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H L Carrell

Publications and source records attributed to H L Carrell.

At least 37 records · Page 2Linked to original sources
PubMed1994

Bay- and fjord-region distortions in dibenz[a,j]anthracene and tetrabenzo[de,hi,mn,qr]naphthacene.

The crystal structure of 7,14-dimethyldibenz[a,j]anthracene (DMDBA) has been determined, and the crystal structure of tetrabenzo[de,hi,mn,qr]naphthacene (TBNC) has been redetermined at higher precision than previously reported. These molecules are polycyclic aromatic hydrocarbons (PAHs) that have, respectively, two hindered bay regions and two fjord regions; the former PAH is a known carcinogen. The extensive out-of-plane bending as a result of steric overcrowding in the bay and fjord regions in these PAHs is shown by these studies. For DMDBA, the angle between the 14-methyl group and the outer rings is 32.6 degrees. For TBNC, the angle between the outer rings of the molecule is 31.9 degrees. These structures are compared with those of related structures of 7,12-dimethylbenz[a]anthracene and dibenzo[g,p]chrysene. It appears that steric overcrowding in such PAHs can cause distortions of up to 33 degrees C. Such steric overcrowding will affect the conformations of bay- and fjord-region diolepoxides, which are the presumed activated metabolites in the carcinogenic process.

Benz(a)Anthracenes↗
PubMed1993

7-Chloromethyl-12-methylbenz(a)anthracene.

C20H15Cl, M(r) = 290.8, monoclinic, P2(1)/c, a = 20.449 (4), b = 11.473 (2), c = 13.025 (2) A, beta = 108.91 (1)degree, V = 2890.9 A, Z = 8, Dx = 1.336 g cm-3, lambda (Cu K alpha) = 1.5418 A, mu = 21.14 cm-1, F(000) = 1216, T = 294 K, R = 0.045, wR = 0.049, for 3471 diffractometer data [Io > or = 3 sigma (I)]. The ring system is puckered as a result of the bulkiness of the 12-methyl group.

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↗
PubMed1993

Structure of ethyl phenyl selenone.

C8H10O2Se, M(r) = 217.13, monoclinic, P2(1)/n, a = 9.511 (2), b = 15.741 (3) c = 11.467 (2) A, beta = 91.31 (2) degrees, V = 1716.3 (6) A3, Z = 8 (two molecules per asymmetric unit), Dx = 1.68 Mg m-3, lambda (Mo K alpha) = 0.71069 A, mu = 4.19 mm-1, F(000) = 864, T congruent to 295 K, R(obs) = 0.060 for 1944 unique reflections with I > 2 sigma (I). The two molecules in the asymmetric unit are very similar; they differ only in the conformation of the ethyl side chain. There is considerable disorder in one molecule, that possibly can be represented by torsion about the Se-C(ethyl) bond. In each case the O atoms of the SeO2 group lie near the plane of the phenyl group. Se-O ... H-C interactions appear to be the only significant intermolecular interactions. These involve an H atom of the alpha-C atom of the ethyl group in addition to the H atoms of the phenyl group.

Antineoplastic Agents↗
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

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↗
PubMed1989

X-ray analysis of D-xylose isomerase at 1.9 A: native enzyme in complex with substrate and with a mechanism-designed inactivator.

The structures of crystalline D-xylose isomerase (D-xylose ketol-isomerase; EC 5.3.1.5) from Streptomyces rubiginosus and of its complexes with substrate and with an active-site-directed inhibitor have been determined by x-ray diffraction techniques and refined to 1.9-A resolution. This study identifies the active site, as well as two metal-binding sites. The metal ions are important in maintaining the structure of the active-site region and one of them binds C3-O and C5-O of the substrate forming a six-membered ring. This study has revealed a very close contact between histidine and C1 of a substrate, suggesting that this is the active-site base that abstracts a proton from substrate. The mechanism-based inhibitor is a substrate analog and is turned over by the enzyme to give a product that alkylates this same histidine, reinforcing our interpretation. The changes in structure of the native enzyme, the enzyme with bound substrate, and the alkylated enzyme indicate that the mechanism involves an "open-chain" conformation of substrate and that the intermediate in the isomerization reaction is probably a cis-ene diol because the active-site histidine is correctly placed to abstract a proton from C1 or C2 of the substrate. A water molecule binds to C1O and C2O of the substrate and so may act as a proton donor or acceptor in the enolization of a ring-opened substrate.

Aldose-Ketose Isomerases↗
PubMed1987

Metabolism of 19-methyl-substituted steroids by human placental aromatase.

