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The reaction of primary 1,3-dinitroalkanes with 2-ene-1,4-dione or 2-ene-4-oxo ester derivatives in acetonitrile with DBU as base, allow the one pot synthesis of 3,5-alkylated acetophenones and methyl benzoate derivatives respectively via an anionic domino process.
Some mono Mannich bases (1-phenyl-3-amino-1-propanone salts) and bis Mannich bases (1-phenyl-3-amino-2-amino-methyl-1-propanone salts) derived from acetophenone and a few representative quaternary derivatives were synthesised and their cytotoxicity was tested using the brine shrimp bioassay. This assay may serve as an intermediate test before further in vivo animal experiments in large scale, since brine shrimp nauplii as whole organisms were used in this test. Mono Mannich bases were generally more cytotoxic than their corresponding bis Mannich bases. Mannich bases synthesised were cytotoxic in both brine shrimp bioassay in this study and cell culture tests using Jurkat and Renca cells in a previous study. However, the order of the cytotoxic potency of the compounds were reverse, which may result from faster deamination of bis derivatives than optimal level, and different species and test media used in the two test systems. Faster deamination of bis derivatives might have led to elimination of active metabolites before reaching its target. The cytotoxicity of the compounds might have been altered by amino acids and proteins present in cell culture medium but not in sea water used in brine shrimp bioassay affecting their transport through the cell membrane and metabolism in the cell by binding with the compounds. With higher cytotoxic activity compared with 5-fluorouracil (CAS 51-21-8) in brine shrimp bioassay, mono Mannich base 1 and its quaternary derivative 4 and quaternary bis derivative 8 seem to be candidate compounds for further drug design.
The effect of the acetophenone derived mono Mannich bases 1-3 and bis Mannich base 7 (bis derivative of compound 3) on cellular glutathione level was investigated in Jurkat cells. The cells were exposed to the compounds in phosphate buffered saline for 1 h in 37 degrees C with gentle shaking and then glutathione level was measured. Especially, mono Mannich base 3 and its bis derivative 7 decreased total glutathione level in a dose-dependent manner. The results provide further support for the thiol alkylation mechanism explaining the cytotoxic activity of Mannich bases.
Ingestion of the Namibian shrub Salsola tuberculatiformis Botsch. by virgin female rats extends the dioestrus period of their oestrous cycles. Methanol extracts of the plant also inhibit adrenal steroidogenesis in the rat. With the aid of a bioassay, in which vaginal smears were used to follow the oestrous cycles of virgin rats, active fractions could be obtained which indicated that the plant contains a number of active compounds. The most active of these are highly unstable compounds which could not be isolated in pure form. However, two stable but less active compounds were identified as 4-hydroxyacetophenone and 4-hydroxy-3-methoxyacetophenone. This study investigated the influence of these acetophenones, their glucosides, and that of ethanol extracts of S. tuberculatiformis on adrenal steroidogenesis. Acetovanillon, a structurally related natural product also known as compound Z, was included in this study. Results show that the shrub contains active substances which interfere with adrenal 11 beta-hydroxylase, the terminal enzyme in glucocorticoid biosynthesis. This interaction with the cytochrome P-450(11)beta-dependent hydroxylase, as well as the inhibition of the conversion of deoxycorticosterone to corticosterone, was used to develop two sensitive and reliable assays for the rapid identification of small amounts of active compounds from S. tuberculatiformis.
We have tested the two-event model for UV mutagenesis producing class 2 suppressor mutations at glutamine tRNA genes in Escherichia coli. In the model used, the induction/indexing lesion is any type of pyrimidine dimer and the premutational photoproduct at the target site is a cytosine-containing dimer. Specific mutation-frequency responses were analyzed under conditions in which the ratio of thymine-thymine dimers to cytosine-containing dimers was modified by using 313-nm light and 0.0%, 0.1%, or 0.2% acetophenone. Changes observed in the production of class 2 suppressor mutations were consistent with the model and suggested that the G X C leads to A X T transitions responsible for class 2 suppressor mutations are targeted by cytosine-containing pyrimidine dimers at the mutational sites.
