75110-13-3

Upstream product

• 57404-88-3 (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene 
• 63323-30-8 (+/-)-r-7,t-8-Dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene 
• 58917-91-2 (+/-)-7α,8β-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene 
• 55097-80-8 (+/-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzopyrene 

Relevant academic research and scientific papers

Physical Binding of Tetraols Derived from 7,8-Dihydroxy-9,10-epoxybenzopyrene to DNA

The major reactive metabolite of the carcinogen trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzopyrene (anti-BPDE) either reacts covalently with DNA or is hydrolyzed to the tetraol 7,8,9,10-tetrahydroxytetrahydrobenzopyrene (BPT).In this work it is shown that BPT binds noncovalently to DNA in aqueous buffer solution (5 mM sodium cacodylate buffer, pH 7.1) at 25 deg C.This binding, at values of the binding ratio r ca. 10-3, defined as the ratio of bound BPT molecules per DNA base, is characterized by two types of binding sites.Site I is characterized by a 10-nm red shift in the absorption spectrum ( a shift from 343 to 353 nm for the most intense absorption band of BPT), a complete quenching of the fluorescence of BPT at this site, and a negative linear dichroism spectrum.These properties are characteristic of an intercalation-type complex, in which the BPT molecule is sandwiched between adjcent base pairs of DNA.Equilibrium dialysis and absorption and fluorescence spectroscopy are the techniques utilized to demonstrate that there is a second type of binding site (II).This binding site is characterized by the following: (1) no shift in the absorption spectrum with respect to that of free BPT molecules in the buffer solution; (2) unchanged fluorescence yield, decay time, and susceptibility to oxygen quenching.It is proposed that site II corresponds to an external type of binding site of BPT on the DNA molecule, and the similarity between this type of binding and that of the covalent adduct formed between anti-BPDE and DNA is noted.At the low values of r studied here (1/950-1/4700), the ratio of BPT molecules at sites I and II lies in the range of 2-4, while 16 - 38percent of the total BPT molecules initially added remain free in solution.

Fluorinated alcohol mediated displacement of the C10 acetoxy group of benzo[a]pyrene-7,8,9,10-tetrahydrotetraol tetraacetates: A new route to diol epoxide-deoxyguanosine adducts

(Chemical Equation Presented) We describe a novel trifluoroethanol (TFE) or hexafluoropropan-2-ol (HFP) mediated substitution reaction of the bay-region C10 acetoxy group in four stereoisomeric 7,8,9,10-tetraacetoxy-7,8,9, 10-tetrahydrobenzo[a]pyrenes (tetraol tetraacetates, two pairs of cis and trans isomers at the 9,10 positions) by the exocyclic N2-amino group of O6-allyl-3′,5′-di-O-(tert-butyldimethylsilyl)-2′- deoxyguanosine (3). The tetraacetates are derived from cis and trans hydrolysis of (±)-7β,8α-dihydroxy-9β,10β-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (B[a]P DE-1) and of (±)-7β,8α- dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P DE-2) at C-10 followed by acetylation. Excellent yields and high regioselectivity were observed. Similar cis/trans product ratios were observed for each set of cis and trans tetraol tetraacetates derived from DE-1 (～75/25) and from DE-2 (～67/33) in HFP. This strongly suggests that the substitution proceeds via an SN1 mechanism involving a carbocation intermediate that is common to the cis and trans tetraacetates. Since it is likely that the cis and trans products from 3 arise from different conformations of the carbocation, its lifetime must be sufficiently long to permit conformational equilibration before its capture by the purine nucleophile. The corresponding reaction of (±)-9α-bromo-7β,8α,10β- triacetoxy-7,8,9,10-tetrahydrobenzo[a]pyrene with 3 in HFP was highly regio- and stereoselective and gave exclusively trans 10β-adducts. This newly developed substitution reaction provides an attractive alternative synthetic strategy for the preparation of polycyclic hydrocarbon adducted oligonucleotide building blocks.

