Strategies for synthesis of adducts of omicron-quinone metabolites of carcinogenic polycyclic aromatic hydrocarbons with 2'-deoxyribonucleosides

Polycyclic aromatic hydrocarbons (PAHs) are major environmental carcinogens produced in the combustion of fossil fuels, tobacco, and other organic matter. Current evidence indicates that PAHs are transformed enzymatically to active metabolites that react with DNA to form adducts that result in mutations. Three activation pathways have been proposed: the diol epoxide path, the radical-cation path, and the quinone path. The latter involves aldo-keto reductase mediated oxidation of PAH dihydrodiol metabolites to catechols that enter into redox cycles with quinones. This results in generation of reactive oxygen species (ROS) that attack DNA, and the PAH quinones also react with DNA to form adducts. Several strategies for synthesis of the stable adducts formed by the o-quinone metabolites of carcinogenic PAHs with 2'-deoxyribonucleosides were investigated and compared. The PAH quinones studied were benz[a]anthracene-3,4-dione and its 7-methyl- and 7,12-dimethyl- derivatives. The parent PAHs represent a range of carcinogenicity from inactive to highly potent. Two synthetic methods were devised that differ in the catalyst employed, Pd(OAc)(2) or CuI. The Pd-mediated method involved coupling a protected amino-catechol PAH derivative with a halo-2'-deoxyribonucleoside. The copper-mediated method entailed reaction of a halo-PAH catechol derivative with a 2'-deoxyribonucleoside. Adducts of benz[a]anthracene-3,4-dione (and its 7-methyl- and 7,12-dimethyl- derivatives) with 2'-deoxyadenosine and 2'-deoxyguanosine were prepared by these methods. Availability of adducts of these types through synthesis makes possible for the first time biological studies to determine the role of these adducts in tumorigenesis. The copper-mediated method offers advantages of economy, adaptability to large-scale preparation, utility for synthesis of (13)C- or (15)N-labeled analogues, and nonformation of bis-adducts as secondary products.     

Palladium-catalyzed synthesis of nucleoside adducts from bay- and fjord-region diol epoxides

Palladium-catalyzed C-N bond formation has been utilized to synthesize covalent 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) adducts of benzo[a]pyrene (BaP) series 1 (syn) and benzo[c]phenanthrene (BcPh) series 2 (anti) diol epoxides. For this, (+/-)-10 alpha-amino-7 beta,8 alpha,9 beta-trisbenzoyloxy-7,8,9,10-tetrahydro BaP and (+/-)-1 beta-amino-2 alpha,3 alpha,4 beta-trisbenzoyloxy-1,2,3,4-tetrahydro BcPh were coupled with 6-halo-9-[3,5-bis-O-(tert-butyldimethylsilyl)-beta-D-erythro-pentofuranosyl]purine and O6-benzyl-3',5'-bis-O-(tert-butyldimethylsilyl)-2-bromo-2'-deoxyinosine, using a (+/-)-BINAP-Pd complex and Cs2CO3. For the synthesis of the dA adducts, both the 6-chloro- as well as the 6-bromopurine nucleoside derivatives were analyzed for the C-N coupling reaction with the hydrocarbon amino tribenzoates. With the BaP amino tribenzoate, the 6-chloronucleoside provided satisfactory results, whereas the 6-bromo analogue proved to be superior with the BcPh amino tribenzoate. Overall, lower yields of the dA adducts were obtained with the more hindered fjord-region BcPh amino tribenzoate as compared to the bay-region BaP amino tribenzoate. In contrast to reactions leading to the dA adducts, the C-N reactions of both BaP and BcPh amino tribenzoates with the 2-bromo-2'-deoxyinosine derivative proceeded in comparable yields. This seems to indicate that such Pd-catalyzed adduct forming reactions at the C-6 position may be influenced by steric constraints of the amine component, whereas those at the C-2 position are less sensitive. Diastereomeric adduct pairs were separated and characterized by spectral methods and by comparisons to adducts produced by direct displacement reactions as well as those formed from DNA alkylation by diol epoxides.     

Palladium-catalyzed amination in the synthesis of polyazamacrocycles

The review describes palladium-catalyzed amination of acyclic di- and polyamines with aryl halides with a view to reveal general relations holding in this process. Conditions for the synthesis of macrocycles via catalytic diamination of 1,2- and 1,3-dibromobenzenes, 1,3-dichloro-2-bromobenzene, 2,6- and 3,5-dibromopyridines, 3,3′- and 4,4′-dibromobiphenyls, 2,7-dibromonaphthalene, 1,8- and 1,5-dichloroanthracene, 1,8- and 1,5-dichloroanthraquinones, and bis(haloaryl) derivatives of cyclen, cyclam, and cholanediol are discussed. The possibility for palladium-catalyzed arylation of cyclic polyamines has been demonstrated. Specificity of macrocyclization processes and relations between the yield of macrocycles and the nature of initial compounds are considered, and data on the synthesis of cyclic dimers are given. Applications of polyazamacroheterocycles as optical sensors for metal cations are described using as examples macrocyclic compounds derived from 1,8-disubstituted anthraquinone.     