AIMS: Mycobacteria are a serious cause of infections in humans, with limited treatment options, as no new antibiotics have been developed against mycobacteria since the 1960s. In this study, the antimycobacterial activity of a small library of acetophenone (AP) compounds was analysed. METHODS AND RESULTS: Twenty-three AP derivatives were examined for activity against mycobacteria using a microbroth assay. The compounds were bacteriostatic, with the most effective (cyclohexylacetophenone and piperidinoacetophenone) having minimal inhibitory concentrations of 246 microM. Active compounds tended to be more hydrophobic, and may work by alkylation of as yet undetermined intracellular target protein(s). Cytotoxicity against eukaryotic cells was also determined and appears to be unrelated to the bacteriostatic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: AP may serve as a novel group of useful therapeutics against the mycobacteria.
A defined mixed culture, consisting of an Arthrobacter sp. and a Micrococcus sp. and able to grow with 4-chloroacetophenone as a sole source of carbon and energy, was isolated. 4-Chlorophenyl acetate, 4-chlorophenol, and 4-chlorocatechol were identified as metabolites through comparison of retention times and UV spectra with those of standard substances. The proposed pathway was further confirmed by investigation of enzymes. The roles of the two collaborating strains were studied by growth experiments and on the level of enzymes. If transient accumulation of 4-chlorophenol was avoided either by the use of phenol-absorbing substances or by careful supplement of 4-chloroacetophenone, the Arthrobacter sp. was able to grow as a pure culture with 4-chloroacetophenone as a sole source of carbon and energy. Several mono-, di-, and trichlorinated acetophenones were mineralized by the Arthrobacter sp.
The metabolism of acetophenone oxime was investigated in liver homogenates obtained from rats, rabbits, mice and hamsters. Significant species variations were observed in anaerobic metabolism studies both in qualitative and quantitative respects. In all cases, the oxime was initially reduced to the corresponding hydroxylamine. Whereas, the hydroxylamine was resistant to further transformation in rat, subsequent reduction to amine was observed in rabbit, mouse and hamster. Hydroxylamine reduction in rat was however observed in animals pretreated with phenobarbital, 3-methylcholanthrene or carbon tetrachloride. Enzymes catalyzing oxime and hydroxylamine reduction were present in both microsomal and cytosol fractions of liver. Highest reductase activity was observed in rat and mouse. Oxime reductase was not stimulated by either phenobarbital or 3-methylcholanthrene, but was inhibited by carbon tetrachloride.
Acetophenone derived mono-Mannich bases (Ig1-Ig4), 1-aryl-3-amino-1-propanone hydrochlorides, which are known to have cytotoxicity in Jurkat cells, were synthesized. Then, they were converted to corresponding azine derivatives (D1-D4), N, N'-bis(3-amino-1-aryl-propylidene)hydrazine dihydrochlorides, which are bifunctional agents. The aryl part was replaced by phenyl in Ig1, Ig2, Ig3, D1, D2, and D3, and by p-hydroxyphenyl in Ig4 and D4. The amine part was replaced by dimethylamine in Ig1, D1, Ig4 and D4, by piperidine in Ig2 and D2, and by morpholine in Ig3 and D3. The aim of this study was to investigate whether the modification in chemical structure, converting the mono-Mannich base to a corresponding azine derivative, improves the cytotoxicity. In addition, the effect of the representative compound, D3, N, N'-bis(3-morpholine-4-yl-1-phenylpropylidene)hydrazine dihydrochloride, on cellular glutathione level after 1 h exposure in phosphate buffer at 37 degrees C was also determined to provide information on a possible mechanism of cytotoxic action. Compounds D2-D4 are reported for the first time in this study. Except for Ig2 and D2, the cytotoxicity of mono-Mannich bases, Ig1, Ig3 and Ig4 and corresponding azine derivatives, D1, D3 and D4 were higher than the reference compound 5-FU. Azine derivatives D1 and D4 had almost equal cytotoxic potency with corresponding mono-Mannich bases Ig1 and Ig4, respectively. On the other hand, azine derivatives D2 and D3, had 1.28 and 1.90-times less cytotoxicity in Jurkat cells compared with the mono-Mannich bases, Ig2 and Ig3, respectively, from which they are derived. Azine derivative D3 dose-dependently decreased the total cellular glutathione level, suggesting that azine derivatives may exert cytotoxicity by thiol alkylation. Azine derivatives with equal or less cytotoxic potency compared to the mono-Mannich bases they are derived from seemed to be less suitable derivatives for the development of new cytotoxic compounds.
