A pharmacological, crystallographic, and quantum chemical study of new inotropic agents.

The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,6,3,2,11,12-hexahydro-6,3-dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-substituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolinediones, was evaluated in spontaneously beating and in electrically driven atria from reserpine-treated guinea pigs. Their effects were compared with those induced by amrinone and milrinone in both the atria preparations. Compounds SF28 (3-acetyl-1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonitrile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were the most effective positive inotropic agents. An inhibition of the negative influence exerted by endogenous adenosine on heart preparations seems to be involved in their contractile activity. SF38 (3-benzoyl-2-phenyl-6(1H)-pyridinone), on the contrary, reduced the contractile force and the frequency rate of guinea pig atria with a mechanism not related to an activation of cholinergic or purinergic inhibitory receptors on the heart. X-ray analysis carried out on the three model compounds, SF28, SF40 (positive inotropic agents), and SF38 (negative inotropic agent), and molecular modeling evidenced that the change from phenyl (SF38) to methyl (SF28) or the introduction of a side cyclic aliphatic chain (SF40) results in a variation of conformational preference and topography which may address the different molecules toward distinct receptor pockets according to the resulting inotropic effect.

Synthesis and cardiotonic activity of novel pyrimidine derivatives: crystallographic and quantum chemical studies.

The synthesis of ethyl or methyl 4-substituted or unsubstituted 2-(dimethylamino)-5-pyrimidinecarboxylates 10-20, which is mainly carried out by reaction of ethyl or methyl 2-[(dimethylamino)methylene]-3-oxoalkanoates with 1,1-dimethylguanidine, is described. The above esters were hydrolyzed to the relative carboxylic acids 21-30, which were decarboxylated to the corresponding 2,4-disubstituted pyrimidines 31-40. All the new synthesized pyrimidines were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Their effects were compared to those induced by milrinone in both atria preparations. Compound 28 (4-benzyl-2-(dimethylamino)-5-pyrimidinecarboxylic acid) was the most effective positive inotropic agent, while the corresponding methyl ester 17 reduced both the contractile force and the frequency of guinea pig atria. An antagonism toward the negative influence exerted by endogenous adenosine on the heart seems to be involved in the contractile activity of compound 28. By contrast, compound 17 might be partial agonist at the purinergic inhibitory (A1) receptor. X-ray analysis carried out on 17 and 28 and molecular modeling investigations extended also to related derivatives allowed a possible rationalization between structure and inotropic activity for this series of compounds.

Photoaddition of 4,6-dimethyltetrahydrobenzoangelicin to thymine in DNA: X-ray studies and experiments with model oligonucleotides.

The crystal structures of 4,6-dimethyltetrahydrobenzoangelicin (THBA), a furocoumarin analog, and of its furan-side cis-syn cycloadduct with thymine formed in the photoreaction with DNA, have been determined. The crystal structure of the latter compound contained only one enantiomeric form corresponding to the addition to a 5'-XpT site. Contrary to most psoralen derivatives studied, THBA showed higher photoreactivity toward synthetic oligonucleotides containing that sequence than toward those with the 5'-TpX sequence.

Benzoangelicins: new monofunctional DNA photobinding agents.

4,6-Dimethylbenzoangelicin, obtained by fusing a benzene ring at the furan side of 4,6-dimethylangelicin, was studied in terms of crystal structure and interactions with DNA in both ground and excited states. 4,6-Dimethylbenzoangelicin has a planar structure and forms a molecular complex with DNA, undergoing intercalation inside the double helix. Under UVA irradiation, it photoconjugates covalently with the macromolecule, showing a DNA photobinding rate slightly lower than that of 8-methoxypsoralen, involving however only its 3,4 double bond, i.e. behaving as a pure monofunctional agent. The parameters of dark binding and photobinding were determined, and two C4 cycloadducts with thymine were isolated and characterized.

Azapsoralens-DNA interactions: crystal structure characterization of furan-side monoadduct and computer-aided studies.

