Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycyclic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mechanisms of activation, (+/)-trans-DB[a,l]P-11,12-dihydrodiol, (+/-)-anti-DB[a,l]PDE and (+/-)-syn-DB[a,l]PDE were synthesized. The key intermediate for these syntheses, 12-methoxy-DB[a,l]P, was successfully obtained by cyclization of 6-(3-methoxybenzyl)benzanthrone with methanesulfonic acid, which in turn was prepared by 1,4 conjugate addition of 3-methoxybenzyl magnesium bromide to benzanthrone. The presence of the DB[a,l]P nucleus in the dihydrodiolepoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,l]P into the parent compound in several steps. The tumor-initiating activity of the two diolepoxides in mouse skin was compared to that of DB[a,l]P-11,12-dihydrodiol and the parent DB[a,l]P. Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 1.33 nmol of compound in 100 microliters of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol in 100 microliters acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 1.33 nmol doses, anti-DB[a,l]PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn-DB[a,l]PDE induced 1.8, 1.5 and 1.8 t/m. At the same three doses, DB[a,l]P-11,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[a,l]P resulted in 9.3, 7.1 and 5.2 t/m. These results confirm that DB[a,l]P is more potent than its 11,12-dihydrodiol and show that the two diolepoxides are less tumorigenic than their precursors. At the medium and low doses, syn-DB[a,l]PDE is more tumorigenic than its congener anti-DB[a,l]PDE.

Cyclodisilazanes with mixed silicon-substituted groups {Cl(CH8)RSi[SiR(CH8)N]2SiR(CH3)Cl} can be prepared either by heating mixtures of [R(CH3)SiNH]3 and R(CH3)SiCl2 or by treating HN[Si(CH3)RCl]2 with butyllithium and heating the product. One or both of the methods are shown to be applicable where R is ethyl, vinyl, phenyl, or 3,3,3-trifluoropropyl as well as methyl. The properties of the intermediate cyclotrisilazanes and disilazanes as well as the dialkylamino derivatives of the cyclodisilazanes are described.

A large proportion of the metabolites formed from benzo[a]pyrene (BP) in cell cultures from rodents, fish and humans result from conjugation of an oxidized metabolite of BP with sulfate, glucuronic acid or glutathione (GSH). To improve the analysis of these metabolites, a reversed-phase ion-pair h.p.l.c. system using a step gradient of methanol:tetrabutyl-ammonium bromide in ammonium formate buffer has been developed for the separation of these three classes of conjugates. This system separated 3-hydroxy-BP glucuronide and sulfate conjugates and resolved them from GSH conjugates of BP 4,5-oxide, 7,8-oxide and 7,8-diol-9,10-epoxide. Cultures of early passage Syrian hamster, Wistar rat and Sencar mouse embryo cells, a bluegill fry (BF-2) cell line and a human hepatoma cell line (HepG2) were exposed to [3H]BP for 24 h. Medium samples from each were extracted with chloroform: methanol:water, and the water-soluble metabolites were analyzed by ion-pair h.p.l.c. The largest peak of metabolites in the media from cell cultures from rodents and the bluegill fry cell line co-eluted with the glucuronic acid conjugate of 3-hydroxy-BP. These phenol-glucuronides represented 48-62% of the total water-soluble metabolites in the fish and rodent cell cultures. Treatment of this material with beta-glucuronidase released 3-hydroxy-BP and 9-hydroxy-BP in ratios from 3:4 to 13.3:1 in various cultures. Media from the bluegill fry cell line and the mouse embryo cell cultures also contained a peak of BP-diol glucuronides; treatment of these peaks with beta-glucuronidase released mainly BP-7,8-diol. In HepG2 cells, 40% of the water-soluble metabolites were identified as sulfate conjugates of 3-hydroxy-BP and 9-hydroxy-BP. No glucuronic acid conjugates of BP metabolites were detected in HepG2 cells. Only small amounts of the water-soluble metabolites from these cell cultures eluted in the same volumes as the synthetic GSH conjugate of BP-4,5-oxide, BP-7,8-oxide and BP-7,8-diol-9,10-oxide. These studies indicate that conjugation with glucuronic acid represents a major pathway of formation of water-soluble metabolites from BP in cells derived from a number of species and demonstrate the value of this ion-pair h.p.l.c. system for the analysis of conjugates formed from BP.

The carcinogenic tobacco-specif ic nitrosamines 4-(methylnitrosemino) -1-(3-pyridyl) -1-butanone (NNK) and N'-nitrosonornicotine (NNN), as well as the model compound 4-(carbethoxynitrosamino) -1-(3-pyridyl) -1butanone, were synthesized with tritium at the 5-position of the pyridine ring. In each case, the tritium labelled compound was prepared by catalytic tritium replacement of the corresponding brominated precursor. This intermediate as well as the a-hydroxy compounds , 1 and 2 are unstable and have not been synthesized. However, 4-(carbethoxynitrosamino) -1-(3-pyridyl) -1-butanone, 1, is a stable precursor to A (2.3). In order to investigate the interactions of NNK, NNN, and 1 with DNA and protein, the tritium labelled compounds were required. Metabolic studies of "K and "N indicate that hydroxylation of the pyridine ring is not a major process ( 4 ) . Thus, to avoid exchange L n -0, tritium was specifically incorporated at the 5-position of the pyridine ring. DNA and globln adducts Scheme 1 RESULTS AND DISCUSSION The synthesis of [5-3H]NNK is illustrated in Scheme 2. The method is based on that used for unlabelled "K ( 5 , 6 ) . Ethyl 5bromonicotinate, 2, was reacted with N-methylpyrrolidinone, 5 , to give the intermediate condensation product 2. Tritiation of 1 by J. C. Wiley Jr. et al.

No abstract