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Biomedical subjects

P Cozzi

Publications and source records attributed to P Cozzi.

At least 37 records · Page 2Linked to original sources
PubMed1997

Synthesis, cytotoxicity, antitumor activity and sequence selective binding of two pyrazole analogs structurally related to the antitumor agents U-71,184 and adozelesin.

Two pyrazole analogs structurally related to the antitumor agents adozelesin and U-71,184 respectively were synthesized. By using a polymerase chain reaction approach, both compounds show selective binding to A + T rich sequences exactly as reference compound U-71,184. In in vitro assays, against L1210 cell lines, both derivatives showed cytotoxicity in the pM range, values comparable with the natural target compound (+)-CC-1065. The most active compound showed very high antitumor activity in mice implanted with L1210 cells (ILS% 363).

Animals↗
PubMed1997

Synthesis, cytotoxicity and antitumor activity of some new simplified pyrazole analogs of the antitumor agent CC-1065. Effect of an hydrophobic group on antitumor activity.

Three simplified pyrazole analogs (7-9) of the antitumor agents CC-1065, were synthesized. In in vitro assays, against L1210 cell lines all derivatives showed a cytotoxicity in a pM range, values close to the natural target compound (+)-CC-1065. In in vivo tests, against disseminate L1210 leukemia cells, synthesized compounds showed a good potency (O.D. 300 micrograms/Kg) but no activity. These observations further validate the effect of the hydrophilic and/or hydrophobic characteristics of the substituents present on the molecules, confirming the relevance of this phenomena on in vivo activity. In fact in this case the increase of hydrophobic characteristics of the molecules produce the loss of activity, probably due to a worse bioavailability of the drugs in animals.

Animals↗
PubMed1997

Synthesis, solvolytic stability and cytotoxicity of a modified derivative of CPzI, a pyrazole analog of the alkylation subunit of the antitumor agent CC-1065: effect of the nitrogen substitution on the functional reactivity.

The synthesis and the comparative preliminary biological evaluation of a new pyrazole analog (16) of the CC-1065 alkylating unit (CPI) are described. This new derivative showed low cytotoxicity against L1210 murine leukemia (IC50 3064 nM) with respect to reference compound, but contrarily to literature data, was found to be more stable to solvolysis than the natural derivative (+/-)-N-Boc-CPI (pH 3, t1/2 = 212 h vs. 37 h). The results of such investigation showed that alkylation of the pyrazole nitrogen caused a loss of cytotoxic activity in vitro against tumor cells. This experimental observation allowed us to confirm the importance of free N-H for the anticellular activity.

Alkylation↗
PubMed1996

Cyclosporine A inhibits airway reactivity and remodeling after chronic antigen challenge in cats.

We determined the effect of cyclosporine A (CSA) on airway reactivity and remodeling after chronic antigen challenge in Ascaris suum (AA)-sensitized cats. CSA efficacy was demonstrated by inhibition of interleukin-2 (IL-2) production from phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear (PBMN) cells. Twenty-four hours after the first AA exposure, cats not receiving cyclosporine (CsA-) demonstrated airway hyperresponsiveness (AHR) to acetycholine (approximately 1.0 log increase in PD200 versus baseline; p < 0.01), and a 13-fold increase in eosinophils in bronchoalveolar lavage fluid (BALF) (p < 0.01). AHR persisted (approximately 1.5 log increase in PD200 p < 0.001 versus baseline), and BALF eosinophilia was unchanged in CsA-cats 72 h after final AA challenge. The percent of normodense BALF eosinophils also decreased substantially in CsA-cats (p < 0.05). Necropsy specimens from CsA-cats demonstrated: (1) increased smooth-muscle thickness; (2) goblet cell and submucosal gland hypertrophy and hyperplasia; and (3) epithelial erosion with eosinophilic infiltration. There was no significant change in AHR, BALF, eosinophilia, or histology after chronic AA challenge in Csa-treated cats. These data suggest that CsA inhibits products of immune cells necessary for the development of AHR, airway inflammation, and airway wall remodeling caused by immune-sensitization in this model of atopic asthma.

