Effects of fluoro substitution on 4-bromodiphenyl ether (PBDE 3).

It is our hypothesis that fluoro substitution provides a powerful tool to modulate the desired characteristics and to increase the specificity of studies of structure-activity relationships. 4-Bromodiphenyl ether (PBDE 3) and its five corresponding monofluorinated analogues (F-PBDEs 3) have been synthesized and fully characterized (using (1)H, (13)C and (19)F NMR spectroscopy, and mass spectrometry). The accurate structure from X-ray crystal analysis was compared with iterative calculations using semi-empirical self-consistent field molecular-orbital (SCF-MO) models. The compounds studied were 4-bromodiphenyl ether (PBDE 3), the (13)C(6)-isotopically labeled PBDE 3 ((13)C(6)-PBDE 3) and 2-fluoro-4-bromodiphenyl ether (3-2F), 2'-fluoro-4-bromodiphenyl ether (3-2'F), 3-fluoro-4-bromodiphenyl ether (3-3F), 3'-fluoro-4-bromodiphenyl ether (3-3'F), and 4'-fluoro-4-bromodiphenyl ether (3-4'F). Solid-state intermolecular interactions for PBDE 3 and the F-PBDEs 3 isomers are dominated by weak C-H(F,Br)...pi and C-H...F interactions. The C-F bond lengths varied between 1.347 (2) and 1.362 (2) A, and the C4-Br bond length between 1.880 (3) and 1.904 (2) A. These bond lengths are correlated with electron-density differences, as determined by (13)C shifts, but not with the strength of the C-F couplings. The interior ring angles of ipso-fluoro substitution increased (121.9-124.0 degrees ) as a result of hyperconjugation, a phenomenon also predicted by the calculation models. An attraction between the vicinal fluoro and halo substituents (observed in fluoro substituted chlorobiphenyls) was not observed for the bromo substituted F-PBDEs. The influence of a fluoro substituent on the conformation was only observable in PBDEs with di-ortho substitution. Calculated and observed torsion angles showed a positive correlation with increasing van der Waals radii and/or the degree of substitution for mono- to tetra-fluoro, chloro, bromo and methyl substitutions in the ortho positions of diphenyl ether. These findings utilizing F-tagged analogues presented here may prove fundamental to the interpretation of the biological effects and toxicities of these persistent environmental pollutants.

Influence of fluoro-substitution on the planarity of 4-chlorobiphenyl (PCB 3).

Accurate structure determinations by X-ray crystal analysis and computation using semi-empirical self-consistent field molecular orbital calculations are described and compared for five monofluorinated analogues of 4-chlorobiphenyl, i.e. 2-fluoro-4-chlorobiphenyl, 2'-fluoro-4-chlorobiphenyl, 3-fluoro-4-chlorobiphenyl, 3'-fluoro-4-chlorobiphenyl and 4'-fluoro-4-chlorobiphenyl. Intermolecular interactions for all monofluorinated isomers are dominated by phenyl-phenyl stacking and C-H-phenyl interactions. C-F bond lengths varied between 1.341 and 1.374 A, C-Cl between 1.733 and 1.765 A, and both correlate with electron-density differences as determined by (13)C NMR shifts. The interior ring angles at ipso-fluoro substitution increase up to 122.2-124.2 degrees due to hyperconjugation by 2p-pi-orbital overlapping, a phenomenon that was also reflected in the computer calculation. The angles of C-F and C-Cl relative to the aromatic ring for vicinal fluoro- and chloro substituents show an attraction, not a repulsion, between the adjacent F and Cl substituents. This finding is explained on the basis of electron donor and acceptor properties. The dihedral angles of ortho-substituted biphenyls show that monofluoro substitution results in slightly smaller increases compared with chlorine, while additional ortho-fluorination results in little further change in the dihedral angle. In contrast, ortho-chlorination strongly decreases the co-planarity. This is likely to be due to interior ring-angle distortion and the size of the halogen substituent. Fluoro substitution does indeed affect the planarity of the PCB3 analogues, but these effects are minor compared with chloro substitution. Fluorine tagging offers promise for use in in vitro and in vivo studies. Differences in computational versus measured data emphasize the need to use a variety of methods to ascertain the true nature of the physical properties of a compound.