Chloride ion catalyzed conformational inversion of carbocation intermediates in the hydrolysis of a benzo[a]pyrene 7,8-diol 9,10-epoxide

A highly efficient procedure for converting 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene (1) to its trans-9,10-chlorohydrin (5) with excellent yield and purity by the reaction of anhydrous HCI in THF has been developed. The rate of reac

Nitrogen dioxide as an oxidizing agent of 8-oxo-7,8-dihydro-2′-deoxyguanosine but not of 2′-deoxyguanosine

The redox reactions of guanine and its widely studied oxidation product, the 8-oxo-7,8-dihydro derivative, are of significant importance for understanding the mechanisms of oxidative damage in DNA. Employing 2′-deoxyguanosine 5′-monophosphate (dGMP) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) in neutral aqueous solutions as model systems, we have used nanosecond laser flash photolysis to demonstrate that neutral radicals, dGMP(-H)?, derived by the one-electron oxidation and deprotonation of dGMP, can oxidize nitrite anions (NO2-) to the nitrogen dioxide radical ?NO2. In turn, we show that ?NO2 can give rise to a one-electron oxidation of 8-oxo-G, but not of dGMP. The one-electron oxidation of dGMP was initiated by a radical cation generated by the laser pulse-induced photoionization of a pyrene derivative with enhanced water solubility, 7,8,9,10-tetrahydroxytetrahydrobenzo[α]pyrene (BPT). The dGMP(-H)? neutral radicals formed via deprotonation of the dGMP?+ radical cations and identified by their characteristic transient absorption spectrum (λmax ～ 310 nm) oxidize nitrite anions with a rate constant of(2.6 ± 0.3) × 106 M-1 s-1. The 8-oxo-dG is oxidized by ?NO2 with a rate constant of (5.3 ± 0.5) × 106 M-1 s-1. The 8-oxo-dG(-H)? neutral radicals thus generated are clearly identified by their characteristic transient absorption spectra (λmax ～ 320 nm). The rate constant of 8-oxo-dG oxidation (k12) by the ?NO2 one-electron oxidant (the ?NO2/NO2- redox potential, E° ≈ 1.04 V vs NHE) is lower than k12 for a series of oxidizing aromatic radical cations with known redox potentials. The k12 values for 8-oxo-dG oxidation by different aromatic radical cations derived from the photoionization of their parent compounds depend on the redox potentials of the latter, which were in the range of 0.8-1.6 V versus NHE. The magnitude of k12 gradually decreases from a value of 2.2 × 109 M-1 s-1 (E° = 1.62 V) to 5.8 × 108 M-1 s-1 (E° = 1.13 V) and eventually to 5 × 107 M-1 s-1 (E° = 0.91 V). The implications of these results, including the possibility that the redox cycling of the ?NO2/NO2- species can be involved in the further oxidative damage of 8-oxo-dG in DNA in cellular environments, are discussed.

New insights on the mechanisms of the pH-independent reactions of benzo[a]pyrene 7,8-diol 9,10-epoxides

The rates and products of the reactions of (±)-7β,8α-dihydroxy-9β,10β-epoxy-7,8,9, 10-tetrahydrobenzo[α]pyrene alpyrene (1) and (±)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9, 10-tetrahydrobenzo[α]pyrene (2) in water and dioxane-water mixtures have been determined over a pH range wider than that of earlier studies. This study provides additional insight on the mechanisms of the pH-independent reactions of 1 and 2. The rate profile for reaction of 1 shows acid-catalyzed hydrolysis at pH 11.5. The rate decrease between pH 10 and pH 11.5 is accompanied by a decrease in the yield of tetrols from 60% (pH 8) to 29% (pH 11.2) and is interpreted to be the result of a partial change in mechanism brought about by attack of hydroxide ion acting as a base to deprotonate a carbocation intermediate and regenerate 1 at pH + and HO-, respectively. The lack of a rate depression at pH 10 and the product studies for the reaction of 2 in dilute sodium azide solutions suggest that the tetrol-forming reactions of the pH-independent reaction of 2 are concerted or near-concerted.