Acetylcholine↗
PubMed1995

Persistent airway hyperresponsiveness and histologic alterations after chronic antigen challenge in cats.

We studied the effect of chronic immune sensitization on the airway reactivity and associated cytologic and histologic alterations in initially nonatopic cats, a species that spontaneously develops idiopathic asthma. Seven cats were sensitized by intramuscular injection of Ascaris suum antigen (AA) for 4 wk, and four other cats served as sham controls. Airway sensitization was demonstrated by an increased response to nebulized AA in sensitized animals (RL = 45.9 +/- 6.1 cm H2O/L/s, versus a baseline response of 24.7 +/- 1.5 cm H2O/L/s, p < 0.01), and hyperresponsiveness was demonstrated by an increased response to acetylcholine (ACh)-challenge 24 h after AA (approximately 1.0 log decrease in PD200, p < 0.01). The number of eosinophils in the sensitized animals' bronchoalveolar lavage (BAL) fluid increased 12-fold (p < 0.01 versus control) in response to AA challenge; 32 +/- 5% of the BAL eosinophils had a specific density < 1.050, versus 8 +/- 2% prior to AA challenge (p < 0.05). There was no change in airway reactivity, eosinophil recovery, or density in the control group 24 h after sham challenge with saline. The same seven sensitized cats further received nebulized AA three times weekly for 4 to 6 wk, after which BAL samples were again obtained and ACh dose-response curves generated 72 h after the final administration of nebulized AA. Airway hyperresponsiveness increased (approximately 1.5 log decrease in PD200, p < 0.001) and the number of eosinophils recovered in BAL fluid was increased 11-fold (p < 0.05). Necropsy specimens demonstrated bronchoconstriction in AA-challenged animals but not controls; luminal narrowing was accompanied by: (1) a 29.0 +/- 0.34% increase in smooth-muscle thickness (p < 0.05); (2) goblet-cell and submucosal-gland hypertrophy and hyperplasia; and (3) epithelial erosion and eosinophilic infiltration. We demonstrate in nonhuman species persistent airway hyperreactivity associated with a complete constellation of histologic changes in epithelium, smooth muscle, and mucus glands, and cytologic changes in BAL fluid, all induced by immune sensitization. Our data suggest that chronic immune sensitization per se could be a salient factor in causing many of the changes associated with chronic bronchial asthma.

Acetylcholine↗
PubMed1995

Cyproheptadine-induced attenuation of type-I immediate-hypersensitivity reactions of airway smooth muscle from immune-sensitized cats.

We assessed the effect of serotonergic inhibition by cyproheptadine on the responsiveness of tracheal smooth muscle (TSM) strips and epithelium-intact third-generation bronchial rings from immune-sensitized (Ascaris suum) cats after exposure to antigen. Cats were sensitized by IM administration of antigen and adjuvant twice over a 4-week period. Sensitization was confirmed in vivo by skin testing with antigen and by physiologic airway responses after exposure to nebulized antigen. Tissues were tethered isometrically to force transducers and were actively equilibrated by exposures to KCl-substituted perfusate. Maximal response after exposure to antigen (expressed as percentage of maximal contraction of each tissue to 63 mM KCl (%KCl) was 169 +/- 18% KCl for sensitized TSM and 43 +/- 18% KCl for sensitized TSM pretreated with cyproheptadine (P < 0.001). Similarly, maximal response to antigen was 81 +/- 27% KCl for sensitized bronchial rings, compared with 16 +/- 14% KCl for sensitized bronchial rings pretreated with cyproheptadine (P = 0.05 vs control). Blockade of leukotriene synthesis by 10(-6) to 10(-4) M A-64077, a selective 5-lipoxygenase inhibitor, had no significant effect on peak response for either TSM (193 +/- 13% KCl vs 169 +/- 18% KCl for sensitized untreated TSM) or bronchial rings (79 +/- 20% KCl vs 81 +/- 27% KCl for sensitized untreated bronchial rings). Release of serotonin from airway tissues was confirmed by the presence of serotonin in the perfusate of 8 sensitized TSM preparations after, but not before, antigen challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1994

Agents combining thromboxane receptor antagonism with thromboxane synthase inhibition: [[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]alkanoic acids.