Palladium-catalyzed pentannulation of polycyclic aromatic hydrocarbons

We present a new and versatile one-step synthesis of a series of small molecular chromophores based on cyclopentannulated polycyclic aromatic hydrocarbons (PAH). Easily available pyrene, anthracene, and perylene bromides serve as starting materials for the reactions. The formation of the five-membered ring is achieved by the straightforward palladium(0)-catalyzed carbannulation with various substituted acetylenes. This approach is applicable either to single or multiple annulation procedures leading to hitherto inaccessible PAH topologies. According to the resulting products of the diverse reactions, a mechanistic explanation is proposed. UV/Vis absorption as well as cyclovoltammetric measurements were performed for characterization demonstrating the value of this annulation technique. Optical absorptions of up to 780 nm and absorption coefficients ranging from 8000 to 34,000 M(-1) cm(-1) were detected.     

Closed-shell polycyclic aromatic hydrocarbon cations: a new category of interstellar polycyclic aromatic hydrocarbons

Density functional theory has been employed to calculate the harmonic frequencies and intensities of a range of polycyclic aromatic hydrocarbon (PAH) cations that explore both size and electronic structure effects on the infrared spectroscopic properties of these species. The sample extends the size range of PAH species considered to more than 50 carbon atoms and includes several representatives from each of two heretofore unexplored categories of PAH cations: (1) fully benzenoid PAH cations whose carbon skeleton is composed of an odd number of carbon atoms (C(odd) PAHs); and (2) protonated PAH cations (HPAH+). Unlike the radical electronic structures of the PAH cations that have been the subject of previous theoretical and experimental work, the species in these two classes have a 'closed'-shell electronic configuration. The calculated spectra of circumcoronene, C54H18, in both neutral and (radical) cationic form are also reported and compared with those of the other species. Overall, the C(odd) PAHs spectra are dominated by strong CC stretching modes near 1600 cm(-1) and display spectra that are remarkably insensitive to molecular size. The HPAH+ species evince a more complex spectrum consistent with the added contributions of aliphatic modes and their generally lower symmetry. Finally, for both classes of closed-shell cations, the intensity of the aromatic CH stretching modes is found to increase with molecular size far out of proportion with the number of CH groups, approaching a value more typical of neutral PAHs for the largest species studied.     

Synthesis of adducts of o-quinone metabolites of carcinogenic polycyclic aromatic hydrocarbons with 2'-deoxyribonucleosides

[structure: see text] The first syntheses of the adducts formed in the reactions of o-quinone metabolites of carcinogenic polycyclic aromatic hydrocarbons (BPQ and BAQ) at 2'-deoxyadenosine and 2'-deoxyguanosine sites in DNA are reported. These syntheses entail Pd-catalyzed coupling of protected amine derivatives of catechols with suitably protected halopurine analogues of 2'-deoxyribonucleosides.     

Synthesis of a three-dimensional spiro-annulated polycyclic aromatic hydrocarbon

We describe the results of our investigation on the preparation, structural characterization, and optical properties of a spiro-annulated polycyclic aromatic hydrocarbon prepared by the cyclodehydrogenation of a hexa{2-(9,9′-spirobifluorenyl)}benzene precursor molecule. Single-crystal X-ray diffraction analysis reveals that the anthracene backbone adopts one of the largest end-to-end twists thus far reported.     

Synthesis of 13C4-labelled oxidized metabolites of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are ubiquitous environmental contaminants that are implicated in causing lung cancer. BaP is a component of tobacco smoke that is transformed enzymatically to active forms that interact with DNA. We reported previously development of a sensitive stable isotope dilution LC/MS method for analysis of BaP metabolites. We now report efficient syntheses of ¹³C₄-BaP and the complete set of its ¹³C₄-labelled oxidized metabolites needed as internal standards They include the metabolites not involved in carcinogenesis (Group A) and the metabolites implicated in initiation of cancer (Group B). The synthetic approach is novel, entailing use of Pd-catalyzed Suzuki, Sonogashira, and Hartwig cross-coupling reactions combined with PtCl₂-catalyzed cyclization of acetylenic compounds. This synthetic method requires fewer steps, employs milder conditions, and product isolation is simpler than conventional methods of PAH synthesis. The syntheses of ¹³C₄-BaP and ¹³C₄-BaP-8-ol each require only four steps, and the ¹³C-atoms are all introduced in a single step. ¹³C₄-BaP-8-ol serves as the synthetic precursor of all the oxidized metabolites of ¹³C-BaP implicated in initiation of cancer. The isotopic purities of the synthetic ¹³C₄-BaP metabolites were estimated to be ≥99.9%.     

