Manuel Melguizo

Reactivity of 6-aminopyrimidin-4(3H)-ones towards dimethyl acetylenedicarboxylate (DMAD). Tandem diels-alder/retro diels-alder (DA/RDA) reaction in the synthesis of 2-aminopyridines.

Abstract The reactions of 6-aminopyrimidin-4(3H)-one derivatives, 1a-d , with DMAD, 2 , are discussed in this paper, 2-aminopyridines, 3 , and 6-amino-5-vinylpyrimidin-4-(3H)-ones, 4 and 5 , have been obtained as main products, which can be explained on the basis of DA/RDA reactions, or Michael Addition on pyrimidine derivatives.

N-(6-amino-3,4-dihydro-3-methyl-5-nitroso-4-oxopyrimidin-2-yl) derivatives of glycine, valine, serine, threonine and methionine : interplay of molecular, molecular-electronic and supramolecular structures

In each of N-(6-amino-3, 4-dihydro-3-methyl-5-nitroso-4-oxopyrimidin-2-yl)valine, C(10)H(15)N(5)O(4) (3) (orthorhombic, P2(1)2(1)2(1)), N-(6-amino-3, 4-dihydro-3-methyl-5-nitroso-4-oxopyrimidin-2-yl)serine monohydrate, C(8)H(11)N(5)O(5).H(2)O (4) (orthorhombic, P2(1)2(1)2(1)), and N-(6-amino-3, 4-dihydro-3-methyl-5-nitroso-4-oxopyrimidin-2-yl)threonine, C(9)H(13)N(5)O(5)(5) (monoclinic, P2(1)), the C-nitroso fragments exhibit almost equal C-N and N-O bond lengths: the C-N range is 1. 315 (3)-1.329 (3) A and the N-O range is 1.293 (3)-1.326 (3) A. In each compound there are also very short intermolecular O-H.O hydrogen bonds, in which carboxyl groups act as hydrogen-bond donors to the nitrosyl O atoms: the O.O distances range from 2.440 (2) to 2. 504 (4) A and the O-H.O angles lie between 161 and 163 degrees. An interpretation of the relationship between the unusual intramolecular bond lengths and the very short intermolecular hydrogen bonds has been developed based on database analysis and computational modelling. In each of (3)-(5) there is an extensive network of intermolecular hydrogen bonds, generating three-dimensional frameworks in (3) and (5), and two-dimensional sheets in (4).

Symmetrically 4,6-disubstituted 2-aminopyrimidines and 2-amino-5-nitrosopyrimidines: interplay of molecular, molecular-electronic and supramolecular structures.

The structures of six symmetrically 4,6-disubstituted 2-aminopyrimidines, four of them containing a 5-nitroso substituent, have been determined. The nitroso compounds, in particular, exhibit polarized molecular-electronic structures leading to extensive charge-assisted hydrogen bonding. The intermolecular interactions observed include hard hydrogen bonds of N-H...N and N-H...O types together with O-H...O and O-H...N types in 2-amino-4,6-bis(2-hydroxyethylamino)-5-nitrosopyrimidine; soft hydrogen bonds of the C-H...O type in both 2-amino-4,6-bis(morpholino)-5-nitrosopyrimidine (3) and 2-amino-4,6-bis(benzylamino)-5-nitrosopyrimidine (4), and of the C-H...pi(arene) type in both 2-amino-4,6-bis(piperidino)pyrimidine (1) and 2-amino-5-nitroso-4,6-bis(3-pyridylmethoxy)pyrimidine (5); and aromatic pi...pi stacking interactions in 2-amino-5-nitroso-4,6-bis(3-pyridylmethoxy)pyrimidine. The supramolecular structures formed by the hard hydrogen bonds are finite, zero-dimensional in (1), one-dimensional in 2-amino-4,6-bis(3-pyridylmethoxy)pyrimidine (2), two-dimensional in both (3) and (4), and three-dimensional in both (5) and 2-amino-4,6-bis(2-hydroxyethylamino)-5-nitrosopyrimidine.