A new class of compounds combining thromboxane-A2 (TxA2) receptor antagonism and thromboxane synthase inhibition is described. A first series of (E)- and (Z)-[[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]pentanoic acids showed relevant thromboxane synthase inhibition associated with weak TxA2 receptor antagonism, while a series of (+/-)-(E)-[[[2-(1H-imidazol-1-yl)-3-phenylpropylidene]amino]oxy] pentanoic acids, structurally derived from the former, showed potent and well-balanced dual activity. Structural requirements for significant single and dual activity are discussed. Two close congeners of the latter series, (+/-)-(E)-5-[[[1-cyclohexyl-2-(1H-imidazol-1-yl)-3- phenylpropylidene]amino]oxy]pentanoic acid 23c and its p-fluorophenyl analog 23m, inhibited TxB2 production in vitro, in rat whole blood during clotting, with IC50 of 0.06 and 0.37 microM and antagonized the binding of [3H]SQ 29548 to washed human platelets, with IC50 of 0.08 and 0.02 microM, respectively. These two compounds were selected for further pharmacological evaluation and were shown to antagonize U46619-induced platelet aggregation in human platelet rich plasma with IC50 of 0.30 and 0.44 microM, respectively. They were both orally available, and in particular 23m caused a long lasting ex vivo TxA2 synthase inhibition in the fed rat. The levorotatory enantiomer of 23c, stereospecifically synthesized as a model compound, was found to be more potent than racemic 23c with regard to TxA2 receptor antagonism (IC50 = 0.04 microM) and equivalent to the latter with regard to TxA2 synthase inhibition. A molecular modeling study concerning the levorotatory enantiomer of 23c (S), TxA2, and representative TxA2 antagonists of different classes led to the definition of a putative pharmacophoric model for the TxA2 receptor ligands.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Reversal of multidrug resistance by new dihydropyridines with low calcium antagonist activity.

The clinical use of Ca++ antagonist agents as modulators of multidrug resistance is limited by their strong vasodilator activity. This study reports data obtained by testing a series of new 1,4 dihydropyridine derivatives (DHPs) for their in vitro resistance modulating activity and their Ca++ antagonist effect. All the tested DHPs are active to increase doxorubicin activity with dose modifying factor values ranging between 2 and 47 on P388/DX cells and 12 and 36 on LoVo/DX cells. Their resistance modulating action is exerted through an increase of DX intracellular level. The Ca++ antagonist activity of DHPs, evaluated as capacity to inhibit the KCl-induced contractions in isolated Guinea pig ileum strips, is not related to their resistance modulating activity. This finding makes it possible to select, for further in vivo evaluations, compounds IX, X and XI, which have strong ability to overcome multidrug resistance and low Ca++ antagonist effect.

Animals↗
PubMed1994

Imidazolylbenzopyrane derivatives: a new class of acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors.

Inhibitors of the enzyme Acyl-CoA: Cholesterol Acyltransferase are regarded as potentially useful agents in the treatment of hypercholesterolemia and atherosclerosis. We report here a novel series of 2, 6-disubstituted-3-imidazolylbenzopyrane derivatives with significant in vitro ACAT inhibitory activity (IC50 range 0.05-0.5 microM). Compounds of this series such as 26 are examples of a new, structurally distinct class of potent ACAT inhibitors with high specificity for the aortic subtype of the enzyme. The structure-activity relationships of the 3-imidazolylbenzopyrane ACAT inhibitors were investigated by systematic manipulation of two regions of the parent compound 1 and the inhibitory activity resulted linked to the substituent in position 6 of the benzopyrane ring and modulated by the size of lipophilic substituents in position 2. Investigation of the mechanism of the inhibitory effect leads to the conclusion that these compounds act in a non-competitive fashion.

