A. Gasco

Structural investigation of Ca2+ antagonists benzofurazanyl and benzofuroxanyl-1,4-dihydropyridines

Abstract The structure of Ca 2+ channel blockers benzofurazanyl- and benzofuroxanyl-1,4-dihydropyridines (1,4-DHPs) was investigated by an integrated NMR, X-ray diffraction and molecular graphics study. 1 H- and 13 C-NMR showed that all the benzofuroxan derivatives exist in solution as tautomeric mixtures. Δ G ° and Δ G ∗ for 4′⇄7′ and 5′⇄7′ benzofuroxanyl tautomeric equilibria were determined for the benzofuroxan derivatives VI and VII . These figures are close to those observed for other substituted benzofuroxans known from literature including DHP derivatives. The conformational domain of all the compounds was analyzed, showing two sets of energetically accessible arrangements of the heterocyclic substructure with respect to C(4)H–DHP hydrogen, antiperiplanar and synperiplanar . Rotameric preference in solution around the C(4)–C(4′) bond in benzofurazanyl derivative IV was sought by normalized transient ΔNOE spectra using interatomic distances derived from AM1 energy minimized structures. A synperiplanar fraction of ca. 75% was calculated, in keeping with results obtained by Rovnyak for Nifedipine. Finally, the solid state preferred conformation was assessed by X-ray analysis for 5′-benzofurazanyl ( V ) and 5′(6′)-benzofuroxanyl ( VII ) derivatives. The latter in the solid state prefers the 5′-form ( VIIa ). The pentatomic ring systems always lie on the same side of the C(4)H–DHP hydrogen. This was also found to be the case for 4′-substituted derivatives and a large number of dihydropyridine derivatives.

Synthesis and vasodilating properties of N-alkylamide derivatives of 4-amino-3-furoxancarboxylic acid and related azo derivatives.

A series of N-alkylamide derivatives of 4-amino-3-furoxancarboxylic acids 5a-11a and their oxidation products, the azo derivatives 5b-11b, were synthesised and studied for their vasodilating properties. All the products were able to release rat aorta strips precontracted with (-)noradrenaline. Azo derivatives proved to be 20-200 times more potent than the parent amines. The large variation of lipophilicity within the two series does not seem to influence significantly the activity. Experiments carried out in the presence of oxyhaemoglobin (HbO(2)) suggest the involvement of nitric oxide (NO*) in the vasodilation.

THE REDUCTION OF BENZOFUROXANS BY FERROUS SALTS AND BY THIOPHENOL

Abstract Treatment of benzofuroxan derivatives with ferrous sulphate in DMSO/water solution affords in high yield o-nitroanilines. o-Nitroaniline was also obtained by reduction of benzofuroxan with thiophenol in presence of catalytic amount of Fe2+ or Fe3+ salts.

1,1-Dinitroethyl substituted furoxans : a new class of vasodilators and inhibitors of platelet aggregation

Abstract The synthesis and structural characterization of a series of 1,1-dinitroethyl substituted furoxans are described. Their vasodilatory properties, evaluated on isolated rings of rabbit thoracic aorta precontracted with noradrenaline, as well as their ability to inhibit the collagen induced aggregation in human platelet-rich plasma, are reported. The most active derivative of the series is 3-(1,1-dinitroethyl)-4-phenylfuroxan 7b . Its vasodilatory property is similar to that of glyceryl trinitrate. In addition, this compound is a more potent platelet aggregation inhibitor than sodium nitroprusside.

Glutathione potentiates cGNP synthesis induced by the two phenylfuroxancarbonitrile isomers in RFL-6 cells

Abstract The cellular mechanism of bioactivation underlying guanylate cyclase activation by the pair of phenylfuroxancarbonitrile isomers 2a, b was investigated. In cultured rat lung fibroblast (RFL-6 cells) it was principally dependent on intracellular thiols.

The cyano-NNO-azoxy function in the design of an irreversible label for α1 adrenoreceptors

Abstract A potential α 1 -adrenergic irreversible antagonist 6, containing the cyano-NNO-azoxy function was synthesized and tested. The effects of norepinephrine on rat thoracic aorta were irreversibly blocked by this compound at the concentration of 1 × 10 −5 M after 60 minutes. Binding studies showed that 6, at 1 × 10 −6 M, did not modify the K D of Prazosin and caused a 30% decrease of the B max . Substitution in 6 of the bis (2-chloroethyl)amino moiety for the cyano-NNO-azoxy function afforded 7 which behaves as an irreversible antagonist able to change K D of Prazosin without influencing B max .