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The title compound, C(9)H(19)N(3)O.C(4)H(7)NO(2), displays strong intramolecular O-H...N [O...N 2.6743 (13) A] and N-H...N [N...N 2.6791 (15) A] hydrogen bonds, and strong intermolecular O-H...N [O...N 2.7949 (15) A] and N-H...O [N...O 3.0924 (16) A] hydrogen bonds. This creates chains of perhydropyrimidine molecules, linked by hydrogen bonds. Each chain is linked to a partner chain, through hydrogen bonds to two butane-2,3-dione monooxime molecules, in a structure reminiscent of a ladder.

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The dissolution of calcite (CaCO3) in aqueous solution at pH below ca. 5-6 is known to proceed via the direct reaction of protons at the solid surface. However, exposure of the mineral to sulfuric acid is shown to lead to the rapid formation of an overlayer of calcium sulfate (gypsum) which completely passivates the surface against further reaction and dissolution. The overlayer is nucleated instantaneously on CaCO3 surfaces. Scanning electron and atomic force microscopy show that strongly adherent overgrowths are encouraged by a lattice matching between the cleavage (211) plane of calcite and the (010) plane of CaSO4·2H2O.

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The molecular geometry of benzo[a]pyrene, its 4-methyl-and 3,11-dimethyl derivatives, benzo[e]pyrene, and two azabenzo[a]pyrenes are described. Results of these three-dimensional crystal structure determinations, together with those from previous studies in this laboratory of 11-methylbenzo[a]pyrene, indicate the extent to which nonbonded interactions between hydrogen atoms contribute to molecular distortions, particularly in the bay-region. This strain is high if a bay-region methyl group is present. The major effect is an increase in the C-C-C angles in that area of the molecule, rather than torsion about bonds. In addition, the effect of a nitrogen atom replacing one of the C-H groups in the aromatic system is shown. Molecules stack in planes approximately 3.5 A apart. In benzo[a]pyrene, 5-azabenzo[a]pyrene and 3,11-dimethylbenzo[a]pyrene crystals the stacking is similar to that in graphite. 4-Methylbenzo[a]pyrene molecules stack with less molecular overlap. The packing in 4-aza-5-methylbenzo[a]pyrene consists of modules of four stacked molecules, packed in a 'tile-like' arrangement. Nonbonded C....H interactions between adjacent molecules lead to a herring-bone arrangement between these stacks. The types of C....H and pi-pi interactions involving PAHs in the crystalline state, described here, can also be expected to be found when the PAHs bind to hydrophobic areas of biological macromolecules such as proteins, nucleic acids and membranes.

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The crystal and molecular structures of ten compounds with strong structural resemblances to the cimetidine group of histamine H2-receptor antagonists, but exhibiting selective H1-receptor antagonist activity, (1)-(7), or H1 and H2 activity (8)-(10), have been determined: (1) 2-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-5- (6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrobromide (temalastine), C21H27BrN5O3+.3Br-, M(r) = 685.09, triclinic, P1, a = 6.314 (2), b = 11.192 (2), c = 19.441 (5) A, alpha = 102.47 (2), beta = 92.77 (2), gamma = 103.28 (2) degrees, V = 1298.51 A3, Z = 2, Dx = 1.75 g cm-3, mu = 61.6 cm-1, F(000) = 672, R = 2.93% for 3208 independent reflexions. (2) 2-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4-pyrimidone, C14H19BrN4O2, M(r) = 355.23, monoclinic, I2/a, a = 16.359 (3), b = 10.469 (6), c = 18.339 (4) A, beta = 90.90 (2) degrees, V = 3140.49 A3, Z = 8, Dx = 1.503 g cm-3, mu = 26.0 cm-1, F(000) = 1176, R = 4.2% for 1872 independent reflexions. (3) 3-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4- amino-1,2,5-thiadiazole-1-oxide, C12H16BrN5OS, M(r) = 358.26, triclinic, P1, a = 14.295 (2), b = 12.447 (2), c = 9.917 (2) A, alpha = 95.77 (2), beta = 113.86 (2), gamma = 106.91 (1) degrees, V = 1495.18 A3, Z = 4, Dx = 1.59 g cm-3, mu = 50.96 cm-1, F(000) = 728, R = 5.98% for 5674 independent reflexions. (4) 3-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4- benzylamino-1,2,5-thiadiazole-1-oxide, C19H22BrN5OS, M(r) = 448.38, monoclinic, P2(1)/c, a = 36.293 (7), b = 4.826 (2), c = 11.528 (3) A, beta = 96.91 (2) degrees, V = 2004.27 A3, Z = 4, Dx = 1.49 g cm-3, mu = 39.2 cm-1, F(000) = 920, R = 12.1% for 1945 independent reflexions. (5) 2-[3-(N-Benzyl-N-2- pyridylamino)propylamino]-4-pyrimidone, C19H21N5O, M(r) = 335.4, orthorhombic, Pbna, a = 7.082 (1), b = 19.889 (3), c = 24.899 (3) A, V = 3507.16 A3, Z = 8, Dx = 1.27 g cm-3, mu = 6.24 cm-1, F(000) = 1424, R = 4.05% from 2470 independent reflexions. (6) 3-[3-(N-4-Fluorobenzyl-N-2- pyridylamino)propylamino]-4-ethylamino-1,2,5-thiadiazole-1-oxide, C19H23FN6OS, M(r) = 402.5, monoclinic, P2(1)/n, a = 6.686 (2), b = 14.717 (3), c = 20.850 (5) A, beta = 97.83 (2) degrees, V = 2032.47 A3, Z = 4, Dx = 1.32 g cm-3, mu = 16.41 cm-1, F(000) = 848, R = 8.5% from 2484 independent reflexions. (7) 5-(6-Methyl-3-pyridylmethyl)-2-[3-(5,6,7,8-tetrahydro-8- quinolyl)propylamino]-4-pyrimidone, C23H29N5O2, M(r) = 407.5, monoclinic, P2(1)/c, a = 14.966 (2), b = 16.075 (2), c = 9.1608 (9) A, beta = 99.158 (8) degrees, V = 2175.83 A3, Z = 4, Dx = 1.24 g cm-3, mu = 6.19 cm-1; F(000) = 872, R = 5.3% from 2784 independent reflexions. (8) 2-(4-Phenylbutylamino)-5-(3-pyridyl-methyl)-4-pyrimidone, C20H26N4O3, M(r) = 370.5, monoclinic, P2(1)/c, a = 8.040 (4), b = 21.279 (4), c = 11.404 (2) A, beta = 92.08 (5) degrees, V = 1949.68 A3, Z = 4, Dx = 1.26 g cm-3, mu = 0.93 cm-1, F(000) = 792, R = 4.05% from 3816 independent reflexions.(ABSTRACT TRUNCATED AT 400 WORDS)

