PubMed Health⌕ Search

Biomedical subjects

D E Zacharias

Publications and source records attributed to D E Zacharias.

At least 19 recordsLinked to original sources
PubMed1996

The structure of a coumarin derivative related to the carcinogen benz[a]anthracene.

The three-dimensional structure of 3-methyl-2H-anthra[1,2-b]pyran-2-one, an anticarcinogenic coumarin related to the carcinogen benz[a]anthracene, has been determined by X-ray diffraction techniques. The molecule, apart from hydrogen atoms in the methyl group, is flat, the maximum deviation from its least squares best plane being 0.13 angstroms. The carbonyl C=O bond length is normal [1.206(1) angstroms] and the bonding throughout the molecule indicates localization of double bonds within the coumarin ring, but some delocalization of electrons in the other rings. Molecules pack in planes parallel to each other, the coumarin ring oxygen atom lying between two aromatic rings of other coumarin molecules. The bulky methyl groups are not involved in such stacking, while the carbonyl groups attract C-H groups in neighboring molecules by way of C-H...O interactions. These are the types of interactions that such coumarins could make if they bound to hydrophobic areas in biological macromolecules.

Antineoplastic Agents↗
PubMed1995

4,5-Dihydrobenzo[a]pyrene-4,5-trans-(e,e)-diol.

The title compound, C20H14O2, is a metabolite of the chemical carcinogen benzo[a]pyrene. The crystal structure consists of groups of molecules in each of which both hydroxy groups donate and accept hydrogen bonds. Stacking of dihydrobenzo[a]pyrene ring systems occurs along the crystallographic c axis.

Benzo(a)pyrene↗
PubMed1993

Structure of strontium citrate pentahydrate.

The crystal structure of tristrontium bis(2-hydroxy-1,2,3-propanetricarboxylate) pentahydrate has been determined. One Sr ion is coordinated with eight O atoms, another with nine and the third with ten at distances ranging from 2.498 (2) to 2.781 (2) A. Two Sr ions are bound to citrate ions in a tridentate manner. Both citrate ions in the asymmetric unit are in an extended conformation. There are 11 hydrogen bonds in one asymmetric unit of the crystal structure.

Citrates↗
PubMed1993

Structure of dipotassium hydrogen citrate.

Dipotassium hydrogen 2-hydroxy-1,2,3-propanetricarboxylate is shown by this crystal structure determination to be ionized at the central carboxyl group and one terminal carboxyl group. Each citrate ion forms an intramolecular hydrogen bond as well as an intermolecular hydrogen bond connecting it to an adjacent citrate ion. Each K ion is surrounded by eight O atoms from several citrate ions. The metal-oxygen distances range from 2.706 to 3.136 A.

Citrates↗
PubMed1993

Structure of a citrate double salt: potassium dihydrogen citrate-lithium potassium hydrogen citrate monohydrate.

The crystal structure of a double salt of potassium dihydrogen citrate and lithium potassium hydrogen citrate monohydrate has been determined. One potassium ion is coordinated with eight O atoms and the other with nine O atoms at M--O distances in the range 2.660 (1) to 3.139 (1) A. Two of these O atoms are shared by both potassium ions. The lithium ion is tetrahedrally surrounded by four O atoms at distances in the range 1.870 (3) to 1.988 (3) A. This crystal structure contains nine hydrogen bonds in the asymmetric unit. The water molecule connects different citrate ions along the c direction by hydrogen bonding.

Citrates↗
PubMed1993

Structures of three electron donor-acceptor complexes of dibenz[a,h]anthracene (DBA).

