Rosella Calvino

NO donors: Focus on furoxan derivatives

The article focuses attention on furoxan derivatives (1,2,5 oxadiazole 2-oxides) as NO donors. Possible mechanisms for NO release from these products in physiological solution and in segments of rabbit femoral artery are briefly considered. The in vitro anti aggregatory activities and the in vitro and in vivo vasodilating properties of a number of furoxans are examined with particular reference to involvement of NO in these actions. The use of the furoxan system to design new NO donor/drug hybrids is discussed in connection with the problem of the balance between NO- and drug dependent activities of the resulting structures. Whether other biological activities (as yet, little studied) of furoxans, such as their antiparasite, antimicrobial, and antitumoral effects, are NO dependent, is a matter still to be explored.

Characterization of a new compound, S35b, as a guanylate cyclase activator in human platelets

The effects of S35b (4-methyl-3-phenyl sulfonylfuroxan), a new phenyl sulfonylfuroxan compound, were investigated on human platelets activated by different agonists. Platelet aggregation evoked by arachidonic acid (AA), collagen, ADP and thrombin was inhibited by the drug in a dose-dependent manner. S35b inhibited the AA-induced increase of cytosolic free Ca2+ ([Ca2+]i) and production of malondialdehyde. A primary action of the compound on cyclooxygenase is unlikely since: (1) U-46619 (15s-hydroxy-11,9-[epoxymethano]-prosta-5Z,13E-dienoic acid, a stable epoxymethano analog of prostaglandin H2) could not reverse the inhibitory effect of S35b on AA-induced aggregation and [Ca2+]i increase; (2) U-46619-induced aggregation and [Ca2+]i rise were inhibited by S35b; and (3) at high collagen concentrations platelet aggregation (which is unresponsive to aspirin under such conditions) was blocked by S35b as well. Thus the drug action is likely to be exerted at an early step of the platelet activation pathway. The elevation in the platelet cGMP level evoked by S35b in a time- and concentration-dependent manner can account for the inhibitory effect: increased cGMP levels could interfere, for instance, with G protein-phospholipase C coupling and subsequent phosphoinositide hydrolysis.

Reversed-phase high-performance liquid chromatographic study of the lipophilicity of a series of analogues of the antibiotic “calvatic acid”

Abstract The lipophilicity of a series of para- and meta-substituted phenyl-ONN-azoxycyanides, analogues of the antibiotic ‘calvatic acid’, was studied by reversed-phase high-performance liquid chromatography using methanol—water or acetonitrile—water as the mobile phase and a LiChrospher 100 RP-18 column. An excellent linear relationship between the logarithm of the capacity factors (log k′) for each compound and the volume fraction of the organic modifier (ϕ) was found. The extrapolation of log k′ to ϕ = 0 gives log kw for every compound. From these values τw constants were calculated for each substituent. Good correlations were found between log kw and log Poct/H2O and between τw and Hanschs π hydrophobic parameter.

A directed synthesis of alkyl, aryl, and heteroaryl-ONN-azoxycyanides

A variety of R-ONN-azoxycyanides can be prepared in high yield from the nitroso-derivatives with Cyanamide and (diacetoxyiodo) benzene.

An analysis of the lipophilicity of furazan and furoxan derivatives using the CLOGP algorithm

The partition coefficients of a series of furazan and furoxan derivatives have been measured and analysed by means of the CLOGP algorithm. The fnon and fnon(O) fragmental constants have been evaluated as well as the pairs of σ/ρ constants, which are able to describe the electronic interactions operating in the substituted systems. Analysis of the alkyl derivatives shows that the ‘benzyl carbon’ requires a large and negative correction factor when linked to either of these two heterocyclic rings rather than to benzene. In contrast, in 1,2,5-thia and 1,2,5-selenadiazole this same carbon behaves similarly to that attached to a phenyl ring.

