Benzo pyrene synthesis

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

Environmental chemicals and pollutants are also capable of inducing P450 enzymes. As previously noted, exposure to benzo[a]pyrene and other polycyclic aromatic hydrocarbons, which are present in tobacco smoke, charcoal-broiled meat, and other organic pyrolysis products, is known to induce CYP1A enzymes and to alter the rates of drug metabolism. Other environmental chemicals known to induce specific P450s include the polychlorinated biphenyls (PCBs), which were once used widely in industry as insulating materials and plasticizers, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a trace byproduct of the chemical synthesis of the defoliant 2,4,5-T (see Chapter 56). 

Other cycloadditions of interest include the photoaddition [Eq. (52)] of pyrimidine derivatives such as cytosine to the carcinogenic hydrocarbon benzo[a]pyrene,191 and the photoaddition of allene as a vital step [Eq. (53)] in the synthesis of an annotinine derivative.192... 

Based on this sequence, Blum et a/.158 have reported a general synthesis of unsubstituted K-region arene imines from the corresponding arene oxides. K-Imines of benz[a] anthracene, 7-methylbenz[a]anthracene, dibenz [a,/i] anthracene, and benzo[a] pyrene have been prepared. Azido alcohol formation from these oxides is generally nonregiospecific and both possible regioisomers of the azido alcohols are formed in different proportions. 

Increased P450 synthesis requires enhanced transcription and translation. A cytoplasmic receptor (termed AhR) for polycyclic aromatic hydrocarbons (eg, benzo[a]pyrene, dioxin) has been identified, and the translocation of the inducer-receptor complex into the nucleus and subsequent activation of regulatory elements of genes have been documented. A pregnane X receptor (PXR), a member of the steroid-retinoid-thyroid hormone receptor family, has recently been shown to mediate CYP3 A induction by various chemicals (dexamethasone, rifampin) in the liver and intestinal mucosa. A similar receptor, the constitutive androstane receptor (CAR) has been identified for the phenobarbital class of inducers (Sueyoshi, 2001 Willson, 2002). 

A similm methodtdqgy was used by Boichardt and coworkers in the synthesis of the phenol (26 Scheme 11). Here, the fact that 4-fluorophenol metallates next to fluorine when the phenol is protected as a TBDMS ether was put to good use for introduction of the hydroxy group, likewise, oxidation of a boron complex was a key step in the synthesis of phenolic dihydrodiols of benzo[a]pyrene, (27) and... 

Provost reaction. This reaction constitutes an important step in a synthesis of frans-7,8-dihydroxy-anfi-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (3), considered to be the ultimate carcinogenic metabolite of benzo[a]pyrene. To obtain satisfactory yields, the silver benzoate should be freshly prepared (method of Newman and Beal, 1, 1004), and the biphase reaction should be stirred efficiently (Vibromixer with a large stirring blade). ... 

The synthesis of LA-pyrenemethylamine conjugate 393 and its self-assembled organic monolayer formed on a gold surface, based as in previous examples on the anchoring ability of the cyclic disulfide moiety of LA, has been carried out <2000ELA21> for the purpose of the potential design of electrochemical immunosensors of monoclonal antibody-benzo [a pyrene interaction. 

Translesion synthesis with DNA Pol of the A-acetyl-2-aminofluorene adduct of guanosine (88) is inefficient with templates containing (88). In the presence of the Revl protein, translesion synthesis occurs and dCTP is the major nucleotide incorporated opposite it, and studies with a mutant DNA Pol I gave similar results. Benzo[a]pyrene is a potent environmental carcinogen, which when metabolised leads to u t -benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide anti-BPDE). With dG, the major lesion is (+)-tra w-a h-B[a]P-A -dG, (89), and is usually repaired by the nucleotide excision repair (NER) pathway. The translesion synthesis past (89) has been examined with a number of polymerases. With human RNA Pol II, (89) is a block to synthesis, whilst DNA Pol k preferentially incorporated the correct nucleotide. In yeast cells, Pol induced a large number of mutations involving Pol p, whilst Pol p alone contributed to 1-3 deletions or insertions. The NER of (89) with UvrB proteins was also studied. ... 

In contrast to the relatively uniform evidence that benzo[a]pyrene is a genotoxin in whole animals, the test material failed to induce unscheduled DNA synthesis (UDS) in the parenchymal liver cells of Brown Norway rats exposed by oral gavage to 12.5 mg/mL (Mullaart et al. 1989). There was, however, a clear increase in single-strand DNA breaks in cells from the two major centers of metabolism (the parenchymal liver and intestinal cells) of the treated animals that was not apparent in the nonparenchymal liver cells. 

PAHs appear to affect other blood elements, as well. The influence of several PAHs on calcium ionophore-induced activation of isolated rabbit platelets was studied (Yamazaki et al. 1990). The activation of the platelets was assessed by measuring thromboxane 62 synthesis in response to stimulation by the calcium ionophore, A-23187. The authors reported that thromboxane 62 synthesis was inhibited by incubation of the stimulated platelets with benz[a]anthracene, chrysene, benzo[a]pyrene, and benzo[g,h,i]perylene, and stimulated by incubation with anthracene and pyrene. However, no statistical analysis was performed on these data, and the changes reported are generally within 10% of control values. In addition, the effects of the PAHs on thromboxane B2 synthesis are bidirectional, and in many instances, the same compound induced both inhibition and stimulation at different concentrations. 

The lymphoid system, because of its rapidly proliferating tissues, is susceptible to PAH-induced toxicity. The mechanism of action for this effect is most likely inhibition of DNA synthesis. No adverse effects on this system associated with PAH exposure have been reported in humans, but several accounts of lymphoid toxicity in animals are available. A single intraperitoneal injection of benzo[a]pyrene to mice resulted in a small spleen with marked cellular depletion, prominent and edematous trabeculae, and large lymphocytes. These lesions resulted in death (Shubik and Porta 1957). The Shubik and Porta (1957) study was severely limited by the following the benzo[a]pyrene was only partly in solution, only one dose was employed, there was a small size, the purity of benzo[a]pyrene was not specified, only one sex was tested, and the presence of benzo[a]pyrene in the peritoneal cavity indicates inadequate absorption. No other similar studies were found in the literature. 

Burlinson B, Ashby J. 1988. Inactivity of benzo(a)pyrene in a weanling rat liver, unscheduled DNA synthesis assay. In Evaluation of short-Term tests for carcinogens Report of the International Collaborative Program. Prog Mutat Res 1 389-390. 

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