(I) Dibenz[a,h]anthracene-1,3,5-trinitrobenzene (1/2) (DBA-TNB), C22H14.2C6H3N3O6, M(r) = 704.57, monoclinic, P2(1)/a, a = 25.744 (3), b = 7.889 (1), c = 7.442 (1) A, beta = 91.61 (1) degree, V = 1510.8 (4) A3, Z = 2, Dx = 1.549 Mg m-3, lambda(Cu K alpha) = 1.5418 A, mu = 0.978 mm-1, F(000) = 724, T = 293 K, R = 0.043 for 2619 data; (II) dibenz[a,h]-anthracene-pyromellitic dianhydride (1/1) (DBA-PMDA), C22H14.C10H2O6, M(r) = 496.47, monoclinic, P2(1)/n, a = 20.784 (2), b = 7.357 (1), c = 7.524 (1) A, beta = 97.71 (1) degree, V = 1140.0 (3) A3, Z = 2, Dx = 1.45 Mg m-3, lambda(Cu K alpha) = 1.5418 A, mu = 0.783 mm-1, F(000) = 512, T = 293 K, R = 0.042 for 1514 data; (III) dibenz[a,h]anthracene-1,8:4,5-naphthalenetetracarboxylic dianhydride (1/1) (DBA-NTDA), C22H14.C14H4O6, M(r) = 546.54, monoclinic, P2(1)/a, a = 19.991 (4), b = 8.324 (2), c = 7.821 (2) A, beta = 105.06 (2) degrees, V = 1256.8 (5) A3, Z = 2, Dx = 1.444 Mg m-3, lambda(Cu K alpha) = 1.5418 A, mu = 0.765 mm-1, F(000) = 564, T = 293 K, R = 0.050 for 1982 data. The donor DBA molecules, located on symmetry centers, stack alternately with the acceptor molecules. The stacks pack in a herringbone motif along the cell axis.

Benz(a)Anthracenes↗
PubMed1993

Structure of the molecular complex of anthracene with 1,8:4,5-naphthalenetetracarboxylic dianhydride.

C14H10.C14H4O6, M(r) = 446.42, monoclinic, P2(1)/a, a = 17.572 (10), b = 7.727 (4), c = 7.398 (4) A, beta = 101.90 (4) degrees, V = 982.9 (9) A3, Z = 2, Dx = 1.508 Mg m-3, lambda (Mo K alpha) = 0.71069 A, mu = 0.100 mm-1, F(000) = 460, T = 293 K, R = 0.050 for 1429 unique reflections with I > 3 sigma (I). The molecules stack with alternating rows of anthracene and dianhydride molecules. The two types of molecule do not lie parallel to each other in these stacks, possibly as a result of interactions between the peripheral H atoms of the anthracene and O atoms of the anhydride.

Anthracenes↗
PubMed1992

11-Methylbenzo[a]pyrene: bay region distortions.

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.

Benzopyrenes↗
PubMed1992

Molecular conformation of estramustine and two analogues.

The crystal and molecular structures of estramustine and two of its analogues have been determined by X-ray crystallographic techniques (a total of three different compounds). The compounds studied are estramustine [1,3,5(10)-estratriene-3,17 beta-diol-3-N,N-bis(2'- chloroethyl)carbamate] and its monohydrate, estromustine [17-oxo-1,3,5(10)-estratriene-3-yl-N,N-bis(2'-chloroethyl)carbamate], and 17-oxo-5-androsten-3 beta-yl-N,N-bis(2'-chloroethyl)carbamate. Three views of estramustine were obtained from the study of its two crystal forms. The main structural features found are as follows: (a) the geometries of the steroid moieties are closely similar to those of the parent steroids, (b) the bonds around the nitrogen atom of the nitrogen mustard grouping lie approximately in a plane in each structure, (c) the plane through the carbon atoms of the steroid A-ring lies approximately perpendicular to the plane through the carbamate atoms in each structure, (d) the carbonyl C-O of the carbamate points to the alpha side of the steroid moiety in each structure, and (e) one chlorine atom of the nitrogen mustard grouping makes a close contact [3.13 A], in each structure, to the nitrogen atom. Hydrogen bonding to the carbamate appears to occur from the alpha side of the steroid; there is no hydrogen bonding to the nitrogen atom of the carbamate group. These structural data provide some steric explanations for the resistance of the carbamate to enzymatic hydrolysis. The long in vivo half-life of the intact estramustine molecule is a result of this stability. This is responsible for the absence of alkylating ability and the propensity of the drug to bind microtubule-associated proteins and express an antimitotic mechanism of action.

Estramustine↗
PubMed1991

Structure and molecular orbital studies of potentially mutagenic methylchrysenes and their pi-pi* electron donor-acceptor molecular complexes.

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.

Chrysenes↗
PubMed1991

The crystal and molecular structure of ellagic acid dihydrate: a dietary anti-cancer agent.