In this paper a theoretical study, concerning molecular mechanics optimised structures, obtained by quantum mechanics as well as molecular mechanics calculations was carried out with the aim of correlating the theoretical model of the interactions between azapsoralens and DNA with the data experimentally obtained. The theoretical model suggests that both furan-side and pyrone-side double bonds may be involved in the cycloaddition with pyrimidines (although the cycloaddition at the level of furan is preferred), and is in line with the capacity of these compounds to form inter-strand cross-links. Moreover, concerning the theoretical intercalation model calculations on 3,4,4',5'-tetramethylazapsoralen intercalated inside a polynucleotide, they suggest a cis-syn arrangement between furan-side of the intercalated ligand and the above situated thymine, with which, under light activation, a cycloadduct may take place, having a cis-syn steric arrangement. Also this datum is in agreement with the cis-syn regio and stereochemistry of the isolated 4,4',5'-trimethylazapsoralen-thymine cycloadduct. Finally, from theoretical data, the role of nitrogen seems not important: in fact only small differences were found with the corresponding methylpsoralens so that the small differences observed may be mainly attributed to steric rather than to electronic effects. In general a good correlation between the theoretical model and the experimental data was observed.

Synthesis and antimicrobial activity of arylazoenamines.

The possibility to obtain new arylazoenamines endowed with antifungal activity was examined by reacting with acids the arylhydrazones of several keto- and aldo-tert, amines as dimethyl-3-aminoacetone, 3-quinuclidinone, 1-methyl-3-piperidone and 2-formyl-1-methylpyrrolidine. The reaction was successful only in the last two cases. From each 1-methyl-3-piperidone arylhydrazone two isomeric arylazoenamines were formed, which were identical with those obtained from the analogous arylhydrazone of 2-formyl-1-methylpyrrolidine. The structure of these compounds was settled on the ground of UV, IR, NMR and mass spectra and confirmed by means of X-ray analysis. A mechanism is proposed for the formation of arylazoenamines through the contraction of piperidine ring and enlargement of the pyrrolidinic one. The prepared compounds [3-arylazo-1-methyl-delta 2-piperideines 17 and 1-methyl-2(arylazo)methylene pyrrolidines 18 exhibited only a very weak antibacterial activity, but were moderately active against several Candida species and other yeast-like fungi.

Azapsoralens: new potential photochemotherapeutic agents for psoriasis.

New bioisoters of psoralen, obtained by replacing carbon 8 of the central benzene ring with a nitrogen, were studied from the photochemical, photobiological and phototherapeutic points of view. In particular, 4,4'-, 4',5'-dimetyl, 4,4',5'-trimethyl and 3,4,4',5'-tetramethylazapsoralen were studied. The crystal and molecular structure of 4,4',5'-trimethylazapsoralen, obtained by X ray diffraction, was also reported. Like psoralen, these compounds form a molecular complex with DNA, undergoing intercalation inside the double helix of the macromolecule. When irridiated with long ultraviolet light (365 nm), the intercalated drug photoconjugates covalently to the macromolecule, forming mono- and diadducts. The photobinding rate show the following order of magnitude: 4,4',5'-trimetylazapsoralen (4,4',5'-TMAP) = 3,4,4',5'-tetramethylazapsoralen (3,4,4',5'-TMAP) greater than 4',5'-dimethylazapsoralen (4',5'-DMAP) = 4,4'-dimethylazapsoralen (4,4'-DMAP). The DNA photobinding rate of 8-methoxypsoralen (8-MOP), taken as reference compound, is similar to that of the two dimetylazapsoralens but lower than tri- and tetramethyl derivatives. The ability of azapsoralens to form cross-links in DNA is lower than that of 8-MOP. However, capacity to induce cross-links does not parallel the DNA photobinding rate; it is higher for trimethyl derivate and lower for tetramethylazapsoralen. Azapsoralens show evident antiproliferative activity. The trimethyl derivative is the most active, followed by tetrametyl, both these compounds showing activity slightly higher than that of 8-MOP. The two dimethylderivatives are less active. The mautagenic activity of azapsoralens on E. coli WP2 TM6 is lower than that of 8-MOP in the same conditions. The new compounds do not show any skin phototoxicity on guinea pig skin. On the basis of its DNA photobinding, antiproliferative activity, mutagenicity and lack of skin phototoxicity, 4,4',5'-TMAP was chosen for clinical evaluation. Clinical results obtained by topical treatment of psoriatic plaques reveal evident therapeutic effectiveness and clearing is between good and moderate, although 8-MOP, used as reference compound, is more effective.

