to overcome all of the different mechanisms of resistance showed by the resistant cell lines used for our experiments. On the contrary, when we used the taxol-resistant A549-T12 cell line, characterized by a mechanism of resistance due to a mutation of the target site of taxol on microtubules, it displayed a partial but significant cross-resistance to 2-Naph-DNB. Although the actual mechanism of this cross-resistance has not yet been definitively elucidated, our results from immunostaining of microtubules suggest that it may be linked to the presence of a shared target site for taxol and 2-Naph-DNB on microtubules.     

Synthesis and biological activity of 5-aryl-4-acyl-3-hydroxy-1-[2-(diethylamino)ethyl]-3-pyrrolin-2-ones

Aseries of 4,5-disubstituted 3-hydroxy-1-(2-diethylaminoethyl)-3-pyrrolin-2-ones were synthesized via reactions of methyl esters of acylpyruvic acid with a mixture of an aromatic aldehyde and 2-(diethylamino) ethylamine. The synthesized compounds were characterized with respect to antiinflammatory, antidepressant, and antibacterial properties and acute toxicity. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 5, pp. 14–16, May, 2006.     

Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A(2A) receptor agonist and adenosine A(3) receptor antagonist activity

The pharmacological properties of the novel ligand, (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol (I), at the human adenosine receptors were investigated using Chinese hamster ovary cell lines recombinantly expressing these receptors. Functional studies were performed using a cyclic AMP-coupled reporter gene system. Binding studies were performed using membranes from these cells. The effects of ligand (I) were also determined on functional responses of human neutrophils and eosinophils. Ligand (I) had a high affinity for the adenosine A(2A) receptor (pKi 7.8+/-0.2) and was a potent agonist at this receptor (pEC(50) 9.0+/-0.2). Ligand (I) had a similar affinity for the adenosine A(3) receptor (pKi 7.8+/-0.1) but displayed no agonist activity, acting instead as a competitive antagonist (pA(2) 8.3+/-0.04). Ligand (I) had lower affinity for adenosine A(1) and A(2B) receptors (pKi相似文献   

Synthesis and antibacterial activity of 1-(5-aryl-4-benzoyl-3-hydroxy-2-oxo-3-pyrrolin-1-yl)-2-(3-benzoylmethylene-2-oxopiperazin-1-yl)ethanes

A series of l-(5-aryl-4-benzoyl-3-hydroxy-2-oxo-3-pyrrolin-l-yl)-2-(3-benzoylmethylene-2-oxopiperazin-1-yl)ethanes have been obtained with 35–37% yields via reactions of benzoylpyruvic acid methyl ester with a mixture of aromatic aldehyde and diethylenetriamine in a 2: 1: 1 molar ratio. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 8, pp. 5–6, August, 2006.