Synthesis of certain new 2,4,5(6) trisubstituted-1,2,4-triazolo[1,5-alpha]pyrimidines as potential antihypertensive agents.

A series of 1,2,4-triazolol[1,5-alpha]pyrimidines bearing at position 2, morpholine, piperidine or piperazine moities has been prepared. In addition, ethyl 4-methyl-2-(4-acylpiperazin-1-yl)-1,2,4-triazolo[1, 5-alpha]pyrimidin-7(4H)-one-6-carboxylates 25,26, which have related structure with prazosin, have been synthesized. Ten representative compounds were tested in vitro and in vivo for their antihypertensive activity where compounds 7, 11 and 25 showed promising activity. The detailed synthesis, spectroscopic and biological data are reported.

A formal total synthesis of (-)-cephalotaxine.

A formal total synthesis of (-)-cephalotaxine (1) has been achieved. The key step is an intramolecular aldol condensation of the diketone 9, which in turn was obtained in three steps from the azabicyclic compound 6 derived from D-proline according to Seebach's procedure. Treatment of 9 with a catalytic amount of sodium 2-methyl-2-butanolate in benzene at room temperature gave the alpha, beta-unsaturated ketone 8 in 43% yield. Catalytic hydrogenation of 8 followed by reduction of the ketone 22 with sodium borohydride and acetylation of the resulting alcohol 23 gave the acetoxy derivative 24, which, after deprotection, was acylated with (methylthio)acetic acid to give the amide 26. Compound 26 was converted into optically active ketolactam 4 following the synthetic operations developed for the synthesis of the racemic compound.

Reduced expression of mismatch repair genes in colorectal cancer patients in Egypt.

An Egyptian hospital-based pilot case-control study was conducted to investigate the relationship between the expression level of mismatch repair (MMR) genes and the risk of colorectal cancer. The relative expression of five known MMR genes, i.e., hMSH2, hMLH1, hPMS1, hPMS2, and GTBP/hMSH6, was measured by a multiplex reverse transcriptase (RT)-polymerase chain reaction (PCR) in peripheral blood lymphocytes from 31 colorectal cancer patients and 47 age- and-sex matched controls. The expression of hMSH2, GTBP/hMSH6, hPMS1 and hPMS2 tended to be lower in patients than controls, but only the difference in hPMS2 expression was statistically significant (p<0. 01). Although 50% of the cases had chemotherapy or radiotherapy within the last six months before the blood was drawn, their gene expression was not statistically different from those who had not undergone such therapies. After adjustment for age and sex, the odds ratios (OR) calculated from a logistical regression model, using the median levels of gene expression of controls as cut-off values, indicated that increased risk was associated with reduced expressions of both hPMS1 (OR = 3.97, 95% confidence interval (CI) = 1.04 to 7.65) and hPMS2 (OR = 2.86, 95% CI = 1.05 to 7.76). Although the results of this study were inconclusive because of the small sample size and use of prevalent cases, it is biologically plausible that patients with colorectal cancers may have a lower expression of MMR genes than healthy controls because malfunction of these genes has been shown in hereditary nonpolyposis colon cancer. The involvement of low hPMS2 expression in colon cancer risk seems to be unique in the Egyptian population. Further studies with newly diagnosed patients before they begin therapy will provide more convincing data about the role of MMR gene expression in the etiology of colorectal cancers in Egypt.

Cardiovascular effects of some 2-substituted triazolo[1,5-a]pyrimidin-7(4H)one-6-carboxylic acid ethyl esters.

The cardiovascular effects of a series of 2-substituted- 1,2,4-triazolo[1,5-a]-pyrimidine derivatives (compounds 1-6) were examined in anaesthetized rats. Of these compounds only compounds 3 and 4 in dose of (15-60 mumole/Kg) induced dose-dependent decreases in the arterial blood pressure and heart rate. The induced cardiovascular changes were not antagonised by histaminergic, cholinergic, serotoninergic receptor blockers, prostaglandin synthesis inhibitors or Cacl2. Treatment of the animals with the compounds (20-30 mumole/Kg) competitively antagonised noradrenaline-induced increase in the arterial blood pressure and significantly antagonised isoprenaline-induced tachycardia but not the induced hypotension. The compounds seemed to possess both alpha 1- and, beta 1-adrenoceptor blocking activities.

Spectrophotometric quantification of astemizole and its demethylated metabolite in urine after TLC separation.

The coupling of TLC and UV measurement for determination of astemizole and its main metabolite, O-demethylated derivative, in urine has been investigated. The metabolite like the drug absorbs maximally at almost the same wavelengths, which makes their simultaneous UV determination in biological fluids quite inapplicable. TLC separation on silica gel F254 utilizing chloroform/methanol (85:15, v/v) achieved the best fractionation of the two compounds from the matrix-components of urine. Concentration levels of 0.5-140 micrograms/ml (ppm) in worked-up sample could be reached by adopting the spectrophotometric measurements at 286 nm for ethanolic extracts of the silica layers carrying each individual compound against a blank silica. Varying levels of the intact drug and its phenolic primary metabolite could be accurately traced in urine samples following a 10 mg single oral dose (approximately 12.5 micrograms/kg) after different time intervals up to 12 h. Synthetic preparation of the metabolite by demethylating astemizole is mentioned and its physicochemical characterization is briefly discussed.

Differential pulse polarographic assay of tolmetin sodium capsules.

Differential pulse polarography (DPP) is proposed as a direct method for the quantitation of tolmetin sodium in a capsule formulation (Tolectin--200 mg as the sodium dihydrate salt). Classical direct-current (DC) polarography has been employed to investigate the nature of the reduction occurring at the surface of the dropping mercury electrode (DME) using acetate buffer of pH 5.0 as the supporting electrolyte. The mean value of the results obtained by DPP expressed as a percentage of the stated amount, and the standard deviation, were found to be 99.87 +/- 0.43. The standard addition procedure used to assess the accuracy of the proposed method gave a mean percentage recovery of the total drug of 100.15 +/- 0.75%.

Spectrophotometric determination of tolmetin sodium in capsule dosage form.

Two different U.V. spectrophotometric modes, zero-order and first derivative, have been applied for the quantitation of tolmetin sodium (Tolectin 200 mg) in bulk form and in its pharmaceutical formulation. Direct U.V.-measurement of aqueous solution of the drug at 325 nm exhibits significant linearity at the concentration range 0.1-1.5 mg% with a coefficient of variation (C.V.) 0.34%. The first derivative (d'A) spectrophotometric measurements at 342 nm yield results with a C.V. 0.29%. Drug assay of the capsule gives percent contents of 100.42 +/- 0.34 and 100.28 +/- 029 by adopting zero-order and d'A spectrophotometry respectively. The reproducibility and accuracy the two proposed methods have been assessed by employing standard additions technique. Accordingly the percent recoveries obtained were 99.60 +/- 0.22 and 100.16 +/- 026 for the zero order and the d'A-spectrophotometry respectively.