Molecular conformation of N,N-dimethyl-4-amino-3-chloroangelicin C13H10O3NCl.

The title compound was characterized by X-ray diffraction analysis. The crystals belong to the triclinic system, space group P1, with four molecules in the unit cell having a = 16.344(5), b = 10.343(3), c = 7.283(2) A, alpha = 109.1(1), beta = 90.2(1), gamma = 94.2(1), dc = 1.51 Mgm-3. The structure was determined from 1945 intensity data with I greater than or equal to 3 sigma (I) collected on a Philips PW 1100 diffractometer and refined by full matrix least-squares to the final R values R = 0.046 and Rw = 0.046. The molecular conformation is close to that of angelicin, the additional methyl groups being sandwiched with respect to the molecular plane, in order to minimize their steric hindrance. The possible intercalation of the title compound inside DNA has been considered.

3-Chloro-4-dimethylaminothioangelicin.

C13H10ClO2NS, Mr = 279.75, monoclinic, P2(1)/a, a = 14.490 (3), b = 22.598 (5), c = 7.336 (2) A, beta = 92.4 (1) degree, U = 2400 (1) A3, Z = 8, D chi = 1.548 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 2.07 cm-1, F(000) = 1152, room temperature, R = 0.037 for 2423 independent reflections with I greater than or equal to 3 sigma(I). Each unit cell contains two independent molecules which differ mainly in the orientation of their N(CH3)2 groups. The two tricyclic moieties of each molecule are not coplanar, the pyran ring being tilted by 7.9 (1) degree with respect to the benzene ring in molecule 1 and by 8.7 (1) degree in molecule 2. There are weak interactions between the molecules involving the carboxylic O atoms and the H atoms of the phenyl moieties.

Structural variations across the lanthanide series of macrocyclic DOTA complexes: insights into the design of contrast agents for magnetic resonance imaging.

It was early shown that the macrocyclic Ln(DOTA) complexes (DOTA = 1,4,7,10-tetra-azacyclododecane-N,N',N' ',N' "-tetraacetic acid) exists in solution as a mixture of two enantiomeric pairs of diastereoisomers differing in the ligand conformation, namely, square antiprismatic (SA) and twisted square antiprismatic (TSA) geometries, respectively. Later, extensive (1)H NMR investigations suggested that a coordination change may be superimposed on this conformational equilibrium involving two additional structures in which the metal ion possesses a coordination number of eight (CN 8). It was predicted that these two species, lacking the apical coordinated water molecule, would maintain the SA and TSA coordination geometries, and therefore, they have been labeled as SA' and TSA', respectively. In this work we report the X-ray solid-state crystal structure determination of six Ln(DOTA) complexes representative of all four coordination geometry typologies deduced from NMR solution studies. A distinctive structural feature that discriminates SA (and SA') and TSA (and TSA') structures is represented by the twist angle between the two square planes of the antiprism, the basal four nitrogen, and the apical four oxygen planes. [Ce(DOTA)(H(2)O)](-) displays a TSA structural typology with a twist angle of 25 degrees and a Ce-O(water) distance of 2.59 A. The SA-type structure has been found in the case of complexes with Pr(III), Nd(III), and Dy(III), where the twist angle is 39, 39, and 38 degrees, respectively, and the metal-water oxygen distance varies significantly (Pr-O(w) 2.529 A; Nd-O(w) 2.508 A; and Dy-O(w) 2.474 A). [Tm(DOTA)](-) displays a TSA'-type structure with a twist angle of 24 degrees. As compared with the TSA structure of the corresponding Ce(III) complex, the Tm(III) complex shows an overall marked shrinkage of all metal-nitrogen and metal-oxygen distances (ca. 0.2 A), which reflects the contraction of the metal ionic radius across the series but also the effect associated with the decrease of the CN from 9 to 8. In [Sc(DOTA)](-), the even smaller ionic radius of Sc(III) shifts the geometry of the coordination cage to the more compact SA' typology with a twist angle of 41 degrees, a value very similar to that found in the SA structures of lanthanide(III) ions with CN 9. Finally, an investigation was made into the hydration spheres of the complexes with SA and TSA geometries to account for the experimental evidence of a markedly different rate of water exchange for the two isomeric structures. This is of fundamental importance to the understanding of the corresponding Gd(III) complexes as MRI contrast agents.