Halide effects in the hydrolysis reactions of (±)-7β,8α-dihydroxy- 9α, 10α-epoxy-7,8,9,10-tetrahydrobenzo-[α]pyrene

Rates of reaction of (±)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10- tetrahydrobenzo[α]pyrene (DE-2) have been determined in 1:9 dioxane-water solutions containing 1.0 M KC1, 0.5 M KBr, and 0.1 M NaI over the pH range 4- 13. These pH-rate profiles are more complicated than those for reaction of DE-2 in 0.2 M NaC1O4 solutions and are interpreted in part by mechanisms in which halide ion attacks the diol epoxide as a nucleophile at intermediate pH, resulting in the formation of a trans-halohydrin. Reaction of DE-2 in these halide solutions at pH - , 0.5 M Br-, and 0.1 M I- on DE-2 are the principal reactions in the pH range ca. 6-9, leading to intermediate trans-halohydrins that hydrolyze to tetrols. At pH ca. 9-11, halohydrin formed from attack of halide ion on DE-2 reverts back to epoxide, leading to a negative break in the pH-rate profile. The main product-forming reaction of DE-2 at pH 11.3 is the spontaneous reaction. At pH > 12, the rate of reaction of DE-2 increases due to a second- order reaction of HO- with DE-2.

Photoemission probes of catalysis of benzo[a]pyrene epoxide reactions in complexes with linear, double-stranded and closed-circular, single-stranded DNA

Fluorescence intensity measurements of overall, pseudo-first-order rate constants for two epoxide-containing metabolites of benzo[a]pyrene (BP) were carried out in Tris, EDTA buffer (pH 7.3) without DNA, and in buffer with double-stranded calf thymus DNA (DS ctDNA) and with closed-circular, single-stranded viral M13mp19 DNA (SS M13 DNA). Highly purified SS M13 DNA was employed in order to avoid polymeric contamination which is present in DNA samples obtained using a standard preparation method relying on phenol extraction and which influences results from measurements of DNA-ligand interactions. The BP metabolites examined were highly carcinogenic (±)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[e]pyrene (BPDE) and less genotoxic benzo[a]pyrene 4,5-oxide (BPO). Without DNA, BPDE hydrolyzes to 7,8,9,10-tetrahydroxytetrahydro-BP, while BPO hydrolyzes to trans-4,5-dihydroxy-4,5-dihydro-BP (BP45D) and rearranges to 4-hydroxy-BP. With DNA, BPDE and BPO hydrolysis and rearrangement are catalyzed, and DNA modification occurs. In DS ctDNA, previous kinetic and binding measurements indicate that catalysis occurs primarily at intercalation sites. In SS M13 DNA (0.20 mM), BPDE has overall, pseudo-first-order rate constants (k) of (12 ± 1) × 10-3 and (2.8 ± 0.5) × 10-3 s-1, at Na+ concentrations of 2.0 and 100 mM, respectively. At these Na+ concentrations, values of k measured in SS M13 DNA are 3-16 times larger than values measured without DNA, but smaller than values measured in DS ctDNA. For BPO, the ordering of k values without DNA, with SS M13 DNA, and with DS ctDNA is the same as for BPDE. At 2.0 mM Na+, the nonreactive diols, trans-7,8-dihydroxy-7,8-dihydro-BP (BP78D) and BP45D, which are model compounds for BPDE and BPO, respectively, have SS M13 DNA association constants [(7.2 ± 0.5) × 103 and (2.7 ± 0.5) × 103 M-1] that are 2.3 times smaller than DS ctDNA association constants. In contrast, at 100 mM Na+, association constants for SS M13 DNA are 2.9-3.1 times larger than for DS ctDNA. Fluorescence lifetime measurements indicate that, in SS M13 DNA, reversible binding involves intercalation into local duplex regions. Estimated catalytic rate constants (kcat) for BPDE hydrolysis in SS M13 DNA, obtained from BP78D association constants and from k values measured with and without DNA, are (22.8 ± 2.5) × 10-3 and (3.5 ± 0.7) × 10-3 s-1, at 2.0 and 100 mM Na+, respectively. For this Na+ concentration range, the ratio of kcat values for DS ctDNA versus SS M13 DNA is almost constant (1.7 ± 0.6) even though the absolute kcat values vary by more than a factor of 5. The similar magnitudes of kcat values for SS M13 DNA and DS ctDNA provide evidence that catalytic sites in SS M13 DNA are similar to intercalated catalytic sites in DS ctDNA.