Pteridine Nucleosides—New Versatile Building Blocks in Oligonucleotide Synthesis

Abstract Chemical syntheses of 1-(2-deoxy-β-D-ribofuranosyl)lumazines and isopterins as well as 8-(2-deoxy-β-D-ribofuranosyl)-4-amino-7(8H)pteridones and -isoxanthopterins have been developed to make the structural analogs of the naturally occurring 2′-deoxyribonucleosides in the pteridine series available. The corresponding phosphoramidites have been used in machine-aided solid-support syntheses leading to new types of fluorescence labeled oligonucleotides. The effects of the various fluorophors on duplex formation and as labels for enzyme reactions is demonstrated.

Anion Complexes with Tetrazine-Based Ligands: Formation of Strong Anion−π Interactions in Solution and in the Solid State

Ligands L1 and L2, consisting of a tetrazine ring decorated with two morpholine pendants of different lengths, show peculiar anion-binding behaviors. In several cases, even the neutral ligands, in addition to their protonated HL(+) and H2L(2+) (L = L1 and L2) forms, bind anions such as F(-), NO3(-), PF6(-), ClO4(-), and SO4(2-) to form stable complexes in water. The crystal structures of H2L1(PF6)2·2H2O, H2L1(ClO4)2·2H2O, H2L2(NO3)2, H2L2(PF6)2·H2O, and H2L2(ClO4)2·H2O show that anion-π interactions are pivotal for the formation of these complexes, although other weak forces may contribute to their stability. Complex stability constants were determined by means of potentiometric titration in aqueous solution at 298.1 K, while dissection of the free-energy change of association (ΔG°) into its enthalpic (ΔH°) and entropic (TΔS°) components was accomplished by means of isothermal titration calorimetry measurements. Stability constants are poorly regulated by anion-ligand charge-charge attraction. Thermodynamic data show that the formation of complexes with neutral ligands, which are principally stabilized by anion-π interactions, is enthalpically favorable (-ΔG°, 11.1-17.5 kJ/mol; ΔH°, -2.3 to -0.5 kJ/mol; TΔS°, 9.0-17.0 kJ/mol), while for charged ligands, enthalpy changes are mostly unfavorable. Complexation reactions are invariably promoted by large and favorable entropic contributions. The importance of desolvation phenomena manifested by such thermodynamic data was confirmed by the hydrodynamic results obtained by means of diffusion NMR spectroscopy. In the case of L2, complexation equilibria were also studied in a 80:20 (v/v) water/ethanol mixture. In this mixed solvent of lower dielectric constant than water, the stability of anion complexes decreases, relative to water. Solvation effects, mostly involving the ligand, are thought to be responsible for this peculiar behavior.

Supramolecular structures of N4-substituted 2,4-diamino-6-benzyloxy-5-nitrosopyrimidines

The molecular and supramolecular structures of eight N(4)-substituted 2,4-diamino-6-benzyloxy-5-nitrosopyrimidines are discussed, along with one analogue containing no nitroso substituent. The nitroso derivatives all exhibit polarized molecular-electronic structures leading to extensive charge-assisted hydrogen bonding between the molecules. The intermolecular interactions include hard hydrogen bonds of N-H...O and N-H...N types, together with O-H...O and O-H...N types in the monohydrate of 2-amino-6-benzyloxy-4-piperidino-5-nitrosopyrimidine, soft hydrogen bonds of C-H...O, C-H...pi(arene) and N-H...pi(arene) types and aromatic pi...pi stacking interactions. The predominant supramolecular structure types take the form of chains and sheets, but no two of the structures determined here exhibit the same combination of hydrogen-bond types.