Suppressing aggregation in a large polycyclic aromatic hydrocarbon

With the approach presented herein, a large aromatic pi-system is synthesized, which shows extraordinarily high solubility and an effective suppression of aggregation. This was due to a distortion of the aromatic core by bulky tert-butyl groups and the solubilizing effects of alkyl chains in the corona of the aromatic core. Therefore not only the processing and cleaning of the materials with standard laboratory techniques became possible, but moreover the first structure-rich UV/vis and a resolved (1)H NMR spectra for an aromatic system two times larger than hexa-peri-hexabenzocoronene were recorded. The bulk properties in an extruded fiber as well as on the surface showed a columnar self-assembly including a phase in which a homeotropic alignment on a substrate was observed, which turns the material into an interesting candidate for future applications in electronic devices.     

Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis

A diastereoselective synthesis of the nucleoside adducts corresponding to a cis ring-opening of the carcinogen (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE-2) by 2'-deoxyadenosine and 2'-deoxyguanosine is described. The key intermediate (+/-)-10alpha-amino-7beta,8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene was synthesized by a highly diastereoselective dihydroxylation wherein phenylboronic acid was a water surrogate. The resulting boronate ester was converted to a tetraol derivative in which two of the four hydroxyl groups (trans 7, 8) were protected as benzoate esters while the remaining two (cis 9, 10) were free. The cis glycol entity was then subjected to a reaction with 1-chlorocarbonyl-1-methylethylacetate to yield an intermediate chloro monoacetoxy dibenzoate. Displacement of the halide with azide, complete cleavage of the esters, and catalytic reduction of the azide yielded the requisite amino triol. Fluoride displacement from appropriately protected nucleoside derivatives, 6-fluoropurine 2'-deoxyribonucleoside and 2-fluoro-2'-deoxyinosine, by the amino triol then yielded diastereomeric pairs of diol epoxide-adducted 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) nucleosides. Small aliquots of these adducts were separated for characterization purposes. The present approach provides the first diastereoselective synthesis of the cis adducts of BaP DE-2 with 2'-deoxyguanosine as well as the first synthesis of both dA and dG adducts from a common intermediate. An informative analysis of the 1H NMR spectra of the cis adducts synthesized and comparisons to the trans adducts are reported. To gain insight into the diastereoselectivity in the key dihydroxylation step, a computational analysis, including molecular mechanics (MMFF94) and semiempirical AM1 geometry optimizations, yielded results that are in fairly good agreement with the experimental observations.     

Palladium-catalyzed amination in the synthesis of aza- and diazacrown trismacrocyclic compounds

Palladium-catalyzed C-N-cross-coupling of N,N′-bis(bromobenzyl) diazacrown compounds with two equivalents of 1-aza-15-crown-5 and 1-aza-18-crown-6 ethers furnished trismacrocyclic compounds with isolated macrocycles. Macrotricyclic cryptands were obtained when diazacrown ethers were used as N-components.     

Analysis of intermediates from polycyclic aromatic hydrocarbon biodegradation

A major difficulty in assessing bioremediation in hydrocarbon impacted field sites is the determination of the extent and products of contaminant biodegradation. Previously, various analytical techniques, including mass spectrometry and chromatography, have been used to characterize components in mixtures resulting from biodegradation. In this work, the applicability of capillary electrophoresis (CE) to this area of research is demonstrated. CE methods were optimized for analysis of compounds that are known metabolites of polycyclic aromatic hydrocarbon (PAH) biodegradation.     

Microwave-assisted amination of a chloropurine derivative in the synthesis of acyclic nucleoside analogues

An efficient protocol for the amination of 6-chloropurine derivatives through nucleophilic aromatic substitution under microwave irradiation was developed and applied to the synthesis in two steps of a series of new acyclic nucleosides (acyclovir analogues) starting from commercially available compounds.     

Palladium-catalyzed amination in the synthesis and modification of acyclic oxadiamino cholane derivatives

Palladium-catalyzed reactions of 24-(haloaryloxy)cholanes and 3,24-bis(haloaryloxy)cholanes with excess oxadiamines gave the corresponding mono- and bis(oxadiamino)-substituted cholanes which were subjected to palladium-catalyzed arylation with 1,3-dibromobenzene, 2,6-dibromopyridine, 1,8-dichloroanthracene, 9-bromoanthracene, 1-chloroanthracene, and 1-chloroanthraquinone. The results of these reactions were found to strongly depend on the haloarene nature. The arylation with 1,3-dibromobenzene and 2,6-dibromopyridine led to the formation of new macrocyclic compounds containing one cholane, one arene, and two oxadiamine fragments.     

Model calculations for reactivities of polycyclic aromatic hydrocarbon metabolites

Structure-resonance theory calculations correlate reactivities and mutagenicities of polycylic aromatic hydrocarbon metabolites.     

Indium-catalyzed construction of polycyclic aromatic hydrocarbon skeletons via dehydration

Polycyclic aromatic compounds can be synthesized from 2-benzylic- or 2-allylbenzaldehydes using a catalytic amount of In(III) or Re(I) complexes. By using this method, polycyclic aza-aromatic compounds can also be prepared efficiently. In these reactions, only water is formed as a side product.