Pseudodestruxins A and B: new cyclic depsipeptides from the coprophilous fungus Nigrosabulum globosum.

Pseudodestruxins A (1) and B (2), two new cyclic peptides, have been isolated from cultures of the coprophilous fungus Nigrosabulum globosum. The structure of pseudodestruxin A (1) was elucidated using 2D NMR techniques and confirmed by single-crystal X-ray diffraction analysis. The structure of 2 was assigned by comparing its NMR and FABMS data with those of compound 1. The known compounds ascochlorin and 5-chlorocollectorin B were also isolated from N. globosum. Although 1 and 2 display antibacterial effects, ascochlorin was found to be responsible for the antifungal activity of the crude extract.

(2'S,3'S,4'R)-5'-O-benzoyl-3'-deoxy-3' beta-diethylphosphono-2'-O-tert-butyldimethylsilyluridine.

3'-Hydroxy-3'-diethylphosphononucleosides readily undergo radical deoxygenation under modified Barton conditions to give two diastereomers of the parent diethyl phosphonate. However, the stereochemistry of the diastereomers is difficult to establish by spectral means. When the major product of one such reaction was obtained in crystalline form, a single crystal diffraction analysis was conducted on that diastereomer, the title compound, C26H39N2O9PSi.

Cyclic (1R,3R)-1,3-dimethyltrimethylene [(5R)-2-hydroxy-5-methyl-5-(2- methyl-1,3-dioxolan-2-yl)-1-cyclohexen-1-yl]-phosphonate, a stable enol.

The title compound, C16H27O6P, was obtained from the rearrangement of the corresponding vinyl phosphate. 31P NMR experiments in solution have shown that this compound equilibrates to a mixture of three isomers in nearly equal proportions. In the crystalline state a single isomer is found which diffraction analysis identified as the enol form of the beta-keto phosphonate having R stereochemistry at atom C(8).

(1 beta, 5 alpha, 6 beta)-10,10- (1,2-ethylenedioxy)-1,5-dimethylbicyclo[4.4.0]decan-4-one.

The title compound (1) [alternative name: 5,8a-dimethyl(decahydronaphthalene)-1-spiro-2'-(1',3'-dioxolan+ ++)-6-one, C14H22O3] was obtained as the major product upon Pd/CaCO3-catalyzed hydrogenation of the corresponding enone (2). The analysis of the crystal structure of (1) has established that the monoacetal is cis-fused and that both rings adopt nearly perfect chair forms. The C(5) methyl group is in an alpha position, resulting directly from syn-hydrogenation of the enone. While there are two possible chair-chair conformations for cis-decalins, the title compound crystallized in the conformation which places the C(5) methyl group in an equatorial position.

Molecular structures of metabolites and analogues of diethylstilbestrol and their relationship to receptor binding and biological activity.

A series of indanyl derivatives of diethylstilbestrol (DES) have recently been identified as inv vivo metabolites of DES. These compounds are of interest because they possess effective uterine estrogen receptor-binding affinity but poor biological activity. The X-ray crystal structures of three of these derivatives were determined and their conformations were compared with those of estradiol and DES. The more active derivatives, indenestrol A (I) and indenestrol B (II) have nearly identical conformations, in which the overall molecule is highly planar, the phenyl ring is twisted out of the plane of the indene rings by approximately 30 degrees, and the distance between the hydroxyl groups is 11.6 A. In the least active derivative, idanestrol (III), the methyl, ethyl, and phenyl substituents were found to be in the same side of the indane ring so that the molecule is constrained to an L-shape. The crystallographically observed conformations of I, II, III, DES, and estradiol, their competative binding affinities, and their in vivo biological activities are consistent with the proposal that the steroid A-ring plays a dominant role in initiating receptor binding while the D-ring orientation relative to the A-ring has a more decisive influence upon activity. The reduction in estrogen receptor-binding affinity and associated reduced activity of III is almost certainly due to its L-shape conformation. The extended conformation of I and II in which both phenolic rings are exposed permitting ready access to both surfaces of either ring probably accounts for the ability of these derivatives to compete so successfully with estradiol for estrogen receptor binding. There are eight different ways in which the molecules of the racemic mixtures of I and II could initiate receptor binding. The reduced biological activity of I and II is probably due to the fact that not all eight binding orientations are compatible with eliciting estrogenic response. Comparison of the observed conformations of I, II, DES, and estradiol suggests that it is the alpha-ring of I and II that minics the steroid A-ring in receptor binding, and that two of the four possible alpha-ring/A-ring matches are most conducive to eliciting hormone activity.