The 19-methyl analogues of androstenedione and its aromatization intermediates (19-hydroxyandrostenedione and 19-oxoandrostenedione) were evaluated as substrates of microsomal aromatase in order to determine the effect of a 19-alkyl substituent on the enzyme's regiospecificity. Neither the androstenedione analogue [10-ethylestr-4-ene-3,17-dione (1c)] nor the 19-oxoandrostenedione analogue [10-acetylestr-4-ene-3,17-dione (3c)] was converted to estrogens or oxygenated metabolites by placental microsomes. In contrast, both analogues of 19-hydroxyandrostenedione [10-[(1S)-1-hydroxyethyl]estr-4-ene-3,17-dione (2c) and 10-[(1R)-1-hydroxyethyl]estr-4-ene-3,17-dione (2e)] were converted to the intermediate analogue 3c in a process requiring O2 and either NADH or NADPH. No change in enzyme regiospecificity was detected. The absolute configuration of 2e was determined by X-ray crystallography. Experiments with 18O2 established that 3c generated from 2c retained little 18O (less than 3%), while 3c arising from 2e retained a significant amount of 18O (approximately equal to 70%). All four 19-methyl steroids elicited type I difference spectra from placental microsomes in addition to acting as competitive inhibitors of aromatase (KI = 81 nM, 11 microM, 9.9 microM, and 150 nM for 1c, 2c, 2e, and 3c, respectively). Pretreatment of microsomes with 4-hydroxyandrostenedione (a suicide inactivator of aromatase) abolished the metabolism of 2c and 2e to 3c, as well as the type I difference spectrum elicited by 2c and 2e.(ABSTRACT TRUNCATED AT 250 WORDS)

Aromatase↗
PubMed1987

Comparison of backbone structures of glucose isomerase from Streptomyces and Arthrobacter.

The C alpha backbones of the glucose isomerase molecules of Streptomyces rubiginosus and Arthrobacter have been determined by X-ray crystallography and compared. Each molecule is a tetramer of eight-stranded alpha/beta barrels, and the mode of association of the tetramers is identical in each case. The Arthrobacter electron density shows four additional amino acids at the carboxyl terminus. There is also an insertion of six amino acids at position 277, and two individual insertions at about positions 348 and 357 (numbering according to the Streptomyces structure). There is a close structural homology throughout the whole molecule, which is most accurate up to position 325. The r.m.s. displacement for 315 homologous C alpha positions up to this position is 0.92 A.

Aldose-Ketose Isomerases↗
PubMed1984

Hydroperoxides as inactivators of aromatase: 10 beta-hydroperoxy-4-estrene-3,17-dione, crystal structure and inactivation characteristics.

The crystal structure of 10 beta-hydroperoxy-4-estrene-3,17-dione (10 beta-OOH) was determined, and its inhibition of human placental aromatase was investigated. In the absence of added NADPH, 10 beta-OOH caused a time-dependent loss of aromatase activity (e.g., 50% loss after 90 s with 2.16 microM 10 beta-OOH). Protection against this loss of activity was provided when a substrate, androstenedione, was included in the incubation. Centrifugation and resuspension of the 10 beta-OOH-treated microsomes in fresh buffer failed to restore the activity, but partial recovery could be effected by dithiothreitol. Experiments to detect destruction of aromatase protoheme were done but were inconclusive. In the presence of NADPH, 10 beta-OOH did not cause a time-dependent loss of activity but was instead a competitive inhibitor (Ki = 330 nM) of androstenedione (Km = 21 nM) aromatization. The added NADPH was not utilized for the aromatization of 10 beta-OOH to estrogens, and enhanced reduction of 10 beta-OOH to 10 beta-hydroxy-4-estrene-3,17-dione could not be detected. In addition, microsomes alone were incapable of using 10 beta-OOH to support the aromatization of androstenedione. Cumene hydroperoxide and H2O2 were also investigated as inactivators of aromatase. Losses of activity comparable to those found for 10 beta-OOH could only be observed at 500-1000-fold higher concentrations of these agents, and no protection was provided by either androstenedione or NADPH. Extensive destruction of microsomal protoheme was found with these nonsteroidal agents.

Androstenedione↗
PubMed1984

X-ray crystal structure of D-xylose isomerase at 4-A resolution.

The structure of D-xylose isomerase from Streptomyces rubiginosus has been determined at 4-A resolution using multiple isomorphous phasing techniques. The folding of the polypeptide chain has been established and consists of two structural domains. The larger domain consists of eight beta-strand alpha-helix (beta alpha) units arranged in a configuration similar to that found for triose phosphate isomerase, 2-keto-3-deoxy-6-phosphogluconate aldolase, and pyruvate kinase. The smaller domain forms a loop away from the larger domain but overlapping the larger domain of another subunit so that a tightly bound dimer is formed. The tetramer then consists of two such dimers. The location of the active site in the enzyme has been tentatively identified from studies using a crystal grown from a solution containing the inhibitor xylitol.

Aldose-Ketose Isomerases↗
PubMed1984

Intercalation model for DNA-cross linking in a 1-nitro-9-aminoacridine derivative, an analog of the antitumor agent "ledakrin" (nitracrine).

