Enrique Angeles

Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study

BackgroundThe development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest.MethodsTwelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period.ResultsAll patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6–170.49 μg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p < 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid.ConclusionMagnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.

A SIMPLE METHOD FOR THE SYNTHESIS OF CARBAMATES

Abstract A new method for carbamate synthesis using aryl and alkylamines with sodium hydride and diethylcarbonate in dry benzene is described.

Oxidative Cleavage of Aldo and Keto Oximes with Chromyl Chloride Adsorbed on Silica and Bentonite Earth

Abstract A number of Aldo, Keto and O-Acetyl oximes have been deblocked using chemisorbed Chromyl chloride on Bentonite and Silica Gel. A comparative study between the Chromyl chloride in solution and supported is also given.

Antiamoebic and toxicity studies of a carbamic acid derivative and its therapeutic effect in a hamster model of hepatic amoebiasis.

ABSTRACT Amoebiasis is an important public health problem in developing countries. Entamoeba histolytica, the causative agent of amoebiasis, may develop resistance to nitroimidazoles, a group of drugs considered to be the most effective against this parasitic disease. Therefore, research on new drugs for the treatment of this common infection still constitutes an important therapeutic demand. In the present study we determined the effects of a carbamate derivative, ethyl 4-chlorophenylcarbamate (C4), on trophozoites of E. histolytica strain HM-1:IMSS. C4 was subject to various toxicity tests, including the determination of mutagenicity for bacterial DNA and changes in the enzymatic activities of eukaryotic cells. Genotoxicity studies were performed by the mutagenicity Ames test (plate incorporation and preincubation methods) with Salmonella enterica serovar Typhimurium, with or without metabolic activation produced by the S9 fraction of rat liver. C4 toxicity studies were performed by measuring enzymatic activity in eukaryotic cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-formazan test with Fischer 344 rat hepatocytes. C4 did not induce either frame-shift mutations in S. enterica serovar Typhimurium TA97 or TA98 or base pair substitutions in strains TA100 and TA102. The compound was not toxic for cultured rat hepatic cells. Trophozoites treated with 100 μg of C4 per ml were inhibited 97.88% at 48 h of culture; moreover, damage to the amoebae was also confirmed by electron microscopy. The antiamoebic activity of C4 was evaluated by using an in vivo model of amoebic liver abscess in hamsters. Doses of 75 and 100 mg/100 g of body weight reduced the extent of the amoebic liver abscess by 84 and 94%, respectively. These results justify further studies to clearly validate whether C4 is a new suitable antiamoebic drug.

Ethyl and methylphenylcarbamates as antihelmintic agents: theoretical study for predicting their biological activity by PM3

Abstract PM3 calculations have been carried out on alkyl 4-(R)-phenylcarbamates and benzimidazole compounds in order to identify electronic features similitude using Principal Component Analysis, Canonic Analysis, stepwise Multiple Regression and Cluster Analysis. We have been able to establish a trend to predict antihelmintic activity for the best candidates of alkyl 4-(R)-phenylcarbamates.

Bromine/bentonite earth system, promoter of phenylmethanes from toluene

The condensation of toluene to produce o- and p-methylphenylmethanes by use of bromine with a bentonitic earth catalyst has been investigated and a mechanism is proposed based on the isolated intermediates and other related reactions.

A diterpenic acid from Stevia lucida

Abstract A new furan diterpenic acid was isolated from Stevia lucida . On the basis of IR, 1 H NMR and mass spectra, as well as chemical evidence, the acid was assigned the structure 5β,9β H ,10α,-labda-7,13(16),14-trien-15,16-epoxy-19-oic-acid.

Isolation and structure of stephalic acid, a new clerodane diterpene from Stevia polycephala

Abstract From the methanolic extract of Stevia polycephala a new clerodane-type diterpene, stephalic acid, was isolated. The structure and stereochemistry were determined by a combination of spectral data and single-crystal X-ray analysis.

Effect of new ethyl and methyl carbamates on Rhipicephalus microplus larvae and adult ticks resistant to conventional ixodicides.

The effects of six new synthetic carbamates on fully engorged females of four Rhipicephalus microplus strains (one reference strain susceptible to conventional ixodicides, two strains multiresistant to ixodicides and one tick field isolate) were compared. In addition, the effect of two other new synthetic carbamates was tested on larvae from the same strains. The first six tested carbamates reduced egg laying and inhibited egg hatching in the four studied strains (P<0.05). Compared with untreated females, the eggs produced by the treated engorged female ticks of all strains had a dark, dry, opaque appearance and were less adherent. The remaining two tested carbamates induced larval mortality in all of the evaluated strains. The three studied R. microplus strains displayed 50% resistance ratios (RR50) of less than 2 when compared to the susceptible reference strain. These results demonstrate that both carbamates with a larvicidal effect and carbamates that inhibit egg laying and embryo development are efficacious against tick strains that are resistant to commercial ixodicides, no cross resistance was observed.

Effect of new ethyl and methyl carbamates on biological parameters and reproduction of the cattle tick Rhipicephalus microplus.

The effect of carbamates on engorged female Rhipicephalus microplus ticks and larvae was evaluated using the adult immersion test (AIT) and the larval packet test (LPT), respectively. Seventeen synthetic carbamates different from current commercial acaricides were synthesised at the National Autonomous University of Mexico. None of the carbamates had an effect on the percentage of females laying eggs. Six of the compounds inhibited egg laying up to 65.4% and inhibited egg hatching by up to 100% (p<0.05). Compared to untreated females, eggs produced by treated females had a dark, dry, opaque appearance and were less adherent. Carbamates LQM 934 and LQM 938 had an effect on larval mortality (p<0.05). Carbamate LQM 934 showed lethal concentrations (LC) of LC90=0.76% and LC99=0.87%, while LQM 938 showed concentrations of LC90=0.267% and LC99=0.305%. The compounds were distributed into three classes of acaricidal activity using the AIT or the LPT. These three classes were as follows: (1) compounds having no apparent effect; (2) compounds that inhibit egg laying and embryo development or (3) compounds that exhibit acaricidal activity to larval ticks.