Stereoselectivity of the epoxidation of 7,8-dihydrobenzo[a]pyrene by prostaglandin H synthase and cytochrome P-450 determined by the identification of polyguanylic acid adducts.

The stereoselectivity of the oxidation of 7,8-dihydrobenzo[a]pyrene (H2BP) to 9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (H4BP-epoxide) by prostaglandin H (PGH) synthase and cytochrome P-450 has been studied using microsomal preparations from ram seminal vesicles and rat liver. Incubations were performed in the presence of polyguanylic acid and the adducts formed between H4BP-epoxide and guanosine were isolated following the recovery and hydrolysis of the poly(G). When (+/-)-H4BP-epoxide was reacted with poly(G), four diastereomeric adducts were formed by the cis and trans addition of the exocyclic amino group of guanine to the benzylic carbon of the epoxide enantiomers.

Potential antitumor agents. 36. Quantitative relationships between experimental antitumor activity, toxicity, and structure for the general class of 9-anilinoacridine antitumor agents.

Quantitative relationships (QSAR) have been derived between antileukemic (L1210) activity and agent physicochemical properties for 509 tumor-active members of the general class of 9-anilinoacridines. One member of this class is the clinical agent m-AMSA (NSC 249992). Agent hydrophobicity proved a significant but not a dominant influence on in vivo potency.

A comparison of mutagenic and carcinogenic activities of aniline mustards.

A set of 15 derivatives of aniline mustard (I) was tested to give a quantitative measure of mutagenicity in Salmonella typhimurium TA-1535 and TA-100 and also carcinogenicity as lung tumors in strain-A mice. The structural variation in the set was chosen to minimize collinearity between hydrophobic, electronic, and molar refractive properties. By these measures, there was not a direct relationship between mutagenicity and carcinogenicity; in fact, since the 4-OPh analogue ranked highest in mutagenicity and among the lowest in carcinogenicity, while the reverse was noted for the 3,5-(NHCONH2)2 analogue, an inverse relationship was marginally significant.

Arachidonic acid-dependent metabolism of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to polyguanylic acid-binding derivatives.

Microsomal and solubilized enzyme preparations from ram seminal vesicles catalyze the oxidation of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[alpha]-pyrene (BP-7,8-diol) to derivatives which covalently bind to polyguanylic acid (poly(G)). Oxidation requires prostaglandin endoperoxide synthetase and its substrate arachidonic acid and is inhibited by indomethacin. High performance liquid chromatographic (HPLC) analysis of the nucleoside adducts obtained following chemical and enzymatic digestion reveals an adduct pattern which is identical to that obtained by the reaction of poly(G) with (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene (diol-epoxide 2).