60864-95-1Relevant articles and documents
Synthesis of 13C4-labelled oxidized metabolites of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene
Wu, Anhui,Xu, Daiwang,Lu, Ding,Penning, Trevor M.,Blair, Ian A.,Harvey, Ronald G.
, p. 7217 - 7233 (2012/09/05)
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 13C 4-BaP metabolites were estimated to be ≥99.9%.
Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis
Lakshman, Mahesh K.,Keeler, John C.,Ngassa, Felix N.,Hilmer, John H.,Pradhan, Padmanava,Zajc, Barbara,Thomasson, Kathryn A.
, p. 68 - 76 (2008/04/18)
A diastereoselective synthesis of the nucleoside adducts corresponding to a cis ring-opening of the carcinogen (±)-7β,8α-dihydroxy- 9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE-2) by 2′-deoxyadenosine and 2′-deoxyguanosine is described. The key
Synthesis of the o-Quinones and Other Oxidized Metabolites of Polycyclic Aromatic Hydrocarbons Implicated in Carcinogenesis
Harvey, Ronald G.,Dai, Qing,Ran, Chongzhao,Penning, Trevor M.
, p. 2024 - 2032 (2007/10/03)
Efficient new syntheses of the o-quinone derivatives of benzo[a]pyrene (BPQ), 7,12-dimethylbenz-[a] anthracene (DMBAQ), and benz[a]anthracene (BAQ), implicated as active carcinogenic metabolites of the parent polycyclic aromatic hydrocarbons (PAHs), are reported. These PAH quinones also serve as starting compounds for the synthesis of the other active metabolites of these PAHs thought to be involved in their mechanism(s) of carcinogenesis. The latter include the corresponding o-catechols, trans-dihydrodiols, and the corresponding anti- and syn-diol epoxides.
Evaluation of the enantiomeric resolution of 7,8-dihydroxy-7,8-dihydrobenzo[a]-pyrene and its 6-fluoro and 6-bromo derivatives on polysaccharide-derived stationary phases
Zajc, Barbara,Grahek, Rok,Kocijan, Andrej,Lakshman, Mahesh K.,Kosmrlj, Janez,Lah, Jure
, p. 3291 - 3294 (2007/10/03)
The enantiomeric resolution and the elution order of (±)-trans-7,8-dihydrodiols of benzo[a]pyrene and its 6-fluoro and 6-bromo derivatives were analyzed on three polysaccharide-based columns: Daicel Chiralcel CA-I (cellulose triacetate), OF, and OG [cellu
Metabolism of benzo[a]pyrene to trans-7,8-dihydroxy-7,8- dihydrobenzo[a]pyrene by recombinant human cytochrome P450 1B1 and purified liver epoxide hydrolase
Shimada, Tsutomu,Gillam, Elizabeth M. J.,Oda, Yoshimitsu,Tsumura, Fujiko,Sutter, Thomas R.,Guengerich, F. Peter,Inoue, Kiyoshi
, p. 623 - 629 (2007/10/03)
Recombinant human enzymes expressed in membranes obtained from Escherichia coli transformed with cytochrome P450 (P450) and NADPH-P450 reductase cDNAs were used to identify the human P450 enzymes that are most active in catalyzing the oxidative transformation of benzo[a]pyrene in vitro. Activation of benzo[a]pyrene to genotoxic products that cause induction of umu gene expression in Salmonella typhimurium NM2009 by P450 1A1 and P450 1B1 enzymes was found to be enhanced by inclusion of purified epoxide hydrolase (isolated from rat or human livers) with the reaction mixture. High- performance liquid chromatographic analysis showed that P450 1B1 catalyzed benzo[a]pyrene to trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene at level of ~3 nmol min-1 nmol of P450-1 only when epoxide hydrolase was present and P450 1A1 (with the hydrolase) was able to catalyze benzo[a]pyrene at one- tenth of the activity catalyzed by P450 1B1. Kinetic analysis showed that ratio of V(max) to K(m) for the formation of trans-7,8-dihydroxy-7,8- dihydrobenzo[a]pyrene in this assay system was 3.2-fold higher in CYP1B1 than in CYP1A1. Other human P450s (including P450s 1A2, 2E1, and 3A4) were found to have very low or undetectable activities toward the formation of trans- 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene. A reconstituted system containing purified P450 1B1, rabbit liver NADPH-P450 reductase, and human liver epoxide hydrolase was found to catalyze benzo[a]pyrene to trans-7,8-dihydroxy-7,8- dihydrobenzo[a]pyrene at a rate of 0.86 nmol min-1 nmol of P450-1; the activities were found to be largely dependent on the presence of sodium cholate in the system. These results suggest that P450 1B1 is a principal enzyme in catalyzing the oxidation of benzo[a]pyrene to trans-7,8-dihydroxy- 7,8-dihydrobenzo[a]pyrene and that the catalytic functions of P450 1B1 may determine the susceptibilities of individuals to benzo[a]-pyrene carcinogenesis.
Resolution of polycyclic aromatic hydrocarbon dihydrodiols via diastereomeric formaldehyde acetals
Lakshman, Mahesh K.,Chaturvedi, Surendrakumar,Kole, Panna L.,Windels, James H.,Myers, Mark B.,Brown, Michael A.
, p. 3375 - 3378 (2007/10/03)
Diastereomeric formaldehyde acetals, formed from the reaction of racemic benzo[a]pyrene dihydrodiol and (-)-chloromethylmenthyl ether, are novel intermediates for effecting the convenient resolution of these metabolites by HPLC. This resolution technique seems generally applicable since the dihydrodiols of benzo[c]phenanthrene can also be readily resolved through this methodology. Key differences in the proton NMR spectra of the diastereomeric dihydrodiol menthyloxymethyl ethers have been identified which could be used for absolute stereochemical assignments.
Enantioselective Synthesis of the (+)-anti-7,8-Dihydrodiol-9,10-epoxide of the Potent Carcinogen Benzopyrene
Huang, Xiaoming,Harris, Thomas M.
, p. 1699 - 1700 (2007/10/02)
The title compound, the most important genotoxic metabolite of benzopyrene, has been prepared efficiently in a synthesis which capitalized on Jacobsen-type enantioselective epoxidation of 9,10-dihydrodibenzopyrene, cleavage of the epoxide by KOH-Me2SO to give the tetrahydro-trans-7,8-diol, and formation of the dibenzoate from which the contaminating antipode was removed by crystallization.
Enantioselective synthesis of the tumorigenic anti-diol epoxide metabolites of benzo[a]pyrene
Harvey, Ronald G.
, p. 2737 - 2740 (2007/10/02)
Efficient, highly enantioselective syntheses of (+) and (-)-anti-benzo[a]pyrene diol epoxide (BPDE) from 9,10-dihydrobenzo[a]pyrene are described. Initial epoxidation catalyzed by (salen) Mn(III) complex gives 7,8-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (
Improved Formal Preparation of Enantiomerically Pure anti-Benzopyrene Diol Epoxide.
Negrete, George R.,Meehan, Thomas
, p. 4727 - 4730 (2007/10/02)
We report an improved, economical formal route to enantiomerically pure anti-benzopyrene diol epoxide (BPDE).A trimethylaluminum catalyzed regio- and stereoselective opening of racemic 7,8-epoxy-7,8,9,10-tetrahydrobenzopyrene with Mosher's acid delivers benzylic esters exclusively.This step is a significant improvement over the lack of regioselectivity of standard procedures.We also show that modification of the subsequent chemical steps further shortens the preparation of enantiomerically pure anti-BPDE.