Structural stability in the 4-zinc human insulin hexamer.

X-ray studies on human insulins prepared by semisynthetic and biosynthetic methods have recently been undertaken. Human insulin differs from porcine insulin only at the COOH terminus of the B-chain. The present study reports the crystal structure of 4-zinc human insulin, which is used clinically as a slow-acting preparation. The structure has been refined, using 1.85-A resolution data, to a residual of 0.173. The unit cell is rhombohedral, space group R3, with hexagonal cell constants a = 80.953 and c = 37.636 A, and it is nearly isomorphous with that of 4-zinc porcine insulin. As a result of a conformational change of the first eight residues of the B-chain of molecule 1 from an extended conformation observed in the 2-zinc structure to an alpha-helical one, the coordination around one of the zinc ions on the 3-fold axis has changed, an additional zinc ion in a general position is bound by the hexamer, and additional hydrogen-bonded interactions help stabilize dimer and hexamer formation. Unlike the surface of the 2-zinc insulin hexamer, which possesses a shallow depression containing a zinc ion and its coordinating water molecules, the 4-zinc human insulin hexamer contains a zinc and chloride ion at the bottom of an 8-A tunnel produced by three parallel alpha-helices. These alpha-helices shield the zinc ion from the environment, decreasing the rate of dissociation of the hexamer, and provide an explanation for the slow-acting aspect of the 4-zinc crystalline form.

Synthesis and characterization of the anomeric pair of 17 beta-glucuronides of ethynylestradiol.

The alpha- and beta-anomers of the 17 beta-D-glucuronide conjugate of ethynylestradiol were synthesized by the SnCl4-promoted reaction between beta-acetoxy GAM and the t-17 beta-hydroxyl group of EE2-3-acetate. The conjugates were resolved by crystallization and HPLC. Positive identification was established by u.v. spectrophotometry, i.r. and mass spectrometry and 1H- and 13C-n.m.r. The structure of the beta-anomer was confirmed by X-ray crystallographic analysis. In addition, the alpha-anomer was refractory to hydrolysis by bovine beta-glucuronidase, establishing a biochemical difference between the conjugate pair.

Synthesis, X-ray crystallographic determination, and opioid activity of erythro-5-methylmethadone enantiomers. Evidence which suggests that mu and delta opioid receptors possess different stereochemical requirements.

Enantiomers of erythro-5-methylmethadone (3) were synthesized from optical antipodes of erythro-3-(dimethyl-amino)-2-butanol. X-ray crystallographic analysis of (-)-3 perchlorate revealed that it possesses the 5S,6S absolute configuration. It was found that (-)-3 is substantially more potent than its enantiomer (+)-3 as an opioid agonist in vivo and in vitro. In vitro tests (guinea pig ileal longitudinal muscle and mouse vas deferens preparations) suggest that (-)-3 mediates its effect chiefly through mu opioid receptors. On the other hand, (+)-3 and the more potent enantiomers of methadone, (-)-1, and isomethadone, (-)-2, appear to have less mu-receptor selectivity and interact with a greater fraction of delta receptors than does (-)-3. The fact that the solid-state conformation of (-)-3 differs from that of (-)-1 and (-)-2, which show great similarity in conformational features, suggests that mu and delta receptors have different conformational requirements. The possibility of different modes of interaction with a single opioid receptor population also is discussed.