Design,synthesis, anti-inflammatory activity and molecular docking of potential novel antipyrine and pyrazolone analogs as cyclooxygenase enzyme (COX) inhibitors

As a part of a directed program for development of new active agents, novel heterocyclic derivatives with antipyrine and pyrazolone moieties -incorporated in- have been designed and synthesized. Starting with 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivative 2a,b novel Mannich bases derivatives have been synthesized and biologically evaluated for their anti-inflammatory activity. Furthermore, the activity of such compounds has been tested interestingly as COX-1 and COX-2 inhibitors. Structure elucidation of the synthesized compounds was attained by the use of elemental analysis, IR, ¹H NMR, ¹³C NMR, and Mass spectrometry techniques. Compounds 3b, 3d and 4b represent the high % inhibition values for both COX-1 and COX-2. On the other hand, compound 8 showed little selectivity against COX-2 while compound 10 showed good selectivity against COX-1 only. Structure activity relationship has been discussed and the results were confirmed by molecular docking calculations.     

Discovery of novel selective GPR120 agonists with potent anti-diabetic activity by hybrid design

GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC₅₀?=?93?nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure–activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications.     

Quantitative changes of free-base,riboside, ribotide and glucoside cytokinins in developing rice grains

Rice grains at various growth stages were analysed for endogenous free-base, riboside, ribotide and glucoside cytokinins on the basis of GC/MS and GC/SIM using deuterium-labeled internal standards. Cytokinins identified were trans- and cis-zeatins, trans- and cis-ribosylzeatins, isopentenyladenosine, isopentenyladenosine monophosphate, trans- and cis-ribosylzeatin monophosphates, trans- and cis-zeatin-O-glucosides, trans- and cis-ribosylzeatin-O-glucosides and zeatin-9-glucoside (trans/cis geometry was not determined). The highest amounts of cytokinins were recorded at the early growth stage, namely either heading, anthesis or milk stage, suggesting that cytokinins may play important roles in the development of the grain. Cis isomers of zeatin derivatives were always present and more abundant than trans isomers. It seemed unlikely that cis isomers were released from t-RNAs during the extraction procedure.     

Use of cyclodextrins in capillary zone electrophoresis for the separation of optical isomers: Resolution of racemic tryptophan derivatives

In this study capillary zone electrophoresis has been used for the separation of racemic tryptophan derivatives in their enantiomers. The effect of cyclodextrins with different shape, added to the background electrolyte, on the migration time of 10 compounds, including methyl tryptophan, hydroxy tryptophan, and tryptophan ester derivatives, has been studied. Furthermore, the effect of cyclodextrins with different shape and that of the composition of the background electrolyte on the enantiomer resolution are discussed. Among different cyclodextrins used α-cyclodextrin and heptakis(2,6-di-O-methyl)-β-cyclodextrin were found to possess the best complexing capacity and thus the resolution power toward analysed compounds.     

Phosphate Derivatives of Thiamine and Na+ Channel in Conducting Membranes

The results show that thiamine derivatives are copurified with the specific proteins forming the Na+ channel in conducting membranes. Therefore, thiamine derivatives could well play a specific role in the molecular aspects of bioelectrogenesis , an interpretation that could help explain the neurological symptoms observed in human pathology as well as in animals experimentally rendered deficient in vitamin B1.     

Inactivation of beef heart mitochondrial F1-ATPase by the 2',3'-dialdehyde derivatives of adenine nucleotides

Beef heart mitochondrial F1-ATPase was inactivated by the 2',3'-dialdehyde derivatives of ATP, ADP and AMP (oATP, oADP, oAMP). In the absence of Mg2+, inactivation resulted from the binding of 1 mol nucleotide analog per active unit of F1. The most efficient analog was oADP, followed by oAMP and oATP. Complete inactivation was correlated with the binding of about 11 mol [14C]oADP/mol F1. After correction for non-specific labeling, the number of specifically bound [14C]oADP was 2-3 mol per mol F1. By SDS-polyacrylamide gel electrophoresis, [14C]oADP was found to bind covalently mainly to the alpha and beta subunits. In the presence of Mg2+, oATP behaved as a substrate and was slowly hydrolyzed.     

Enzymatic continuous production of N-acetyl-l-methionine from N-acetyl-dl-methioninamide with Erwinia carotovora containing a new amidase activity

A procedure for production of $\text{N-}\text{acetyl-}\text{l}\text{-methionine}$ ($\text{N-}\text{Ac-}\text{l}\text{-Met}$) from its racemic mixture by enzymatic continuous hydrolysis of the l-enantiomer of $\text{N-}\text{acetyl-}\text{dl}\text{-methioninamide}$ ($\text{N-Ac-}\text{dl}\text{-Met · NH}{}_2$) is described. For this hydrolysis, whole cells of Erwinia carotovora immobilized by κ-carrageenan gel were employed. The complete conversion of $\text{N-}\text{Ac-}\text{dl}\text{-Met · NH}{}_2$ to $\text{N-}\text{Ac-}\text{l}\text{-Met}$ was achieved by using a column packed with the immobilized cells. The half-life of the enzyme activity of the column was calculated to be ～100 days. Pure crystalline $\text{N-}\text{Ac-}\text{l}\text{-Met}$ was readily isolated from the effluent with >87.5% yield. $\text{N-}\text{Ac-}\text{d}\text{-Met · NH}{}_2$ was easily racemized by incubating in ethanol containing 0.1 m NaOH for 30 min at 80°C, and used again for substrate.     

Chaephilones A and B,Two New Azaphilone Derivatives Isolated from Chaetomium globosum

Two new azaphilone derivatives, chaephilones A ( 1 ) and B ( 2 ), were isolated from the fungus Chaetomium globosum, together with four structurally related analogs 3  –  6 . The structures of 1 and 2 were elucidated by comprehensive spectroscopic analyses including HR‐ESI‐MS and NMR. The known compounds were identified as chaetomugilin Q ( 3 ), chaetomugilin D ( 4 ), 11‐epichaetomugilin A ( 5 ), and chaetomugilin S ( 6 ) by comparing their NMR data and optical rotation values with those reported. Compound 2 represents the first example of azaphilone with an open furan ring. Compounds 1 and 2 were evaluated for cytotoxic activities against five human cancer cell lines (HL‐60, SMMC‐7721, A‐549, MCF‐7, and SW480) by the MTS method.     

天然抗脑缺血药物丁苯酞类衍生物的研究进展

丁苯酞 (NBP) 是我国研制的具有自主知识产权的抗脑缺血药物,具有抗血小板聚集、抗血栓、减轻脑水肿等多种生物活性。但其 总体疗效不高,且极难溶于水,限制了其在临床上广泛应用,故研究人员对其进行了多方面的结构修饰与改造。综述近年来对 NBP 的结构 改造及其衍生物的研究进展,旨在为该类药物进一步研发提供参考。     

Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase

The enzyme type 5 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17β-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with Δ⁴-androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17β-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17β-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia.