Competing intermolecular interactions in some 'bridge-flipped' isomeric phenylhydrazones.

To examine the roles of competing intermolecular interactions in differentiating the molecular packing arrangements of some isomeric phenylhydrazones from each other, the crystal structures of five nitrile-halogen substituted phenylhydrazones and two nitro-halogen substituted phenylhydrazones have been determined and are described here: (E)-4-cyanobenzaldehyde 4-chlorophenylhydrazone, C(14)H(10)ClN(3), (Ia); (E)-4-cyanobenzaldehyde 4-bromophenylhydrazone, C(14)H(10)BrN(3), (Ib); (E)-4-cyanobenzaldehyde 4-iodophenylhydrazone, C(14)H(10)IN(3), (Ic); (E)-4-bromobenzaldehyde 4-cyanophenylhydrazone, C(14)H(10)BrN(3), (IIb); (E)-4-iodobenzaldehyde 4-cyanophenylhydrazone, C(14)H(10)IN(3), (IIc); (E)-4-chlorobenzaldehyde 4-nitrophenylhydrazone, C(13)H(10)ClN(3)O(2), (III); and (E)-4-nitrobenzaldehyde 4-chlorophenylhydrazone, C(13)H(10)ClN(3)O(2), (IV). Both (Ia) and (Ib) are disordered (less than 7% of the molecules have the minor orientation in each structure). Pairs (Ia)/(Ib) and (IIb)/(IIc), related by a halogen exchange, are isomorphous, but none of the 'bridge-flipped' isomeric pairs, viz.

Intermolecular C-F...H-C contacts in the molecular packing of three isostructural N-(fluorophenyl)mannopyranosylamines.

Among the three compounds reported here, namely N-(4-fluorophenyl)-β-D-mannopyranosylamine, (I), N-(3-fluorophenyl)-β-D-mannopyranosylamine, (II), and N-(2-fluorophenyl)-β-D-mannopyranosylamine, (III), all with chemical formula C(12)H(16)FNO(5), (I) and (II) are isostructural, whereas (III) assumes the same packing arrangement as the unfluorinated analogue N-phenyl-β-D-mannopyranosylamine, (IV), which has been reported previously. Similarities with respect to the intermolecular hydrogen-bonding patterns exist across the series (I)-(III). A packing motif that distinguishes the shared packing arrangement of (I) and (II) from that of (III) is a C-F.

4-(4-Chlorobenzylidenehydrazonomethyl)benzonitrile and the bromo and iodo analogs.

4-Cyano-4'-chlorobenzalazine [systematic name: 4-(4-chlorobenzylidenehydrazonomethyl)benzonitrile], C(15)H(10)ClN(3), occurs in two polymorphs. Polymorph A is isostructural with the corresponding dichloro compound. Polymorph B is isostructural with the bromo and iodo analogs, viz.

Isostructuralism among bridge-flipped' isomeric benzylideneanilines and phenylhydrazones.

Bridge-flipped' isomers may be defined as pairs of molecules related by a reversal of a bridge of atoms connecting two major parts of the individual molecules. This kind of isomerism is commonly found among benzylideneanilines and phenylhydrazones. Isostructural pairs might be suitable for co-crystallization and are thus useful in the preparation of new solid materials.

Isomeric Schiff bases related by dual imino-group reversals.

Two isomeric pairs of Schiff bases, N,N'-bis(2-methoxybenzylidene)-p-phenylenediamine, C(22)H(20)N(2)O(2), (I), and 2,2'-dimethoxy-N,N-(p-phenylenedimethylene)dianiline, C(22)H(20)N(2)O(2), (II), and (E,E)-1,4-bis(3-iodophenyl)-2,3-diazabuta-1,3-diene (alternative name: 3-iodobenzaldehyde azine), C(14)H(10)I(2)N(2), (III), and N,N'-bis(3-iodophenyl)ethylenediimine, C(14)H(10)I(2)N(2) [JAYFEV; Cho, Moore & Wilson (2005). Acta Cryst. E61, o3773-o3774], differ pairwise only in the orientation of their imino linkages and in all four individual cases occupy inversion centers in the crystal, yet all four compounds are found to assume unique packing arrangements.

The saccharide-hydrazide linkage: molecular and crystal structures of the semicarbazide derivatives of D-glucose, D-galactose, and D-xylose, including a 'forbidden' conformation of the galactose derivative.