Two new acetophenone diglycosides, erythroxylosides A and B, were isolated from the aerial portion of Erythroxylum cambodianum together with (+)-catechin, (-)-epicatechin, quercetin 3-O-rutinoside, (3S,5R,6R,7E,9S-megastigman-7-ene-3,5,6,9-tetrol 3-O-beta-D-glucopyranoside and citroside A. The structural elucidations were based on analyses of chemical and spectroscopic data.
Oxidation of oximes via photosensitized electron transfer (PET) results in the formation of the corresponding ketones as the major product via oxime radical cations and iminoxyl radicals. The influence of electron-releasing and electron-accepting substituents on these reactions was studied. The observed substituent effect strongly supports formation of iminoxyl radicals from the oximes via an electron transfer-proton transfer sequence rather than direct hydrogen atom abstraction. Correlation of the relative conversion of the oximes with Hammett parameters shows that radical effects dominate for the meta-substituted acetophenone oximes (rho(rad)/rho(pol) = 5.4; r2 = 0.93), whereas the para-substituted oximes are influenced almost equally by radical and ionic effects (rho(rad)/rho(pol) = -1.1; r2 = 0.98). From these data sets we conclude that the follow-up reactions proceed through a number of intermediates with both radical and ionic character. This was confirmed by product studies with the use of an isotopically labeled nucleophile. In addition to the major oxidation product (ketone), a chlorine-containing product was often identified as well. Studies on the formation of this product show that the most likely pathway is either via a direct nucleophilic addition in a complex formed between the oxime radical cation and the chloranil radical anion or via a radical substitution (SH2) mechanism. These studies show that with the increasing use of oximes as drugs and pesticides, intake of these chemicals followed by enzymatic oxidation may result in the formation of a variety of reactive intermediates, which may lead to cell and tissue damage.
A fluorometric method for the determination of N-nitroso-N-methylurea (NMU) has been developed. It is based on the N-methylation reaction of nicotinamide with NMU and a subsequent condensation reaction with acetophenone, followed by an acid treatment to form a fluorescent 2,7-naphthyridine derivative. This method enabled the determination of NMU in the range 0.05 - 2 nmol/200 microl with a relative standard deviation of ca. 3%. It was applied to the determination of NMU formed from a precursor N-methylurea (MU) under simulated gastric conditions containing nitrite and thiocyanate ions at pH 3.0 in the presence of fresh orange juice and milk. NMU was extracted by an Extrelut 20 column and then determined. The mean recoveries of NMU added to the simulated gastric juice containing water, orange juice and milk were 86.5, 85.1 and 69.8%, respectively. The amounts of NMU formed from MU were found to decrease to below 25% in the presence of orange juice and milk.
A gas chromatographic method to determine the conversion of asymmetric hydrosilylation of acetophenone has been established. The gas chromatographic conditions were as follows: column, 10% PEG20M on white 102 support (DMCS), 1 m x 2 mm i.d. stainless-steel column; column temp., 160 degrees C; injector temp., 200 degrees C; thermal conductivity detector temp., 190 degrees C; carrier gas H2 with flow rate of 50 mL/min. The results show that the method is simple and rapid, and has good reproducibility. The coefficient of variation of the method was less than 1% (n = 6). The results were also confirmed with 1HNMR.