Animals↗
PubMed1993

Imidazol-1-yl and pyridin-3-yl derivatives of 4-phenyl-1,4-dihydropyridines combining Ca2+ antagonism and thromboxane A2 synthase inhibition.

A series of derivatives of 4-phenyl-1,4-dihydropyridine bearing imidazol-1-yl or pyridin-3-yl moieties on the phenyl ring were synthesized with the aim of combining Ca2+ antagonism and thromboxane A2 (TxA2) synthase inhibition in the same molecule. Some of these compounds showed significant combined Ca2+ antagonism and TxA2 synthase inhibition in vitro, while others showed only one single activity. Structural requirements for significant single or combined activities are discussed. Theoretical conformational analysis, by molecular mechanics and semiempirical AM1 calculations, was performed for 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)phenyl]- 3,5-pyridinedicarboxylic acid, diethyl ester (FCE 24265) and two close congeners. FCE 24265, which inhibited TxB2 production in rat whole blood with IC50 = 1.7 x 10(-7) M and antagonized K+ induced contraction in guinea pig aorta with IC50 = 6.0 x 10(-8) M, was selected for further pharmacological evaluation. Our results show that this compound is less potent than nifedipine both in vitro and in vivo yet presents a favorable profile in vivo, lowering blood pressure without inducing reflex tachycardia. Moreover, its additional potent and selective TxA2 synthase inhibitory activity makes this compound an interesting pharmacologic tool in pathologies where both enhanced TxA2 synthesis and cellular Ca2+ overload are involved.

Animals↗
PubMed1989

Plasma LH and gonadal LH-binding cells in normal and surgically decapitated chick embryos.

Plasma luteinizing hormone (LH) concentrations and the numerical density (Nv) of gonadal LH-binding (LH-positive) cells were determined in intact male and female chick embryos from Days 10.5 through 18.5 of incubation for plasma LH and from Days 6.5 through 19.5 for LH-binding cells, as well as in Day 15.5 decapitated ("hypophysectomized") embryos with pituitary transplants for both plasma LH and LH-binding cells. The data demonstrate that LH is already present in the plasma of male and female embryos as early as Day 10.5, the first day examined. Plasma LH levels in hypophysectomized embryos were statistically significantly lower than those of intact embryos, while pituitary transplants to the chorioallantoic membrane of hypophysectomized embryos elevated plasma LH concentrations to levels not statistically different from those of intacts. The "role(s)" of plasma LH levels and changes in form and numerical density (Nv) of gonadal LH-binding cells in the maturation of the pituitary-gonadal axes of the chick embryo are discussed and evaluated.

Animals↗
PubMed1987

Synthesis of some 3-hydroxy-5-aminopentanoic acid derivatives.

The 5-amino analogues of mevalonic acid and mevalonolactone, 5-amino-3-hydroxy-3-methylpentanoic acid (VII a) and 4-hydroxy-4-methyl-2-piperidone (III a), and some related compounds were synthesized as possible inhibitors of cholesterol biosynthesis. None of them was found effective on the synthesis of cholesterol in rat liver slices and on HMG-CoA reductase activity in vitro, but 4-hydroxy-4-(4-chlorophenyl)-2-piperidone (III b) raised high density lipoproteins (HDL) in normolipaemic rats.

Amino Acids↗
PubMed1987

Ethyl 2-([5,6-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenyl]oxy)- 2-methylpropanoate as a new potent oxyisobutyrate hypolipidaemic with unusual features.

Some compounds containing the N-imidazolyl and the ethyl oxy-isobutyrate groups linked to a naphthalene ring structure and some related analogues were synthesized and tested for hypolipidaemic activity. Ethyl 2-([5,6- dihydro-7-(1H-imidazol-1-yl)-2-naphthalenyl]oxy)- 2-methylpropanoate (V) proved to be a strong hypolipidaemic agent, several times more potent than clofibrate. Structural requirements for activity and differences from clofibrate analogues are discussed.