The crystal and molecular structure of ellagic acid dihydrate has been determined by X-ray diffraction techniques. This acid inhibits the carcinogenic properties of a variety of chemical compounds including benzo[alpha]pyrene-7,8-diol-9,10-epoxide, aflatoxin B1, N-methyl-N-nitrosourea, 3-methyl-cholanthrene and 7,12-dimethylbenz[alpha]anthracene. Ellagic acid dihydrate forms triclinic crystals with unit cell dimensions: a = 7.656(1) A, b = 9.563(1)A, c = 4.623(1) A, alpha = 97.88(1) degrees, beta = 103.2(1) degrees, gamma = 102.22(1) degrees, V = 315.9 A3, space group = P1. There is a center of symmetry in the crystal coinciding with the center of the molecule, so that there is only one molecule in the unit cell. Ellagic acid is planar and molecules are interconnected by hydrogen bonds to water, giving rise to layers of molecules throughout the crystal. Its activity and anti-cancer properties are compared with those of a similar naturally occurring compound, quercetin.

Antineoplastic Agents↗
PubMed1988

9-Amino-1,2,3,4-tetrahydroacridine hydrochloride monohydrate (THA.HCl).

C13H15N2+.Cl-.H2O, Mr = 252.74, monoclinic, P2(1)/c, a = 8.776(2), b = 8.514(1), c = 18.046 (4) A, beta = 107.09 (2) degrees, V = 1288.8 (5) A3, Z = 4, D chi = 1.302 Mg m-3, lambda (Cu K alpha) = 1.5418 A, mu = 0.238 mm-1, F(000) = 536, T = 293 K, final R = 0.042 for 2080 observed data. Atoms C2 and C3 of the reduced ring are disordered. The crystal structure has an extensive network of hydrogen bonds in which the water molecule donates its H atoms to two Cl ions and accepts the H atom from the protonated ring N atom. The amino group also donates its H atoms in hydrogen bonding to two Cl ions.

Aminacrine↗
PubMed1987

Benzamide-DNA interactions: deductions from binding, enzyme kinetics and from X-ray structural analysis of a 9-ethyladenine-benzamide adduct.

The interaction of benzamide with the isolated components of calf thymus poly(ADP-ribose) polymerase and with liver nuclei has been investigated. A benzamide-agarose affinity gel matrix was prepared by coupling o-aminobenzoic acid with Affi-Gel 10, followed by amidation. The benzamide-agarose matrix bound the DNA that is coenzymic with poly(ADP-ribose) polymerase; the matrix, however, did not bind the purified poly(ADP-ribose) polymerase protein. A highly radioactive derivative of benzamide, the 125I-labelled adduct of o-aminobenzamide and the Bolton-Hunter reagent, was prepared and its binding to liver nuclear DNA, calf thymus DNA and specific coenzymic DNA of poly(ADP-ribose) polymerase was compared. The binding of labelled benzamide to coenzymic DNA was several-fold higher than its binding to unfractionated calf thymus DNA. A DNA-related enzyme inhibitory site of benzamide was demonstrated in a reconstructed poly(ADP-ribose) polymerase system, made up from purified enzyme protein and varying concentrations of a synthetic octadeoxynucleotide that serves as coenzyme. As a model for benzamide binding to DNA, a crystalline complex of 9-ethyladenine and benzamide was prepared and its X-ray crystallographic structure was determined; this indicated a specific hydrogen bond between an amide hydrogen atom and N-3 of adenine. The benzamide also formed a hydrogen bond to another benzamide molecule. The aromatic ring of benzamide does not intercalate between ethyladenine molecules, but lies nearly perpendicular to the planes of stacking ethyladenine molecules in a manner reminiscent of the binding of ethidium bromide to polynucleotides. Thus we have identified DNA as a site of binding of benzamide; this binding is critically dependent on the nature of the DNA and is high for coenzymic DNA that is isolated with the purified enzyme as a tightly associated species. A possible model for such binding has been suggested from the structural analysis of a benzamide-ethyladenine complex.

Adenine↗
PubMed1987

7,12-Dimethylbenz[a]anthracene: refined structure, electron density distribution and endo-peroxide structure.