Hydro­gen bonding in 2-amino-4-methoxy-6-methyl­pyrimidine, 2-benzyl­amino-4-benzyl­oxy-6-methyl­pyrimidine and 4-benzyl­amino-2,6-bis­(benzyl­oxy)­pyrimidine: π-stacked chains of fused R22(8) rings, and centrosymmetric R22(8) dimers

Molecules of 2-amino-4-methoxy-6-methylpyrimidine, C(6)H(9)N(3)O, (I), lie on mirror planes in space group Pnma and are linked by two N-H...N hydrogen bonds [H...N = 2.26 and 2.34 A, N...N = 3.136 (2) and 3.212 (2) A, and N-H...N = 175 and 172 degrees ] into chains of edge-fused R(2)(2)(8) rings, which themselves are linked into sheets by aromatic pi-pi-stacking interactions. In 2-benzylamino-4-benzyloxy-6-methylpyrimidine, C(19)H(19)N(3)O, (II), and 4-benzylamino-2,6-bis(benzyloxy)pyrimidine, C(25)H(23)N(3)O(2), (III), the molecules are linked by paired N-H.N hydrogen bonds [H...N = 2.16 A, N.N = 3.039 (2) A and N-H...N = 165 degrees in (II); H...N = 2.15 A, N...N = 2.980 (2) A and N-H...N = 176 degrees in (III)] into centrosymmetric R(2)(2)(8) dimers, with no direction-specific interactions between these dimeric units.

Structure–activity relationship study of nitrosopyrimidines acting as antifungal agents

The design, synthesis, in vitro evaluation, and conformational study of nitrosopyrimidine derivatives acting as antifungal agents are reported. Different compounds structurally related with 4,6-bis(alkyl or arylamino)-5-nitrosopyrimidines were evaluated. Some of these nitrosopyrimidines have displayed a significant antifungal activity against human pathogenic strains. In this paper, we report a new group of nitrosopyrimidines acting as antifungal agents. Among them, compounds 2a, 2b and 15, the latter obtained from a molecular modeling study, exhibited antifungal activity against Candida albicans, Candida tropicalis and Cryptococcus neoformans. We have performed a conformational and electronic analysis on these compounds by using quantum mechanics calculations in conjunction with Molecular Electrostatic Potentials (MEP) obtained from B3LYP/6-31G(d) calculations. Our experimental and theoretical results have led us to identify a topographical template which may provide a guide for the design of new nitrosopyrimidines with antifungal effects.

Nitro-linolenic acid is a nitric oxide donor

Nitro-fatty acids (NO2-FAs), which are the result of the interaction between reactive nitrogen species (RNS) and non-saturated fatty acids, constitute a new research area in plant systems, and their study has significantly increased. Very recently, the endogenous presence of nitro-linolenic acid (NO2-Ln) has been reported in the model plant Arabidopsis thaliana. In this regard, the signaling role of this molecule has been shown to be key in setting up a defense mechanism by inducing the chaperone network in plants. Here, we report on the ability of NO2-Ln to release nitric oxide (NO) in an aqueous medium with several approaches, such as by a spectrofluorometric probe with DAF-2, the oxyhemoglobin oxidation method, ozone chemiluminescence, and also by confocal laser scanning microscopy in Arabidopsis cell cultures. Jointly, this ability gives NO2-Ln the potential to act as a signaling molecule by the direct release of NO, due to its capacity to induce different changes mediated by NO or NO-related molecules such as nitration and S-nitrosylation or by the electrophilic capacity of these molecules through a nitroalkylation mechanism.

A theoretical investigation on the reactivity of 6-amino-3-methylpyrimidin-4(3H)-ones towards DMAD. Tandem Diels-Alder retro Diels-Alder (DA/RDA) reaction

Abstract The reactivity of 6-aminopyrimidin-4(3H)-ones towards DMAD is successfully explained by theoretical investigation (PM3 semiempirical methods). All the PM3 results (activation energies (AE) for the transition states and the heat of formation ( ΔH ) for the products) support our previous experimental work [J. Cobo et all. Synlett. 1993 , 4 , 297–299; Tetrahedron 1994 , 50 , 10345–10354]. In those reactions two main products were obtained: the pyridine derivatives 5 as major ones, which are formed by a tandem DA/RDA reaction with extrusion of the methylisocyanate fragment; and 5-ethenylpyrimidin-4(3H)-ones 10 as minor ones, which arised from a Michael addition, being in competition with the above normal DA.