Biomedical subjects
Publications and source records attributed to P Da Re.
A number of flavone and xanthone derivatives bearing some characteristic features of fluoroquinolones such as the fluorine atom and an ortho piperazine ring are described. The new compounds have been tested for possible cytotoxic and antimicrobial activities. Cytotoxicity of both groups of compounds is rather poor, while the antibacterial activity is restricted to xanthones.
A number of xanthone derivatives bearing the basic chain of naftifine and butenafine antimycotics in 1, 2, 3, and 4 nuclear positions are described. The in vitro antifungal activity against representative strains of molds and yeasts is reported. Only butenafine xanthone analogues show significant activity against Cryptococcus neoformans, in particular the regioisomer 4d (1.5 micrograms/ml).
Some flavone-2'-carboxylic acid analogues are described. Direct in vitro toxicity of the synthesized compounds was evaluated towards four tumoral cell lines, and the ability of these compounds to stimulate mouse peritoneal macrophages in culture to become tumoricidal (indirect toxicity) was also studied. Direct cytotoxic activity was very low for all derivatives. However, almost all compounds showed a remarkable increase of indirect cytotoxicity. In particular, compound 3i, which has an F atom in the 7 position of the flavone ring, was able to increase significantly the macrophage's lytic properties, and has been selected for further investigations.
A topological modification of ipriflavone 1, a recent antiosteoporotic drug, is described. The flavone moiety of 1 has been replaced by a xanthone one. Among the new derivatives, the 3,6-diisopropoxyxanthone (2a) has shown significant bone resorption inhibition in in vitro and in vivo tests.
Some geiparvarin bioisosteres and homologues are described. The compounds were tested on LoVo cells (human colon carcinoma cell line). The EC50 values of the synthesized compounds ranged from 35.04 microM (compound 3) to 11.88 microM (compound 4), while the EC50 value of geiparvarin 1 was 13.30 microM.
With the aim to split the pharmacological properties of lefetamine (CAS 14148-99-3), some structural modifications of this compound have been studied. The basic group of lefetamine has been shifted from the alkyl chain to the vicinal phenyl ring and the N-substitution has been changed. The dimethylaminomethyl derivatives and chiefly the o-morpholinometyhl exhibited a strong anti-visceral chemical antinociception activity stripped of thermal antinociception properties and physical dependence liability. Furthermore, through the introduction of a diethylaminomethyl group in the lefetamine structure some derivatives were selected exhibiting besided a significant increase in the anti-visceral chemical antinociception activity, remarkable local anesthetic properties.
Some simple geiparvarin analogues, in which the coumarin moiety has been replaced with an X-substituted benzene ring, are described. The compounds were tested on LoVo cells (human colon carcinoma cell line) and some of them show a cytotoxicity comparable with that of the prototype. A QSAR analysis was also attempted, but it did not provide satisfactory results, mainly because of the limited range of variation of the biological activity.
Geiparvarin is an antiproliferative compound whose mechanism of action has not yet been identified. We have investigated the biochemical action on purified microtubular protein, as well as on tubulin, of geiparvarin and of some derivatives resulting from its conjugation with two synthetic oestrogens, diethylstilboestrol and meso-hexoestrol, in comparison with the antimicrotubular action of the reference oestrogens. Geiparvarin and derivatives did not inhibit colchicine binding to tubulin nor did they significantly influence GTP-induced polymerization. On the contrary, they effectively counteracted the stimulating effect of taxol on microtubule formation, both in the presence and in the absence of microtubule-associated proteins. A competitive inhibition mechanism at the taxol binding site of tubulin may thus be proposed to explain the antimicrotubular action of geiparvarin.
Some coumarin-, flavonol- and flavanon-acetic acids are described. The cytotoxicity of the synthesized compounds was determined on a human colon carcinoma cell line (LoVo) through evaluation of neutral red uptake, performed by the Riddel method. All tested derivatives were able to induce a statistically significant reduction of lysosomal neutral red uptake at 5 x 10(-5) M concentration. Some compounds were more active than the reference compound flavon-8-acetic acid.