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The crystal and molecular structures of 11 6-substituted pyridazinone derivatives: 6-phenyl-3(2H)-pyridazinone-acetic acid (1/1) (1), 6-(4-aminophenyl)- 3(2H)-pyridazinone (2), 6-(4-aminophenyl)- 5-methyl-3(2H)-pyridazinone (3), 6-(4-acetamidophenyl)- 3(2H)-pyridazinone (4), 6-(4-acetamido-2- methoxyphenyl)-3(2H)-pyridazinone (5), 6-(2-aminophenyl)-3(2H)- pyridazinone (6), 6-phenyl-3(2H)- pyrazinone (7), 6-(4-aminophenyl)-4,5-dihydro- 3(2H)-pyridazinone (8), (R)-(-)-6[4-(3-bromopropionamido)phenyl]- 4,5-dihydro-5-methyl-3(2H)-pyridazinone (9), (R)-(-)-6-(4-ammoniophenyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (-)-tartrate-dichloromethane-methanol (1/1/1) (10), 4,5-dihydro-6-methyl-3(2H)-pyridazinone (11) have been determined as part of a study to determine the relationship between their cardiovascular properties and molecular structure and dimensions. For the two optically resolved chiral derivatives (9) and (10) the absolute configuration has been determined.

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Prizidilol, a compound combining vasodilator and beta-blocker functionalities in the same molecule, has been synthesized and characterized by Smith Kline and French Research Ltd. Crystal data: C17H25N5O2 x 1/2H2SO4 x H2O, M(r) = 398.47, orthorhombic, a = 10.722 (2), b = 11.635 (6), c = 34.105 (3) A, V = 4254.61 A3, Pbnm (non-standard form of Pnma) (D16(2h), No. 62), Z = 8, F(000) = 1704, Dx = 1.244 Mg m-3, mu(Cu K alpha) = 11.673 cm-1, R = 0.064 for 2432 independent reflections with I > 3 sigma(I). Prizidilol shows strong conformational similarities to propranolol and is protonated at the secondary amine. The 6-phenyl-3-hydrazinopyridazine residue is not planar. The hydroxy group at the asymmetric carbon is disordered so that both enantiomers are found at each molecular site. The sulfate ions and disordered water molecules lie in the crystallographic mirror plane.