The X-ray crystal structures of the semicarbazide derivatives of D-glucose, D-galactose, and D-xylose are described. All are glycopyranosyl derivatives in the solid state. The glucose semicarbazide crystallizes as a dihydrate.

Molecular modeling study of chiral drug crystals: lattice energy calculations.

The lattice energies of a number of chiral drugs with known crystal structures were calculated using Dreiding II force field. The lattice energies, including van der Waals, Coulombic, and hydrogen-bonding energies, of homochiral and racemic crystals of some ephedrine derivatives and of several other chiral drugs, are compared. The calculated energies are correlated with experimental data to probe the underlying intermolecular forces responsible for the formation of racemic species, racemic conglomerates, or racemic compounds, termed chiral discrimination.

Molecular and crystal structures of N-aryl-beta-D-glycopyranosylamines from mannose and galactose.

The molecular and crystal structures of 12 N-aryl-beta-D-glycopyranosylamines have been determined by X-ray crystallography. Six of these are mannose derivatives, the N-p-bromophenyl (1), N-p-tolyl (2), N-m-chlorophenyl (3), N-p-methoxyphenyl (4), N-o-chlorophenyl (5), and N-o-tolyl (6) derivatives that are formed by reaction with the corresponding substituted anilines. The remaining six are galactose derivatives, the N-phenyl (7), N-p-chlorophenyl (8), N-p-bromophenyl (9), N-p-iodophenyl (10), N-p-nitrophenyl (11) and N-p-tolyl (12), derivatives prepared similarly.

Molecular and crystal structures of N-arylglycopyranosylamines formed by reaction between sulfanilamide and D-ribose, D-arabinose and D-mannose.

The X-ray crystal structures of three monosaccharide derivatives prepared by the reaction of sulfanilamide with D-ribose, D-arabinose, and D-mannose have been determined. The derivatives are N-(p-sulfamoylphenyl)-alpha-D-ribopyranosylamine (1), N-(p-sulfamoylphenyl)-alpha-D-arabinopyranosylamine (2), and N-(p-sulfamoylphenyl)-beta-D-mannopyranosylamine monohydrate (3). The monosaccharide ring of 1 and 2 has the 1C4 conformation, stabilized in 1 by an intramolecular hydrogen bond from 0-2 to 0-4.

Packing similarities of three isosteric molecules: 4,5-dichlorophthalic anhydride, 4,5-dibromophthalic anhydride and 5,6-dichlorobenzfurazan 1-oxide, including three polymorphs of 5,6-dichlorobenzfurazan 1-oxide.

4,5-Dichlorophthalic anhydride (CPA) lies on a twofold axis in space group C2/c; the molecules pack as stacks of two-dimensional sheets. Polymorph A of 5,6-dichlorobenzfurazan 1-oxide (CBF; systematic name 5,6-dichloro-2,1,3-benzoxadiazole 1-oxide) is isomorphous with CPA with disordered CBF molecules being pseudo-isosteric with the CPA molecule. Polymorph C of CBF has similar unit-cell dimensions but the arrangement of the molecules in the cell is different.

Schiff bases or glycosylamines: crystal and molecular structures of four derivatives of D-mannose.

Crystal and molecular structures of four derivatives of D-mannose are described. Each could exist as either an open-chain Schiff base or as a glycosylamine in the solid state. The derivative formed upon reaction of D-mannose with hydroxylamine is an open-chain oxime, but those formed upon reaction with semicarbazide, aniline, and p-chloroaniline are glycosylamines.

Synthesis and dopamine receptor modulating activity of unsubstituted and substituted triproline analogues of L-prolyl-L-leucyl-glycinamide (PLG).

Triprolines Pro-Pro-Pro-NH2 (4), Pro-Pro-D-Pro-NH2 (5), Pro-Pro(trans-3-Me)-D-Pro-NH2 (6), and Pro-Pro(cis-3-Me)-D-Pro-NH2 (7) were made as conformationally constrained analogues of Pro-Leu-Gly-NH2. Triprolines 4-6 produced significant increases in the high- and low-affinity state ratio (RH/RL) of the dopamine receptor, but only 4 was found to increase apomorphine induced rotations in 6-hydroxydopamine-lesioned rats.

Synthesis and dopamine receptor modulating activity of substituted bicyclic thiazolidine lactam peptidomimetics of L-prolyl-L-leucyl-glycinamide.