Unsymmetrically substituted furoxans. Part 18. Smiles rearrangement in furoxan systems and in related furazans

The preparation and the base-promoted Smiles rearrangement of phenylfurazans (series a), 3-phenylfuroxan (series b) and 4-phenylfuroxan (series c) bearing 2-hydroxyethylthio (1), 2-hydroxyethylsulfonyl (2), carbamoylmethylthio (3) and carbamoylmethylsulfonyl (4) functions at the hetero-ring are described. Under similar conditions compounds of the series a and b gave the expected Smiles rearrangment products with the only exception being the amide derivatives 3 which were hydrolysed to their corresponding acid. The behaviour of the 4-phenylfuroxan series to Smiles rearrangment was quite different. Under conditions close to those adopted for the corresponding 3-phenyl isomers, 1c and 2c decomposed into unidentified polar products. 3c afforded as principal product 3-mercapto 4-phenylfurazan while 4c afforded (Z)-2-hydroxyimino-2-phenylacetonitrile. Possible mechanisms of formation of these products are discussed.

S35b, a new phenylsulfonylfuroxan compound, inhibits thrombin-induced synthesis of platelet-activating factor and prostacyclin in human endothelial cells

Endothelial cells (EC) produce platelet activating factor (PAF) and prostacyclin (PGI2) in response to inflammatory agents such as thrombin. Upon cell stimulation a calcium-dependent phospholipase A2 (PLA2) is activated which hydrolyzes a membrane phospholipid to yield 1-0-alkyl-2-lyso-sn-glycero-3-phospho-choline (lyso-PAF) and free arachidonic acid. Lyso-PAF is in turn converted into PAF by a specific acetyltransferase and arachidonic acid is metabolized via cyclic endoperoxides to PGI2. In the present study we report that S35b (4-methyl-3-phenylsulfonylfuroxan), an new phenyl-sulfonylfuroxan compound with potent antiaggregatory effect, inhibits thrombin-induced PAF synthesis and acetyltransferase activation as well as PGI2 production in human umbilical vein endothelial cells (HUVEC) in a concentration dependent way. Additionally, we show that S35b stimulates the production of cyclic GMP (cGMP) in HUVEC in a concentration- and time-dependent manner. At high concentration, S35b potentiates the cAMP increase induced by iloprost or forskolin without having a significant influence on cAMP level itself. Potentiation of cAMP increase during agonist-induced EC stimulation seems not to be important for the effect of S35b on cellular function as the compound is active in inhibiting PAF production when endothelial cells are pretreated with indomethacin to block PGI2 synthesis. The increase of cGMP evoked by S35b may account for the effect on endothelial cell function.

Unsymmetrically substituted furoxans. Part 6. 3-Nitro-4-phenylfuroxan: reaction with sodium methoxide and X-ray structural analysis

The reaction of sodium methoxide with the by-product obtained by the action of an excess of 85% hydrogen peroxide in trifluoroacetic acid on 3-amino-4-phenylfuroxan suggests, for this derivative, the 3-nitro-4-phenylfuroxan structure. X-Ray analysis confirms this deduction.

X-Ray and nuclear magnetic resonance structural study of acylglyoximes and related substances

A series of reactions used in the literature to synthesize acylglyoximes were reinvestigated and the mixtures of products obtained resolved by chromatography. NMR spectroscopy revealed that some of the derivatives described in literature as dioximes actually have an isoxazoline structure. X-Ray analysis was employed to establish unequivocally the structures of syn-diacetylglyoxime and the (Z)-3-acetyl-5-hydroxy-4-hydroxyimino-5-methyl-4,5-dihydroisoxazole hemihydrate. In addition, the structure of the derivative produced by treatment of 5-hydroxy-4-hydroxyimino-3-methyl-5-phenyl-4,5-dihydroisoxazole with dinitrogen tetraoxide in dry diethyl ether is also described.

Oximation of acetyl(hydroxyimino)acetone: nuclear magnetic resonance spectroscopic, chemical, and X-ray crystallographic studies of the reaction products

The oximation of acetyl(hydroxyimino)acetone (1) with hydroxylamine affords a mixture of oxime derivatives. The products obtained by the action of an equimolar amount of hydroxylamine on (1) are the two 3,5-dimethyl-5-hydroxy-4-hydroxyimino-2-isoxazoline isomers (3a and b). The main products obtained by the action of an excess of hydroxylamine on (1) are two pentane-2,3,4-trione trioxime isomers (4a and b) and a little amount of 4-acetyl-3-methylfuroxan oxime (5). N.m.r. and chemical data of all these derivatives are discussed in order to determine both structures and configuration. X-Ray analysis of (3a), (4a), and (5) are also reported.