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An oxidant burden established by hydrogen peroxide (H2O2) overload may elicit postischemic myocardial damage. We assess herein the influence of H2O2-induced oxidative stress on heart muscle pyridine nucleotide metabolism. Exposure of neonatal rat cardiomyocytes to 50 microM-1.0 mM H2O2 bolus rapidly shifted their pyridine-nucleotide redox balance toward oxidation. At least 30% of the observed NADPH oxidation was independent of glutathione cycle activity and appeared chemical in nature with H2O2 itself, and not a radical metabolite, acting as oxidant. Cell exposure to H2O2 also depleted cardiomyocyte pyridine nucleotides as a consequence of enhanced utilization. The oxidative stress activated one major route of pyridine nucleotide catabolism (i.e., protein ADP-ribosylation) without acute inhibitory effect upon the other (cleavage by NAD glycohydrolase). The limited NAD sparing by metal chelators and inhibitors of ADP-ribosylation reflected pyridine nucleotide utilization for repair of single-strand DNA breaks caused by hydroxyl-like radicals formed intracellularly through iron-dependent H2O2 reduction. Cardiomyocyte NAD depletion during H2O2-induced oxidative stress was independent of cell integrity and lipid peroxidation. The NAD lost after a discrete H2O2 "pulse" was only partly replenished over a 24-h postinjury period. These data demonstrate that cardiomyocyte pyridine nucleotide metabolism is a nonperoxidative injury target that is chronically affected by H2O2 overload. Derangement of myocardial pyridine nucleotide pools due to oxidative stress may contribute to ischemic heart injury in vivo by interfering with cardiac hydrogen metabolism and redox balance.

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Substitution of a methyl group in the 11-position of benzo[a]pyrene (B[a]P) enhances its carcinogenicity. An X-ray crystallographic determination of the three-dimensional structure of 11-methylbenzo[a]pyrene (11-MeB[a]P) shows that steric overcrowding in the bay region is relieved somewhat by distortions of the bay-region bond angles in the plane of the ring system. A comparison with the structure of 7,12-dimethylbenz[a]anthracene (DMBA), which shows out-of-plane distortions to relieve such strain, shows that, in general, H...H intramolecular interactions between neighboring rings in a polycyclic aromatic hydrocarbon are the primary determinants of the nature of the molecular distortions as a result of steric overcrowding (mainly in-plane for 11-MeB[a]P and mainly out-of-plane for DMBA). The 11-MeB[a]P molecule exhibits considerable flexibility as evidenced by slightly different conformations in the two molecules found in the asymmetric unit of the crystal. One molecule is fairly flat with bond angle distortions in the bay region, while the other is slightly buckled as a result of some twist (15 degrees) in the bay region. Computer modeling indicates that steric overcrowding as a result of the bay-region 11-methyl group may affect the conformation of the ring that bears the diol and epoxide groups in the anti-diolepoxide. The nature of this distortion may, in turn, provide a clue to the reason for the greater carcinogenicity of B[a]P when methylated at the 11-position in the non-benzo bay region site. In addition, the 11-methyl group, because of its bulk, may affect the orientation of the polycyclic hydrocarbon as it lies between the nucleic-acid bases when covalently bound to DNA.

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The mutagenic and carcinogenic potency of 5-methylchrysene contrasts strongly with the lack of such activity in any other monomethylchrysene. In order to improve our understanding of the biochemical properties of these compounds, their electronic and molecular structures and pi-pi* electron donor-acceptor complexes have been examined by X-ray diffraction and molecular orbital methods. The crystal structures of the hydrocarbons chrysene (redetermination), 1-methylchrysene and 6-methylchrysene, and of the 1:1 complexes of 1,3,5-trinitrobenzene with chrysene, 2-methylchrysene, 3-methylchrysene, 4-methylchrysene, 5-methylchrysene, 6-methylchrysene, the 2:1 complex with 1-methylchrysene and the 1:1 complex of 5-methylchrysene with pyromellitic dianhydride have been determined. 5-Methylchrysene, the carcinogenic hydrocarbon, shows considerable disorder alone and in complexes. In the complexes the stacking of molecules involves an alternation of hydrocarbon with complexing agent, with the aromatic ring of 1,3,5-trinitrobenzene lying over a hydrocarbon bond involved in ring fusion, as suggested by a consideration of HOMO's and LUMO's in molecular orbital theory.

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The method of constructing low-energy conformations using template joining can provide an efficient means of searching the conformational space of molecules. The simplest algorithm to perform this task would construct each potential conformation from scratch. However, new algorithms, some of which use techniques from Artificial Intelligence, have been developed which can greatly improve the efficiency of this approach.

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Many methodologies for performing automated conformational analysis require some means of "perceiving" a molecule to determine features of interest. Algorithms for finding rings, bond orders, and stereocenters and detecting the presence of substructural fragments have been developed. These algorithms are described, emphasizing their importance in conformational analysis.

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The results of a wide-ranging investigation into some of the different methods available for performing the 'joining' of templates to build molecular models show that the choice of algorithm can significantly affect the quality of the results obtained, and different algorithms are most suited to particular categories of join.

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A program which utilizes the techniques of Artificial Intelligence and Expert Systems to solve problems in the area of Conformational Analysis is described. The program searches conformational space in a systematic fashion, based on the technique known as heuristic state-space search. The program proceeds by recognizing conformational units, assigning one or more conformational templates to each unit, and joining them to form conformational suggestions. These suggestions are criticized to discover logical inconsistencies, and any resulting stresses are resolved. The resulting conformational suggestions are sometimes accurate enough for immediate use, or may be further refined by a numerical program. The latter combination is shown to be quite efficient compared to purely numerical conformational search techniques.

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