Convenient syntheses of dibenzo[c,p]chrysene and its possible proximate and ultimate carcinogens: in vitro metabolism and DNA adduction studies.
Dibenzo[c,p]chrysene (DB[c,p]C) is the only hexacyclic polycyclic aromatic hydrocarbon having two fjord regions, both in different chemical environments. Its environmental presence and relative tumorigenic potency are not known due to the lack of synthetic standards. We report here the synthesis of dibenzo[c,p]chrysene (1), its proximate carcinogens, i.e., trans-1,2-dihydroxy-1,2-dihydro-DB[c,p]C (2) and trans-11,12-dihydroxy-11,12-dihydro-DB[c,p]C (3), and possible ultimate carcinogens, i.e., anti-trans-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-DB[c,p]C (4) and anti-trans-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydro-DB[c,p]C (5). The syntheses of 1 and the appropriately methoxy-substituted DB[c,p]C (12 and 27), key intermediates for the synthesis of its proximate and ultimate metabolites, were tried first using a Suzuki cross-coupling reaction. However, the cyclization of olefins (10 and 11) gave poor yields of the desired products. An alternate method was thus developed employing a photochemical approach. The in vitro metabolism of DB[c,p]C was established with the S9 fraction of liver homogenate from phenobarbital/beta-naphthoflavone-induced Sprague-Dawley rats. The major dihydrodiol formed was identified as the fjord region 11,12-dihydroxy-11,12-dihydro-DB[c,p]C, while the major and minor phenols were identified as 11-hydroxy-DB[c,p]C and 12-hydroxy-DB[c,p]C, respectively. Further, the DNA adduction studies with the calf thymus DNA led to a mixture of dA and dG adducts for both fjord region diol epoxides (4 and 5). Interestingly, the dA to dG ratio for 1,2-dihydroxy-3,4-epoxide was much higher (3.2) compared to that of 11,12-dihydroxy-13,14-epoxide (0.5).
Sharma
Arun K
AK
Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Department of Pharmacology, H078, 500 University Drive, Hershey, PA 17033, USA.
Lin
Jyh-Ming
JM
Desai
Dhimant
D
Amin
Shantu
S
D000818:Animals; D002274:Carcinogens, Environmental / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D002911:Chrysenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D018736:DNA Adducts / Q000138:chemical synthesis; D008099:Liver / Q000187:drug effects; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019324:beta-Naphthoflavone / Q000494:pharmacology
D002274:Carcinogens, Environmental; D002911:Chrysenes; D018736:DNA Adducts; C502062:dibenzo(c,p)chrysene; D019324:beta-Naphthoflavone; D010634:Phenobarbital