Animals↗
PubMed1986

N-imidazolylchroman-4-ones, N-imidazolyl-1-tetralones, and their alcohols as hypolipemic agents raising high-density lipoproteins.

A series of 3-(1-imidazolyl)chroman-4-ones and 2-(1-imidazolyl)-1-tetralones II, some of their alcohols, and some related compounds were synthesized and tested for hypolipidemic activity. Compounds II, bearing appropriate lipophilic substituents on the phenyl ring, strongly reduced total serum cholesterol while raising high-density lipoprotein cholesterol in diet-induced hypercholesterolemic rats. 3-(1-Imidazolyl)chroman-4-ols and 2-(1-imidazolyl)-1-tetralols corresponding to II retained the hypolipidemic activity while removal of the carbonyl or hydroxy group adjacent to imidazole gave inactive compounds. Although many of the active compounds significantly increased liver weight, the one studied as a model, 6-chloro-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (5), caused no peroxisome proliferation. Compound 5 and the corresponding alcohol 40, as representatives of the ketone and alcohol series, showed significant hypolipidemic activity in normolipemic rats. Some of the compounds assayed in cholesterol biosynthesis inhibited acetate incorporation but none inhibited HMG-CoA reductase. 5-Bromo-6-hydroxy-2-(1-imidazolyl)-3,4-dihydro-1(2H)-naphthalenone (38), which showed strong activity but caused little hepatomegaly in the rat, was chosen for further pharmacological evaluation.

Alcohols↗
PubMed1983

Synthesis of 3-hydroxy-3-cyclohexylbutyric acid derivatives. 1. Cyclic homologues of 3-hydroxy-3-methylglutaric acid.

Z and E isomers of 3-methyl-3-(carboxymethyl)hexahydro-1 (3H)-isobenzofuranones (I), lactones of 3-hydroxy-3-(2-carboxycyclohexyl) butyric acids (II), were prepared and tested on cholesterol biosynthesis in vitro. Compound I of the Z series was prepared through its ethyl ester by hydrogenation, over Rh/Al2O3 catalyst, of the phenyl ring of 3-methyl-3-[(ethoxycarbonyl)methyl]-1(3H)-isobenzofuranone. Compound I of the E series was prepared, through its ethyl ester, by Reformatsky reaction from ethyl (E)-2-acetylcyclohexanecarboxylate. 3-Methyl-3-(carboxymethyl)-5,6,7,8-tetrahydro-1(3H)-isobenzofuranone, 3-methyl-3-ethyl-5,6,7,8-tetrahydro-1(3H)-isobenzofuranone, and 3-methyl-3-(carboxymethyl)-1(3H)-isobenzofuranone were also prepared and tested. The above compounds inhibited acetate incorporation in cholesterol and fatty acids in rat liver slices at 5 X 10(-3) M but lack specific inhibitory activity on HMG-CoA reductase.

Acetates↗
PubMed1983

Synthesis of 3-hydroxy-3-cyclohexylbutyric acid derivatives. 2. Cyclic analogues of mevalonic acid.

The sodium salt of (Z)-3-hydroxy-3-(2-hydroxycyclohexyl)butyric acid (I) and its lactone (II) were prepared through the corresponding tert-butyl ester by hydrogenation, over Rh/Al2O3 catalyst, of the phenyl ring of tert-butyl 3-hydroxy-3-(2-hydroxyphenyl)butyrate (III). (Z)-3-Hydroxy-3-(2-methoxycyclohexyl)butyric acid was prepared similarly. (Z)-4-Methyloctahydro-2H-1-benzopyran-2-one was prepared by hydrogenation, over Rh/Al2O3 catalyst, of 4-methylcoumarine, prepared in turn from III by a one-pot procedure comprising hydrolysis, lactonization, and dehydration. The above compounds inhibit acetate incorporation in cholesterol and fatty acids in rat liver slices at 5 X 10(-3) M, but they lack specific inhibitory activity on HMG-CoA reductase.

Animals↗