Chromone, flavone and xanthone analogues of geiparvarin (1) are described. Compounds 2a and 2b are more active in inhibiting the proliferation of F10 metastatic murine melanoma cells. In particular, 2a is 13 times more active at microM concentration after 48 h exposure.
The X-ray fluorescence spectroscopy (XRF) on solid samples is applied to the organic bromine impurities assay on pharmaceutical formulations of sodium diclofenac (DCF). A wide range of Br contents (7-1564 ppm) in the tablets is obtained, depending on manufacturer source and batch preparation. As the impurities concern only the sodium diclofenac employed, and the presence of Br might be a toxicity index arising from the synthetic procedure, the assay of each DCF batch is suggested.
The o-, m- and p-acetoxymethyl-N,N,N-trimethylbenzenemethanaminium iodide (2a-c) as cyclovinilogues of acetylcholine are described. This structural modification allows to modulate the cholinergic activity of the natural neurotransmitter along the sequence: agonist----partial agonist----antagonist, which is referred to meta (2b), para (2c) and ortho (2a) regioisomers, respectively.
Some new dimefline-type derivatives have been synthesized and their pharmacological activity, as well as their distribution coefficients have been determined. The distribution coefficients of a number of previously published analogue compounds have also been measured and the QSAR analysis of the whole set has been carried out. The results of such analysis allow to point out which factors are influencing the biological activity of this group of compounds.
The synthesis and the pharmacological properties of some new prazosin analogues are described.
The synthesis and pharmacological evaluation of a number of symmetrical bivalent ligand type beta-adrenolytics related to practolol are reported. The best results have been observed with N,N'-bis[3-[2-hydroxy-3-[1-methylethyl)amino]propoxy]phenyl] ethanediamide.
A number of symmetrical as well as asymmetrical bis-arenoxypropanolamines have been synthesized and evaluated for their beta-adrenolytic properties. The pharmacological characterization of these compounds was performed in vitro by direct studies (3H-dihydroalprenolol was used as the specific ligand for beta-receptors), and by determining the beta-blocking capacity on isoproterenol (ISO)-induced increased heart rate (isolated guinea-pig atrium); and in vivo by evaluating the antagonism on ISO-induced hypotension and tachycardia, as well as the intrinsic sympathomimetic activity (ISA) on reserpinized and vagotomized rats. The best result was observed with the simplest derivative, i.e. the bis-phenoxypropanolamine compound, which shows in vitro and in vivo potencies almost comparable to propranolol and, moreover, significant bronchodilating activity.
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Tiadenol-nicotinate is an ester in which two molecules of nicotinic acid are linked to one molecule of tiadenol. In the present study the antilipolytic activity of tiadenol-nicotinate was evaluated in isolated rat fat cells and a direct comparison was made with the parent drugs. Basal lipolysis was not affected by tiadenol-nicotinate or by nicotinic acid, but it was reduced by a high concentration of tiadenol (10(-3) M) alone or associated with a double concentration of nicotinic acid. Tiadenol-nicotinate (10(-5)-10(-3) M) was very effective in antagonizing the lipolytic action of epinephrine (10(-6) M) and of theophylline (3 X 10(-4) M). The latter drugs were equally sensitive to the inhibitory effect of tiadenol, while nicotinic acid reduced the action of theophylline more than the effect of the catecholamine. Neither of the parent drugs was as effective as tiadenol-nicotinate at this level. However, nicotinic acid potentiated the antilipolytic effect of tiadenol, thus making it possible to reach an inhibitory effect quantitatively similar to or even higher than the effect of tiadenol-nicotinate. These results show that tiadenol-nicotinate is a potent antilipolytic agent in vitro and that its effect may be due to hydrolysis of the ester and release of the parent drugs. The possible therapeutic value of tiadenol-nicotinate is discussed.