A novel synthetic compound PHID (8-Phenyl-6a, 7, 8, 9, 9a, 10-hexahydro-6H-isoindolo [5, 6-g] quinoxaline-7, 9-dione) protects SH-SY5Y cells against MPP(+)-induced cytotoxicity through inhibition of reactive oxygen species generation and JNK signaling

1-Methyl-4-phenylpyridinium ion (MPP⁺), a neurotoxin selective to dopaminergic neurons and an inhibitor of mitochondrial complex I, has been widely used as an etiologic model of Parkinson's disease. In this study, we investigated the protective effects of a novel synthetic compound, 8-Phenyl-6a,7,8,9,9a,10-hexahydro-6H-isoindolo[5,6-g]quinoxaline-7,9-dione (PHID), on MPP⁺-induced cytotoxicity in SH-SY5Y cells. MPP⁺ induced apoptosis characterized by generation of reactive oxygen species, caspase-3 activation, poly ADP ribose polymerase proteolysis and increase in Bax/Bcl-2 ratio were blocked by PHID in a dose-dependent fashion. Furthermore, MPP⁺-mediated activation of stress-activated protein kinase/c-Jun N-terminal kinase (JNK) was also inhibited by PHID in a dose-dependent manner. The results indicate that PHID protects against MPP⁺-induced apoptosis by blocking reactive oxygen species stimulation and JNK signaling pathways in SH-SY5Y cells, implicating the novel compound in the prevention of progressive neurodegenerative diseases such as Parkinson's disease.     

Effect of peptidase inhibitors on [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8-induced antinociception

The effect of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- -azabicyclo(3.3.0)octane-3-carboxylic acid (Hoe 498 diacid) and the aminopeptidase inhibitor bestatin on antinociception induced in rats by intraventricular injections of [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8 was investigated. Potentiation and prolongation of the antinociception was observed after pretreatment with bestatin. Further potentiation of the antinociception elicited by the heptapeptide was obtained in rats pretreated with a combination of bestatin and Hoe 498 diacid. In contrast, antinociception elicited by the octapeptide was not potentiated further by pretreatment with the bestatin and Hoe 498 diacid combination.     

Antioxidant and anticancer activity of 3'-formyl-4', 6'-dihydroxy-2'-methoxy-5'-methylchalcone and (2S)-8-formyl-5-hydroxy-7-methoxy-6-methylflavanone

Two new flavonoids - 3'-formyl-4',6'-dihydroxy-2'-methoxy-5'-methylchalcone (FMC) and (2S)-8-formyl-5-hydroxy-7-methoxy-6-methylflavanone (FMF) - isolated from the buds of Cleistocalyx operculatus, were investigated for their antioxidant and anticancer activity. Total antioxidant activity and reducing ability were measured. 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and superoxide anion radical scavenging assays were carried out to evaluate the antioxidant potential of the two compounds. The antioxidant activity of the two compounds increased in a concentration-dependent manner. FMC and FMF at a concentration of 500 microM inhibited lipid peroxidation by 64.3 +/- 2.5% and 60.3 +/- 2.3%, respectively, an antioxidant activity approximately similar to that of 500 microM alpha-tocopherol (66.3 +/- 2.5%). Similarly, the effect of FMC and FMF on reducing power increased in a concentration-dependent manner. In DPPH radical scavenging assays, the IC50 values of FMC and FMF were 50.2 +/- 2.8 microM and 75.8 +/- 2.5 microM, respectively. Moreover, FMC and FMF scavenged the superoxide generated by the phenazine methosulfate (PMS)/reduced beta-nicotinamide adenine dinucleotide (NADH) nitroblue tetrazolium (NBT) system, with IC50 values of 56.3 +/- 2.3 microM and 317.5 +/- 2.9 microM, respectively. The anticancer activity of the two compounds were determined in five human cancer cell lines, SMMC-7721 (liver cancer), 8898 (pancreatic cancer), K562 (chronic leukaemia), HeLa (tumour of cervix uteri) and 95-D (high metastic lung carcinoma). FMC and FMF showed broad-spectrum anticancer activity against all the human cancer cell lines tested. The results obtained in the current study indicate that the two flavonoids could be a potential source of natural antioxidant and anticancer agents. To our knowledge, this is the first report on bioactivity of FMC and FMF.     

General pharmacological action of tritoqualine (TRQ; (+/-)-(R*)-7-amino-4, 5, 6-triethoxy-3-[(R*)-5, 6, 7, 8-tetrahydro-4-methoxy-6-methyl-1, 3-dioxolo [4, 5-g] isoquinolin-5-yl] phthalide

The general pharmacological action of TRQ was investigated, and the following results were obtained: With regard to its influence on the central nervous system, TRQ moderately potentiated the actions of hexobarbital (sleeping time) and methamphetamine (stereotyped behavior) at doses above 100 mg/kg, p.o. TRQ, however, had little influence on behavioral changes, EEG and motor function. TRQ only had slight influence on the respiratory and cardiovascular system at doses ranging from 0.1 to 3 mg/kg, i.v. Significant decrease in SBP and increases of HR, FAF and respiratory rate were observed after high doses (10-30 mg/kg, i.v.) of TRQ. TRQ also had little influence on contractility and pacemaker in isolated hearts, but moderately increased the coronary flow. The inhibitory effect of TRQ on the isolated smooth muscle was observed at high concentration and was non-specific. Furthermore, TRQ exhibited little influence on the autonomic nervous system. Among the effects of TRQ on the gastrointestinal system, it was shown that TRQ moderately increased the outflow of bile after doses above 1 mg/kg, i.v. TRQ also showed no remarkable actions on other aspects of the gastrointestinal system and blood coagulation system. Considering the present results, it may be suggested that there should be no serious problems in the application of TRQ as a hepatoprotective agent.     