Four strains of microorganisms which have activity of chloroacetophenone reduction were screened, in which Saccharomyces cerevisiae B5 showed the highest activity and good stereoselectivity. This strains showed different activity on the reduction of various substrates in the following order: 2'-chloroacetophenone > 2-chloromethylacetophenone > 4'-chloroacetophenone > 3'-chloroacetophenone > acetophenone. Ethanol is the best cosubstrate and its optimal concentration is 5%.
3-[Bis-(2-hydroxyethyl)-amino]-acetophenone-[4.5-diphenyl-oxazolyl-(2)]-hydrazone (IMET 98/69) was found to afford maximum "rates of protection" in intraperitoneally (i.p.) or intranasally (i.n.) induced Mengo virus encephalitis in mice when administered once daily at doses of 1 mmole/kg (456.5 mg/kg) subcutaneously (s.c.) or 4 mmoles/kg (1 826 mg/kg) perorally (p.o.). Three days of treatment were sufficient if started on the day before or at the time of virus inoculation. Initiation of treatment 6 hours after inoculation was no longer effective. In a remarkable number of brains from infected and treated mice no virus was detectable, while in the remaining brains the appearance of virus was strongly delayed, and its amount significantly reduced.
3-Hydroxy-4-methoxy-acetophenone (HMA) isolated from Cynanchum paniculatum was found to have analgesic effect and inhibitory action on the gastro-intestinal motility. The effect and action were equivalent to that of paeonol, HMA displayed a very low degree of antibacterial activity against Escherichia coli and Shigella flexneri.
The present paper evaluated the effect of the potential beta-adrenoreceptor blocker 2-(3-isopropylamino-2-hydroxypropoxy)-5-(propoxymethyl) acetophenone (FoA33) on the oxidative and phosphorylating processes of the cardiac muscle influenced by small doses of isoprenaline (2 mg.kg-1). Under selected experimental conditions, the consumption of oxygen by the mitochondria of the cardiac muscle in states S3 and S4, rate of production of energy by mitochondria (OPR), coefficient of oxidative phosphorylyzation (ADP:O), respiratory control index (RCI) as well as the effect on the specific activity of the cytochromoxidase marker of mitochondria (COX) were examined. It follows from the obtained results that in contrast to large doses of isoprenaline (10-50 mg.kg-1) producing necrosis and affecting metabolic processes, small doses of isoprenaline (2 mg.kg-1) in many parameters activate the bioenergetic activity of the cardiac mitochondria, which is only minimally changed in combination with the beta-adrenoreceptor blocker (FoA33).
The proton NMR spectrum of the doubly enriched acetophenone-carbonyl,methyl-13C2 isotopomer dissolved in a liquid-crystalline solvent (LXNMR) was analyzed to yield a data set of 19 dipolar couplings. The presence of so many couplings, and in particular the dependence of some of them on the acetyl carbons enabled the investigation of the structure of the acetyl moiety and of possible cooperative motions about the aryl-carbonyl and carbonyl-methyl bonds. Methodological aspects, and approximations relating to the application of the vibrational correction procedure in the presence of large-amplitude torsional motions, are discussed. Results show that it is possible to discriminate between a continuous and a discrete conformer distribution about the angle phi(1) but not among a few proposed continuous shapes of U(iso)({phi}). In this study, the use of dipolar couplings with a non-negligible contribution from the indirect spin-spin coupling tensor J, (D(C8C9) in our case), for structural determination is extended from rigid to flexible molecules. The 1/2J(aniso)(C8C9) contribution was derived theoretically using the density functional theory linear response (DFT-LR) first-principles calculation of the J(C8C9) spin-spin coupling tensor.