Biomedical subjects

H L Carrell

Publications and source records attributed to H L Carrell.

At least 19 recordsLinked to original sources

PubMed1999

Three-dimensional structure of anti-5,6-dimethylchrysene-1, 2-dihydrodiol-3,4-epoxide: a diol epoxide with a bay region methyl group.

The three-dimensional structure of a dihydrodiol epoxide of 5, 6-dimethylchrysene was elucidated by X-ray diffraction techniques. The effects of the steric overcrowding by the 5-methyl group in the bay region of this compound are described. The carbon atom of the 5-methyl group is found to lie out of the plane of the aromatic system, thereby avoiding the nearer C-H group of the epoxide ring; this C-H hydrogen atom is pushed in the opposite direction. As a result, the molecule is distorted so that the relative orientations of the epoxide group and the aromatic ring systems are very different for the diol epoxides of (nearly planar) benzo[a]pyrene (studied by Neidle and co-workers) and (distorted) 5, 6-dimethylchrysene (described here). The main effect of the 5-methyl group is to change the relative angle between the epoxide-bearing ring (the site of attack when the diol epoxide acts as an alkylating agent) and the aromatic ring system (which is presumed to lie partially between the DNA bases in the DNA adduct that is about to be formed). This may favor some specific alkylation geometry.

Bay-Region, Polycyclic Aromatic Hydrocarbon↗

PubMed1998

Crystallization and preliminary X-ray diffraction studies of E. coli porphobilinogen synthase and its heavy-atom derivatives.

Porphobilinogen synthase (PBGS) catalyzes the condensation of two identical substrate molecules, 5-aminolevulinic acid (ALA), in an asymmetric manner to form porphobilinogen. E. coli PBGS is an homooctameric enzyme. The number of active sites is not clear, but each subunit binds one ZnII ion and one MgII ion. Diffraction-quality crystals of native E. coli PBGS have been obtained, and unit-cell dimensions (a = 130.8, c = 144.0 A) are reported. These crystals diffract to about 3.0 A resolution.

Crystallization↗

PubMed1998

Trimethyl isocyanurate and triethyl isocyanurate.

The crystal structures of trimethyl isocyanurate, C6H9N3O3, (1), and triethyl isocyanurate, C9H15N3O3, (2), contain topologically similar C--H...O hydrogen-bonded networks. In (1), there are two symmetry-independent molecules and each forms its own layer structure. In (2), two of the ethyl groups point one way with respect to the heterocyclic ring, while the third points in the opposite direction.

Crystallography, X-Ray↗

PubMed1998

Dibenzo[a,l]pyrene (dibenzo[def,p]chrysene): fjord-region distortions.

The molecular dimensions of the potent chemical carcinogen dibenzo[def,p]chrysene, also known as dibenzo[a,l]pyrene, have been determined by X-ray diffraction methods. This analysis shows that the molecule is considerably distorted so that it is non-planar with an angle of 27.6 degrees between the outermost rings and a widening of C-C-C bond angles in the fjord region. The dimensions of the molecular distortion due to atomic overcrowding in the fjord region are presented. This polycyclic aromatic hydrocarbon is a more potent carcinogen than is benzo[a]pyrene or its 11-methyl derivative. Comparisons of the distortions in dibenzo[a,l]pyrene with the geometries of various other polycyclic aromatic hydrocarbons containing fjord- or bay-region methyl groups provide structural data on the ratio of angular to torsional distortion in such overcrowded molecules.

Benzopyrenes↗

PubMed1997

Benzo[a]pyrene and its analogues: structural studies of molecular strain.

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.

Benzo(a)pyrene↗

PubMed1996

2-bromoacetoxybenzoic acid, a brominated aspirin analog.

The crystal structure of 2-bromoacetoxybenzoic acid, C9H7BrO4, shows it to be a close structural analog of aspirin. The carboxylic acid moiety is twisted by 7.7 (4) degrees out of the plane of the aromatic ring. The acetyl group, like that of aspirin, shows bond-angle distortions from ideal values while remaining essentially planar. The Br atom is rotationally disordered and has been modeled as occupying two sites related by a 13 (1) degree rotation about the C8--C9 bond.

Aspirin↗

PubMed1996

1-(4-iodobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid, an iodinated indomethacin analog.

The crystal structure of 1-(4-iodobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid, C19H16INO4, an analog of indomethacin, is reported. Bond distances and angles in the title compound closely resemble those reported for indomethacin and reflect the presence of steric strain at the site of the linkage between the 4-iodobenzoyl group and the indole moiety. The orientation of the 4-iodobenzoyl group with respect to the indole ring is not the same in the title compound as it is in indomethacin; the two structures are related by a rotation of 186 degrees about the C2--N1--C10--C11 torsion angle.

Crystallography, X-Ray↗

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↗

PubMed1996

Bay-region distortions in a methanol adduct of a bay-region diol epoxide of the carcinogen 5-methylchrysene.

The three-dimensional structure of the product of the reaction of a diol epoxide of the carcinogen 5-methylchrysene with methanol has been determined by an X-ray diffraction analysis. The diol epoxide used to obtain this compound contains a stereochemically hindered bay region because of the location of the 5-methyl group, and this might be expected to affect the type of chemical reaction that occurs. The crystal structure analysis of this adduct of a polycyclic aromatic hydrocarbon (PAH) showed that a methoxy group has been added at the carbon atom of the epoxy group that is nearest to the aromatic system. The bond that is formed is axial to the ring system so that the carbon and hydrogen atoms of the methoxy group are considerably displaced from the PAH ring plane. The bay-region methyl group at position 5 is displaced out of the ring plane in the opposite direction. The major steric distortion in this methanol adduct is shown, by a comparison with crystal structures of related non-methylated compounds, to be in the area of the 5-methyl group and not in the tetrol-bearing ring. The steric effects that caused the axial conformation of the newly formed bond would also be expected to pertain in the DNA adduct of a PAH with a bay-region methyl group. Since the presence of the bay-region methyl group in 5-methylchrysene has been shown to enhance the carcinogenicity of this PAH over the parent compound or compounds with methyl groups in other positions of the molecule, it might be anticipated that this axial bond is found in carcinogenic lesions in DNA, and that any factor that ensures this axial conformation may accentuate the carcinogenic potential of a PAH of the appropriate size.