The crystal structure of 7,12-dimethylbenz[a]anthracene (DMBA) has been refined from new X-ray diffraction data collected at low temperature (180 K). This has allowed the location of the hydrogen atom positions not previously reported in earlier structure determinations and refinements; a more precise molecular geometry is therefore now presented. In addition, an analysis of the electron density in this carcinogenic molecule has been made by multipole refinement. These two types of studies give information on the amount of strain in the bay region and the distribution of electron density in the molecule. The molecule is highly distorted in the bay region as a result of steric overcrowding between hydrogen atoms (minimum H ... H 2.06 A) so that torsion angles of 18 degrees and 22 degrees occur in this area. The bonds in the bay region and to the two methyl groups appear to be electron-rich; however, while the K-region of DMBA has a high pi-bond density computed from interatomic distances, the multipole analysis does not indicate that it is highly electron-rich. The 7- and 12-positions (equivalent to the 9- and 10-positions of anthracene) are highly reactive and appear to show a deficiency of electron density. Molecular dioxygen can add across these positions to give a peroxy compound. The crystal structure of such an endo-peroxide of DMBA has also been studied at 180 K although not to the high precision obtained for the parent compound. Some distortions are apparent in this molecule; in particular small CH3-C-O angles (101-104 degrees) are observed, indicative of some strain in the molecule. A computer graphics analysis of the diol epoxides of DMBA, generated from X-ray coordinates of DMBA and reported values for a diol epoxide of benzo[a]pyrene, show that steric overcrowding may affect the conformation of certain isomers of the diol epoxides.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Bay region distortions in cyclopenta[a]phenanthrenes.

Two newly synthesized cyclopenta[a]phenanthrenes, namely the 1-methyl (VIII) and 7,11-dimethyl (VII) derivatives of the parent ketone 15,16-dihydrocyclopenta[a]phenanthren-17-one (I), have been tested for their capacity to produce skin tumors in mice. The former (VIII) is essentially inactive, whereas the latter (VII) is very potent in both repeated application and two-stage tests. X-ray crystallographic structure analyses have been carried out on seven derivatives of (I), namely its 11-methyl (II), 11,12-dimethyl (III), 11-methoxy (V), 11-ethyl (VI) and 7,11-dimethyl (VII) analogues (carcinogens), the 1-methyl derivative (VIII), and 11,12,15,16-tetrahydro-11-methyl-17-oxocyclopenta[a]phenanthrene (IV) (both non-carcinogens). The detailed molecular structures resulting from these studies have shown the effects of steric interactions and substitutions on the bay-region geometry. The methyl group on C(11) causes distortions of the molecule in the bay region. Out-of-plane distortions in the bay regions of the 11-methyl derivatives (II, III, VII) are greater than for the 11-methoxy or the 11-ethyl derivatives (V, VI). Molecules (except for III and IV) are packed in the crystals with interactions that include C = O...H interactions; this packing is in layers that are nearly parallel to each other. A hydrogen atom of the 11-methyl group appears, from computer modeling, to interact sterically with the hydrogen atom of the bay-region expoxide group in the activated diol-epoxide; this steric interaction may force one conformer of the diol-epoxide to be the predominant form, thereby accounting for the importance of a bay-region methyl group. Further computer modeling has been used to analyze possible modes of interaction of the diol-epoxides of cyclopenta[a]phenanthrenes with DNA.

Animals↗
PubMed1984

The bay-region geometry of some 5-methylchrysenes: steric effects in 5,6- and 5,12-dimethylchrysenes.

The presence of a bay-region methyl group in carcinogenic polycyclic aromatic hydrocarbons leads to considerable distortion in the molecule. This is illustrated in the structures, obtained by X-ray diffraction techniques, of 5,12- and 5,6-dimethylchrysene. The molecular distortions result from steric requirements, such as that the minimum H...H distance is 1.8 A and the minimum C...C distance is 2.90 A; distortions to accommodate these requirements may be both in-plane (by increasing the angles at carbon atoms in the bay-region from 120 degrees to approximately 124 degrees) and out-of-plane by torsion about certain bonds in the bay-region. It is shown that more in-plane distortions are found for 5-methylchrysene derivatives than for methylbenz[a]anthracene derivatives and this, it is suggested, results from the nature of the flexibility of the chrysene compared with the benz[a]anthracene fragment at the bay-region.

Carcinogens↗
PubMed1982

X-ray crystallographic proof of electrophilic attack at the pyrimidine/imidazole ring junction in guanosine.

The crystal structure of a novel nucleoside isolated from guanosine/p-methylbenzyl chloride reactions demonstrates linkage between the methylene carbon of the benzyl moiety and carbon-5 of guanosine, and loss of the carbonyl function at carbon-6 of guanosine, to yield 4-(p-methylbenzyl)-5-guanidino-1-beta-D-ribofurasylimidazole. These findings suggest that carbon-5 of guanine in DNA is a potential site of reaction for electrophilic ultimate carcinogens.

Carcinogens↗