Synthesis and biochemical properties of 8-amino-6-fluoro-9-beta-D-ribofuranosyl-9H-purine

The synthesis and characterization of 8-amino-6-fluoro-9-beta-D-ribofuranosyl-9H-purine (3a) are presented. This compound is a substrate for adenosine deaminase and adenosine kinase. In L1210 cells 3a is converted to 8-aminoinosine monophosphate (4b), apparently by the action of AMP deaminase on the monophosphate of 3a, as well as to the triphosphate derivative of 3a. Pentostatin was used to inhibit adenosine deaminase, and coformycin was used to inhibit AMP deaminase in experiments designed to delineate the metabolic fate of 3a. Pentostatin was without influence on the cytotoxicity of 3a, but coformycin potentiated the cytotoxicity. The potentiation was associated with an increased cellular concentration of phosphates of 3a and a decreased concentration of 4b.     

Reaktionen mit 4-Hydroxy-5-oximino-7-methyl-5H-pyrano[2,3-b]pyridin-8-oxid

Reactions with 4-Hydroxy-5-oximino-7-methyl-5H-pyrano[2,3-b]pyridine 8-Oxide The pyrano[2,3-b]pyridine 1a with a vinylogous hydroxamic acid structure reacts with dimethyl sulphate, acetic anhydride or nitric acid to give the monomethyl ether 2 , the diacetyl compound 3 or the mono- and dinitro derivatives 5 and 6 . Reduction reactions leading to 4-hydroxy-5-oximinopyrano[2,3-b]pyridine 4 or the 4-hydroxy-2-pyridone derivative 8 are also described.     

Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of 4-amino-2, 3-diaryl-5, 6, 7, 8-tetrahydrofuro(and thieno)[2, 3-b]-quinolines,and 4-amino-5, 6, 7, 8, 9-pentahydro-2, 3-diphenylcyclohepta[e]furo(and thieno)-[2, 3-b]pyridines

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition activities of a series of 4-amino-2, 3-diaryl-5, 6, 7, 8-tetrahydrofuro[2, 3-b]quinolines (10-12)/4-amino-5, 6, 7, 8-tetrahydro-2, 3-diphenylthieno[2, 3-b]quinoline (14) and 4-amino-5, 6, 7, 8, 9-pentahydro-2, 3-diphenylcyclohepta[e]furo[2, 3-b]pyridine (13)/4-amino-5, 6, 7, 8, 9-pentahydro-2, 3-phenylcyclohepta[e]thieno[2, 3-b]pyridine (15) are described. These compounds are tacrine (THA) analogues which have been prepared either from readily available 2-amino-3-cyano-4, 5-diarylfurans (16-18) or from 2-amino-3-cyano-4, 5-diphenylthiophene (19), via Friedl?nder condensation with cyclohexanone or cycloheptanone. These compounds are competitive inhibitors for acetylcholinesterase, the more potent being compound (13) which is three-fold less active than tacrine. The butyrylcholinesterase inhibition activity is significant only in compounds 10 and133, which are ten-fold less active than tacrine. It is found that the products 11 and 12 strongly inhibit acetylcholinesterase, and show excellent selectivity regarding butyrylcholinesterase.     

Analgesic narcotic antagonists. 6. 7 beta, 8 beta-Methano- and 7 beta, 8 beta-epoxydihydrocodeinone

Reaction of codeinone (2) with CH2N2 in the presence of Pd(OAc)2 yielded mixtures of starting material and (2) and 7 beta, 8 beta-methanodihydrocodeinone (3). Initial resolution of this mixture was achieved via carbonyl reduction followed by chromatography to give pure 7 beta, 8 beta-methanodihydrocodeine (4), which was oxidized to 3. Reaction of the mixture containing 2 and 3 with mercaptoethanol and NaOH [2 leads to 8 beta-[(hydroxyethyl)thio]dihydrocodeinone (5)] allowed selective crystallization of 3. The beta configuration of the cyclopropane ring in 3 was established by cleavage with aqueous HCl to give the 8 beta-(chloromethyl) compound 6, followed by carbonyl reduction and dehalogenation to 8 beta-methyldihydrocodeine (8). Reaction of the N-(cycloalkylmethyl) derivatives (13 and 18) of 2 with CH2N2/Pd(OA)2 gave potential mixed agonist-antagonists and 14 and 19, which were purified by reduction-oxidation (14) or mercaptoethanol-base treatment (19). Compound 2, on oxidation with alkaline peroxide, gave the previously reported 7 beta, 8 beta-epoxydihydrocodeinone (22) as the hemimethanol ketal (21). Compound 3 was about ninefold more potent an agonist than dihydrocodeine, and the N-(cyclopropylmethyl)-7 beta, 8 beta-methano compound 19 had moderately potent mixed agonist-narcotic antagonist properties.     

7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用

目的寻找新的广谱、高效、低毒喹诺酮类抗菌药物。方法设计合成7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物,测定其体内外活性。结果共合成了20个新化合物,经¹HNMR,MS和HRMS确证其结构。其中5个目标化合物(22～26)有广谱活性,尤其对革兰氏阳性菌具有很强的活性。其中化合物24对所试的13株革兰氏阳性菌的MIC值均0.03 mg·L^-1,其活性优于对照药克林沙星和加替沙星,对所试的6株革兰氏阴性菌,其活性相当于或低于对照药。结论化合物(22～26)值得进一步评价。