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.
Ran
Chongzhao
C
The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois 60637, USA.
Dai
Qing
Q
Ruan
Qian
Q
Penning
Trevor M
TM
Blair
Ian A
IA
Harvey
Ronald G
RG
D000586:Amination; D001564:Benzo(a)pyrene / Q000737:chemistry / Q000378:metabolism; D002273:Carcinogens / Q000737:chemistry*; D002396:Catechols / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D003853:Deoxyribonucleosides / Q000737:chemistry*; D054879:Halogenation; D007536:Isomerism; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry*; D011809:Quinones / Q000737:chemistry* / Q000378:metabolism*
D002273:Carcinogens; D002396:Catechols; D003853:Deoxyribonucleosides; D011084:Polycyclic Aromatic Hydrocarbons; D011809:Quinones; D001564:Benzo(a)pyrene; D010165:Palladium; D003300:Copper