Trapping of a carbocationic intermediate in the spontaneous hydrolysis reaction of 7β,8α-dihydroxy-9β,10β-epoxy-7,8,9,10-tetrahydrobenzo[3]- pyrene: Mechanism of the spontaneous and general acid catalyzed hydrolysis reactions of bay-region benzo[a]pyrene 7,8-diol9,10-epoxides

The hydrolysis reactions of racemic 7β,8α-dihydroxy-9β,10β-epoxy-7,8,9,10-tetrahydrobenzo[a] pyrene (DE-1) and racemic 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a] pyrene (DE-2) in 1:9 dioxane-water solutions are catalyzed by a series of general acids consisting of Cl2CHPO3H-, ClCH2PO3H-, H2PO4-, and C2H5PO3H-. For the hydrolysis of DE-1 catalyzed by H3O+, H2O, and the above series of general acids, a plot of log kHA vs pKa gave a Br?nsted α of 0.39. A similar Br?nsted plot for the hydrolysis of DE-2 catalyzed by H3O+, Cl2CHPO3H-, ClCH2PO3H-, H2PO4-, and C2H5PO3H- gave an α of 0.40. It is concluded that the mechanism of the hydrolyses of both DE-1 and DE-2 catalyzed by the above general acids with pKa's 2O+, must occur by concerted proton transfer and benzyl C-O bond cleavage to yield carbocation intermediates. Dipolar intermediates are ruled out. An intermediate in the spontaneous reaction of DE-1 was trapped, subsequent to its rate-limiting formation, by azide and N-acetylcysteine anions. It is proposed that the rate-limiting step for the spontaneous reaction of DE-1 is formation of a benzylic carbocation intermediate, with a neutral water molecule acting as a proton donor. The rate constant for reaction of this carbocation with solvent is estimated to be 1.7 × 1077 s-1. Trapping of an intermediate by azide and N-acetylcysteine anions subsequent to a rate-limiting step in the spontaneous hydrolysis of DE-2 was not detected. Possible explanations for the differences in the hydrolysis reactions of DE-1 and DE-2 are given.

Bifunctional Catalysis in the Nucleotide-Catalyzed Hydrolysis of (+/-)-7β,8α-Dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzopyrene

The rates of reaction of (+/-)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzopyrene (DE-2) in 1:9 dioxane-water (v/v) solutions containing the 2'-, 3'-, and 5'-monophosphate derivatives of guanosine, adenosine, and cytidine have been determined.From plots of kobsd vs. concentration of nucleotide at several different pH values, it could be concluded that the monohydrogen phosphate ionization state was responsible for catalyzing the hydrolysis of DE-2.It was therefore assumed that the monohydrogen phosphate group acted as a general acid catalyst in the epoxide hydrolysis reaction.The second-order rate constants for the general acid catalyzed hydrolysis of DE-2 by the nucleotides listed above were determined.The 2'- and 5'-monophosphates of guanosine and adenosine are better general acid catalysts than the corresponding 3'-isomers, although the 3'-isomers are stronger acids.The guanosine and adenosine nucleotides are better catalysts than the cytidine monophosphates.It is concluded that not only does the monohydrogen phosphate group act as a general acid but the secondary interactions of a stacking nature between the aryl group of DE-2 and the base are important for catalytic effectiveness.

Guanosine 5'-Monophosphate Catalyzed Hydrolisis of Diastereomeric Benzopyrene-7,8-diol 9,10-Epoxides

The rates of reaction of 7β, 8α-dihydroxy-9β,10β-epoxy-7,8,9,10-tetrahydrobenzopyrene and 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzopyrene in aqueous dioxane solutions in the presence of 5'-guanosine monophosphate (5'-GMP) and guanosine (G) have been determined. 5'-GMP in the monohydrogen form (GMPH(-)) exhibits pronounced general acid catalysis in the hydrolysis of these epoxides under conditions where the corresponding nucleoside G is unreactive.Although the pKa values for GMPH(-) and inorganic dihydrogen phosphate ion (H2PO4(-)) are very similar, GMPH(-) is 60-80 times more efficient than H2PO4(-) in catalyzing the hydrolysis of the diol epoxides.Significant solvent effects on both GMPH(-) and H2PO4(-) have been observed.