Farmaco (Societa chimica italiana : 1989)最新文献

A new synthetic route to obtain the carboxylate analog of mannose 6-phosphate (M6-P) is presented. The effects of the M6-P, the carboxylate and two other analogs (the phosphonate and the α,β ethylenic carboxylate) on the proliferation of human keratinocytes and dermal fibroblasts as well as on the proliferation of a murine fibroblast cell line, 3T3-J2 are tested. We observed that M6-P is a potent inhibitor of proliferation of both fibroblasts and keratinocytes. Among its analogs, the phosphonate showed a similar effect on human dermal fibroblasts but not on keratinocytes.

Metronidazole (MTZ), a drug used for the treatment of protozoal infections caused by protozoa and anaerobic microorganisms, was conjugated to linear or branched poly(ethylene glycol) of 5,000, 10,000 and 20,000 Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. The modification allowed overcoming the known MTZ solubility problem leading us to obtain a bioconjugate more suitable for parental administration. The conjugates of various molecular weight polymers have been tested in vitro toward chemical degradation and digestive enzymes. It was found that molecular weight and shape of PEG is critical for the prodrugs stability. Good resistance in the stomach acidic media was found and a slow release of the drug in the large intestinal fluid may take place. In vivo studies carried out following i.v. or s.c. administration to mice revealed improved pharmacokinetics properties upon conjugation.

Endothelins (ETs) are the most ubiquitous, highly potent and unusually long-lasting peptidic constrictors of human vessels known. Elevated levels of the plasma concentration of ETs were observed in several diseases such as hypertension, acute myocardial infarction, congestive heart failure, renal failure, pulmonary hypertension, and atherosclerosis. ETs exert their activities via specific seven-transmembrane, G protein-coupled receptors. To date two receptor subtypes, endothelin A (ET_A) and endothelin B (ET_B), have been identified and cloned. A literature survey revealed that a number of compounds that bind ET receptors with affinity and selectivity are known, nevertheless these compounds belong only to few chemical classes. The aim of this work is the identification of an “hit compound” with novel chemical structure endowed with reasonable ET affinity and selectivity. Accordingly, new variously substituted 2-carboxamido-3-carboxythiophene derivatives (29–52) were synthesized. These compounds were tested for their ability to inhibit ETs binding in radioligand binding assay using CHO cells stably expressing human ET_A and ET_B receptors.

A rapid, simple and sensitive high-performance liquid chromatography (HPLC) method has been developed for quantification of amlodipine in plasma. The assay enables the measurement of amlodipine for therapeutic drug monitoring with a minimum detectable limit of 0.2 ng ml⁻¹. The method involves simple, one-step extraction procedure and analytical recovery was about 97%. The separation was performed on an analytical 125 × 4.6 mm i.d. Nucleosil C₈ column. The wavelength was set at 239 nm. The mobile phase was a mixture of 0.01 M sodium dihydrogen phosphate buffer and acetonitrile (63:37, v/v) adjusted to pH 3.5 at a flow rate of 1.5 ml min^–1. The calibration curve was linear over the concentration range 0.5–16 ng ml⁻¹. The coefficients of variation for inter-day and intra-day assay were found to be less than 10%.

A series of N-1,3 disubstituted 2,1,3-benzothiadiazine derivatives (BTDs) were synthesized and evaluated for their inhibitory activity versus enzymatic isoform PDE4 extracted from U937 cell line. Some of the tested compounds showed a high PDE4 inhibitory activity at 100 μM and the IC₅₀ value of the most interesting terms were evaluated. The structure–activity relationships of these compounds showed that the 3,5-di-tert-butyl-4-hydroxybenzyl moiety at N-1 position is important to obtain activity at micromolar level as previously reported. For the same compounds the antioxidant activity were evaluated highlighting 14 as the most significative one. The introduction of other bulky substituents in N-1 position is detrimental.

This article reviews past and ongoing research in the author's laboratory directed toward the synthesis of natural products displaying an azaspirocyclic framework, or incorporating a medium-ring nitrogen heterocycle. New synthetic technologies were devised in order to address the synthetic problems posed by the target molecules. Thus, efforts in the area of azaspirocyclic substances have relied on an oxidative amidation of phenols promoted by iodobenzene diacetate, whereas access to medium-ring nitrogen heterocycles has been secured by means of a ring expansion sequence that relies on the fragmentation of an aziridine triggered by a homo-Brook transposition. Details of the development of these technologies are presented, together with applications to the total synthesis of FR-901483, TAN-1251C, cylindricines, and mitomycinoids.

The fourth-order derivative spectrum from the alcoholic sample is used. HCT can be determined by a specific peak–trough, of low intensity, at 330–340 nm. For IST evaluation, a peak–trough around 250–310 nm is available, common to both products, whose amplitude increases linearly only for low concentration values, while it decreases at higher values. The most difficult aspect of the analysis lies in how to find the optimal concentration range, so that both signals can be evaluated simultaneously. The best results were achieved by using a linear regression for HCT and a regression plane for IST.

In this work, electrochemical oxidation of albendazole (ABZ) was carried out using a glassy carbon-rotating disk electrode. Development of electroanalytical methodology for ABZ quantification in pharmaceutical formulations was also proposed by using linear sweep voltammetric technique. Electrochemical oxidation is observed for ABZ at E_1/2 = 0.99 V vs. Ag/AgCl_sat, when an anodic wave is observed. Kinetic parameters obtained for ABZ oxidation exhibited a standard heterogeneous rate constant for the electrodic process equal to (1.51 ± 0.07) × 10^–5 cm s^–1, with a αn_a value equal to 0.76. Limiting current dependence against ABZ concentration exhibited linearity on 5.0 × 10^–5 to 1.0 × 10^–2 mol l^–1 range, being obtained a detection limit of 2.4 × 10^–5 mol l^–1. Proposed methodology was applied to ABZ quantification in pharmaceutical formulations.