Ledakrin (nitracrine), C-283, is a 1-nitro-9-aminoacridine derivative that is used in Poland as an antitumor agent. In order to investigate the basis of the activity of this compound the structure of another analog, [9-(3-dimethyl-1-methylpropylimino)-1-nitro-9,10-dihydroacridin e], C-829, that has similar activity, was determined by X-ray crystallographic techniques and was compared with that of ledakrin, already reported in the literature. In both molecules the proximity of the 1-nitro to the substituted 9-aminoacridine group causes extensive distortions. These compounds are believed to act, after metabolic "activation", by cross-linking DNA. Such cross-linking does not occur in the absence of the 1-nitro group or if the nitro group is moved to the 2-, 3- or 4-position. Computer-assisted model-building has been used to test possible intercalative models. It has shown that functional groups on C-829 or C-283 are, when the acridine portion of the molecule is intercalated as in a proflavine dinucleoside phosphate complex, in positions suitable for DNA cross-linking by activated 1-nitro-9-aminoacridine derivatives.

Aminoacridines↗
PubMed1984

Stereochemical properties of nucleosides alkylated by activated carcinogens.

An initial stage in the mechanism of chemical carcinogenesis by "activated" carcinogenic polycyclic aromatic hydrocarbons is believed to involve alkylation of DNA. However, very high (atomic) resolution studies of alkylated DNA are not technically feasible at this time, and therefore the detailed, high-resolution three-dimensional structures of portions of alkylated DNA have been determined. The initial phase of this study (reported here) has involved the preparation of a series of adenosines and 2'-deoxyadenosines substituted at N6 by related aralkyls of differing carcinogenic potential. We report here the crystal structure determinations of four of these compounds: Compound 1, N6-(anthracenyl-9-methyl)adenosine; Compound 2, N6-(10-methyl-anthracenyl-9-methyl)adenosine; Compound 3, N6-[12-methyl-benz(a)anthracenyl-7-methyl]adenosine; and Compound 5, N6-(10-methylanthracenyl-9-methyl)-2'-deoxyadenosine. Results are compared with those for a previously published analysis Compound 6, N6-[12-methylbenz(a)anthracenyl-7-methyl]-2'-deoxyadenosine. Several results of structural interest have emerged. All five compounds have the syn-conformational relationship between the sugar (ribose or 2'-deoxyribose) and the base (adenine), in contrast to the anti arrangement in B-DNA and in nonalkylated nucleosides. In four of the five compounds, there is an intramolecular hydrogen bond between the 5'-hydroxyl group and adenine. However, in the fifth molecule, this hydrogen bond is not found, and yet the conformation is syn. This indicates that formation of this internal hydrogen bond is not a prerequisite for the adoption of the syn-conformation. In general, the overall conformations of all five compounds are similar, the base lying approximately perpendicular to the polycyclic aromatic ring system. The packing of molecules in the unit cell is also of interest because it consists of alternations of adenine and polycyclic aromatic ring systems in columns through the crystal, indicating that this may serve as a model for the interaction with DNA. The oxygen atom of the sugar ring points towards the hydrocarbon ring system of another molecule. It is premature at this stage of our study to speculate as to the effects of alkylation on the conformational properties of either RNA or DNA. The only comment that appears justified is that the propensity of these adducts to adopt the syn-conformation may be indicative of a preference of alkylated DNA for the Z-conformation (even if the form that is initially attacked is B-DNA).(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylating Agents↗
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↗
PubMed1981

Crystal structure of a carcinogen:nucleoside adduct.

The product of reaction between the carcinogen, 7-bromomethyl-12-methylbenz[a]anthracene, and 2'-deoxyadenosine, i.e., N6-(12-methylbenz[a]anthracenyl-7-methyl)deoxyadenosine, has been prepared and characterized, and its structure has been determined by X-ray crystallographic techniques. The major structural features are: (a) the adenine and polycyclic aromatic hydrocarbon residues lie nearly perpendicular to one another; (b) the conformation about the glycosidic bond is syn, rather than anti, and an internal hydrogen bond between the deoxyribose 5'-hydroxyl group and N(3) of the adenine residue is present; and (c) the more planar anthracene portion of the hydrocarbon is stacked between adenine residues of other molecules throughout the crystal.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Molecular structures of 5,6- and 7,8-benzoflavones, inhibitors of aryl hydrocarbon hydroxylase.

The crystal and molecular structures of two isomeric inhibitors of carcinogenesis by certain polycyclic aromatic hydrocarbons are described. The two compounds are 7,8-benzoflavone and 5,6-benzoflavone, which are shown by X-ray crystallographic studies to differ appreciably in their three-dimensional structures. Polycyclic aromatic hydrocarbons are metabolically activated by an enzyme system that is responsibe for the detoxification of many chemicals that enter the body. The two benzoflavones described here differ in their effect towards specific enzymes in the metabolizing system. Potential energy calculations predict that a nonplanar conformation is most probable for these flavone derivatives, as a result of the presence of a biphenyl-like system. Such a conformation is found for 7,8-benzoflavone with a torsion angle of 23 degrees between the phenyl group and the rest of the molecule. The isomeric 5,6-benzoflavone is, in contrast, found to be a predominantly flat molecule. There is an interaction between O(4) and a neighboring -C-H group which may explain the planarity of 5,6-benzoflavone. A comparison is made with structures of some common carcinogenic polycyclic aromatic hydrocarbons, the activities of which these two benzoflavones inhibit.

Aryl Hydrocarbon Hydroxylases↗