Carcinogens↗

PubMed1995

Probing the roles of active site residues in D-xylose isomerase.

The roles of active site residues His54, Phe94, Lys183, and His220 in the Streptomyces rubiginosus D-xylose isomerase were probed by site-directed mutagenesis. The kinetic properties and crystal structures of the mutant enzymes were characterized. The pH dependence of diethylpyrocarbonate modification of His54 suggests that His54 does not catalyze ring-opening as a general acid. His54 appears to be involved in anomeric selection and stabilization of the acyclic transition state by hydrogen bonding. Phe94 stabilizes the acyclic-extended transition state directly by hydrophobic interactions and/or indirectly by interactions with Trp137 and Phe26. Lys183 and His220 mutants have little or no activity and the structures of these mutants with D-xylose reveal cyclic alpha-D-xylopyranose. Lys183 functions structurally by maintaining the position of Pro187 and Glu186 and catalytically by interacting with acyclic-extended sugars. His220 provides structure for the M2-metal binding site with properties which are necessary for extension and isomerization of the substrate. A second M2 metal binding site (M2') is observed at a relatively lower occupancy when substrate is added consistent with the hypothesis that the metal moves as the hydride is shifted on the extended substrate.

Aldose-Ketose Isomerases↗

PubMed1994

Perturbing the metal site in D-xylose isomerase. Effect of mutations of His-220 on enzyme stability.

The histidine residue at position 220 in the Streptomyces rubiginosus D-xylose isomerase is conserved in all D-xylose isomerases. The three-dimensional structure of D-xylose isomerase reveals that His-220 is part of the octahedral coordination sphere of M2, one of two metal ions (Mn2+) in the active site. This work describes the effects of replacing His-220 with Ser, Glu, Asn, and Lys. The consequences of these amino acid substitutions on enzyme activity, thermostability, and structure were analyzed by kinetic, denaturation, and crystallographic methods. The kcat values H220S, H220N, and H220E are only 0.3-0.5% of the wild-type values, and the Km for each of these mutant enzymes increased by 30-40-fold over the wild-type value. The mutant enzyme H220K did not exhibit any measurable activity. Thermal denaturation studies (Tm values) indicate that the H220S and H220N mutant enzymes are approximately 5-8 degrees C less stable than the wild-type enzyme, whereas H220E and H220K are 13-24 degrees C less stable than the wild-type enzyme. To analyze the molecular basis for this decreased thermostability, the crystal structures of the H220S, H220N, and H220E mutant enzymes complexed with Mn2+ have been determined at 1.95, 1.90, and 1.75 A, respectively. In the H220S structure, a water molecule effectively replaces the N epsilon-2 atom of the imidazole ring of His-220 and mediates the interaction between Mn2+ at the M2 site and Ser-220. A similar water-mediated interaction between the metal ion and Asn-220 is observed in H220N. No direct or water-mediated interactions between the carboxyl group of Glu-220 and the metal are observed in H220E. Whereas octahedral coordination is maintained for the metal at the M2 site in H220S and H220N, a pentahedral coordination with the metal at the M2 site is observed in H220E. Metal activation measurements support the observation that metal binding is perturbed and is responsible for thermal lability of His-220 mutants.

Aldose-Ketose Isomerases↗

PubMed1994

Crystallographic studies of two alcohol dehydrogenase-bound analogues of thiazole-4-carboxamide adenine dinucleotide (TAD), the active anabolite of the antitumor agent tiazofurin.

Thiazole-4-carboxamide adenine dinucleotide (TAD) is the active anabolite of the antitumor drug tiazofurin. Beta-methylene TAD (beta-TAD) is a phosphodiesterase-resistant analogue of TAD, active in tiazofurin-resistant cells. Beta-methylene SAD (beta-SAD) is the active selenium derivative of beta-TAD. Both agents are analogues of the cofactor NAD and are capable of acting as general dehydrogenase inhibitors. Crystal structures of beta-TAD and beta-SAD bound to horse liver alcohol dehydrogenase (LADH) are presented at 2.9 and 2.7 A, respectively. Both complexes crystallize in the orthorhombic space group C222(1) and are isomorphous to apo-LADH. Complexes containing beta-TAD and beta-SAD were refined to crystallographic R values of 15% and 16%, respectively, for reflections between 8 A and the minimum d spacing. Conformations of both inhibitors are similar. beta-TAD and beta-SAD bind to the "open" form of LADH in the normal cofactor-binding cleft between the coenzyme and catalytic domains of each monomer. Binding at the adenosine end of each inhibitor resembles that of NAD. However, the positions of the thiazole and selenazole heterocycles are displaced away from the catalytic Zn cation by approximately 4 A. Close intramolecular S-O and Se-O contacts observed in the parent nucleoside analogues are maintained in both LADH-bound beta-TAD and beta-SAD, respectively. These conformational constraints may influence the binding specificity of the inhibitors.

Adenosine Diphosphate↗

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↗