6-Substituted bicyclic thiazolidine lactam peptidomimetics of Pro-Leu-Gly-NH(2) (1) were synthesized to test the hypothesis that incorporation of a hydrophobic side chain into the bicyclic thiazolidine lactam scaffold would further enhance the dopamine receptor modulating activity of such peptidomimetics. The substituents employed were the isobutyl, butyl, and benzyl groups to give peptidomimetics 3-5, respectively. These peptidomimetics were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism and were compared with the unsubstituted bicyclic thiazolidine lactam Pro-Leu-Gly-NH(2) peptidomimetic 2.

Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring alpha,alpha-disubstituted amino acids.

In the present study, L-prolyl-L-leucyl-glycinamide (1) peptidomimetics 3a-3d and 4a-4d were synthesized utilizing alpha, alpha-disubstituted amino acids. These analogues were designed to explore the conformational effects of constraints at the phi3 and psi3 torsion angles. Constrained conformations were verified by the use of X-ray crystallography and circular dichroism.

Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide.

In the present study, the synthesis of the 5.5.6.

Design, synthesis, and dopamine receptor modulating activity of diketopiperazine peptidomimetics of L-prolyl-L-leucylglycinamide.

The diketopiperazine "C5" conformational mimic has been incorporated into the L-prolyl-L-leucylglycinamide (PLG, 1) structure and into the bicyclic lactam PLG peptidomimetic structure 3 to give compounds 5 and 6, respectively. These analogues were designed to explore the idea that the N-terminal "C5" conformation, which was found in the crystal structure of 2 and which was mimicked in 4 by the diketopiperazine function, was a factor in the high potency of these two agents. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) D2 receptor competitive binding assay, both 5 and 6 were found to increase the affinity of the dopamine receptor for agonists and both were found to increase the percentage of D2 receptors which existed in the high-affinity state.

6 beta-Propynyl-substituted steroids: mechanism-based enzyme-activated irreversible inhibitors of aromatase.

The synthesis and aromatase inhibitory profile of 6 alpha and 6 beta-propargyl androstenedione and estrenedione are described. The targeted compounds 1 and 2 were prepared by addition of the propargyl Gringard to the 5 alpha,6 alpha-epoxy bisketal 6 or the 5 alpha,6 alpha-epoxy diacetate 7 followed by dehydration of the 6 beta-propargyl 5 alpha-hydroxy diones 10 and 11 using thionyl chloride. Treatment of the 6 beta-propargyl analogs 1 and 2 with hydrochloric acid gave the corresponding 6 alpha-propargyl isomers 3 and 4.

Conformational analysis of homochiral and heterochiral diprolines as beta-turn-forming peptidomimetics: unsubstituted and substituted models.

The effect of replacing one of the proline residues in either unsubstituted homochiral or heterochiral diproline segments with either a 2- or a 3-substituted prolyl residue on the allowed conformational of the diproline template has been examined. In heterochiral (L-D) diprolines, placement of a 2-methyl-D-proline residue in the i + 2 position and placement of either a cis- or trans-3-methyl-L-proline residue in the i + 1 position results in substituted diproline peptides that adopt the same type II beta-turn conformation as that defined experimentally for the unsubstituted diproline peptides. In contrast, placement of a cis-3-methyl-D-proline residue in the i + 1 position of a homochiral (D-D) diproline peptide seems to promote a different conformation than that seen in the unsubstituted case, whereas the trans-3-methyl-D-proline residue seems to provide a stabilizing influence for the predicted type VI' beta-turn.

Heterocyclic N-acetoxyarylamines, models for the putative ultimate carcinogens of aromatic amines: 2-acetoxyamino-5-phenylpyridine and 2-acetoxyaminopyridine.

The structures of O-acetyl-N-(5-phenyl-2-pyridyl)-hydroxylamine, C13H12N2O2, (I), and O-acetyl-N-(2-pyridyl)hydroxylamine, C7H8N2O2. (II), have been determined in order to confirm earlier structure assignments based on spectroscopic information. Compound (I) is the probable mutagenic metabolite of the phenylalanine pyrolysis product 2-amino-5-phenyl-pyridine.

Oxidative transformation of 2-hydroxyestrone. Stability and reactivity of 2,3-estrone quinone and its relationship to estrogen carcinogenicity.

The carcinogenicity of estrogens in rodents and man has been attributed to either alkylation of cellular macromolecules and/or redox-cycling, generation of active radicals, and DNA damage. Metabolic activation of estradiol leading to the formation of catechol estrogens is believed to be a prerequisite for its genotoxic effects. 4-Hydroxyestradiol, although not 2-hydroxyestradiol, is a potent inducer of tumors in hamsters.

Opioid antagonist activity of naltrexone-derived bivalent ligands: importance of a properly oriented molecular scaffold to guide "address" recognition at kappa opioid receptors.

The presence of a molecular scaffold to orient a basic group is important for potent and selective kappa opioid antagonist selectivity. An attempt to determine how the geometry of the scaffold affects this selectivity has led to the synthesis of a bivalent ligand (5) whose linker constrains the N17' basic nitrogen (the "address") to a position that is 6.5 A from N17' in the kappa antagonist norBNI (1) when these molecules are superimposed.

Reactions of 3,4-estrone quinone with mimics of amino acid side chains.

Reaction of 3,4-estrone o-quinone (3,4-EQ) with several amino acid side chain mimics, including 4-ethylphenol, 4-methylimidazole, acetic acid, and propanethiol, gave a mixture of several products including the catechol, Michael addition products, and dimeric products of the catechol. On the other hand, several other amino acid side chain mimics, including ethanol, acetamide, 1-ethylguanidine, and 3-methylindole, did not result in any addition products or catechol formation. Michael addition to 3,4-EQ with 4-methylimidazole, acetate, and 4-ethyl phenoxide resulted in 1,4-addition, leading to C-1 adducts while reaction with propanethiol gave the C-2 addition product.

Relationships between crystal structures, thermal properties, and solvate stability of dialkylhydroxypyridones and their formic acid solvates.

Four 1,2-dialkyl-3-hydroxy-4-pyridones (DAHPs), which are iron chelators potentially suitable for oral administration, and their formic acid solvates (DAHP-Fs) were examined in powder form by powder X-ray diffraction (PXD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and hot-stage microscopy (HSM). The experimental PXD pattern of each DAHP-F is different from that of the corresponding DAHP, indicating different crystalline phases. The PXD patterns calculated from the published crystal structures closely resemble the corresponding PXD patterns determined experimentally, indicating that the powdered materials studied are structurally identical with the single crystals previously examined.

kappa Opioid receptor selective affinity labels: electrophilic benzeneacetamides as kappa-selective opioid antagonists.

2-(3,4-Dichlorophenyl)-N-methyl-N-[1-(3- or 4-substituted phenyl)-2-(1-pyrrolidinyl)ethyl]-acetamides 3-6 were synthesized as kappa-selective affinity labels and evaluated for opioid activity. In smooth muscle preparations, the non-electrophilic parent compound (+)-S-2 and the affinity labels 3-6 behaved as kappa agonists in that they were potently antagonized by norbinaltorphimine (norBNI). In addition to the high binding affinity and selectivity of the 3-isothiocyanate 3 (DIPPA) to kappa opioid receptors, wash studies have suggested that this involves covalent binding.

Design, synthesis, X-ray analysis, and dopamine receptor-modulating activity of mimics of the "C5" hydrogen-bonded conformation in the peptidomimetic 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1- pyrrolidineacetamide.

3(R)-(7a(S)-Hexahydro-1-oxo-3,3-dimethyl-1H-pyrrolo[1,2-c]imidazol-2-yl) - oxo-1-pyrrolidine-acetamide (2) and 3(R)-[1-(2,5-dioxopyrrolidino[3,4-c]piperazino)]-2-oxo-1- pyrrolidineacetamide (3) were designed and prepared as mimics of the "C5" hydrogen-bonded structure found in the crystal structure of 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1- pyrrolidineacetamide (1). Both compounds effectively restrict the psi 1 torsional angle to very near the value found in the X-ray structure of 1 as seen in the X-ray crystallographic determination of 2 and methyl 3(R)-[1-(2,5-dioxopyrrolidino[3,4-c]piperazino)]-2-oxo-1- pyrrolidineacetate (11), a diketopiperazine intermediate in the synthesis of 3. These analogs were tested for their ability to enhance the binding of the dopamine D2 receptor agonist N-propylnorapomorphine (NPA) in the absence and presence of 5'-guanylylimidodiphosphate (Gpp(NH)p).