Synthesis and reactivity of food derived promutagens and procarcinogens IQx and Trp-P-2.

摘要

N-acetyl-N-acetoxy-2-amino-3-methylaminoimidazo[4,5-f]quinoxaline, N-Ac-N-OAc-IQx, 2, was synthesized as a model derivative of the food derived mutagen and carcinogen IQx, 1. The decomposition kinetics showed pH dependence that is consistent with the uncatalyzed decomposition of the neutral form of 2. The products of the decomposition in phosphate and acetate buffers were identified. Addition of nucleophiles N ₃− and dG at neutral pH did not affect the rate of decomposition of 2. This is also consistent with the formation of a nitrenium ion intermediate as the rate determining step during the decomposition of 2. The k_az/k_s and k_dG/K _s selectivity ratios were determined to be (5.2 ± 0.5) × 104 M−1 and (9.1 ± 2.1) × 102 M−1, respectively. The structure of the product at neutral pH and also in the presence of the added nucleophiles is consistent with the formation of a nitrenium ion intermediate during the decomposition of 2. In the presence of dG, both the C-8 and N-2 adducts were isolated. The major adduct formed in the presence of dG was the C-8 adduct.; 3-(N-Acetoxy-N-acetyl)-amino-1-methyl-5H-pyrido[4,3- b]indole, N-OAc-N-Ac-Trp-P-2, 4, was synthesized as a model derivative of the food derived mutagen and carcinogen Trp-P-2, 3. The kinetics of the decomposition of 4 show that there are two consecutive processes at most pH values. One of the processes corresponds to the disappearance of 4 according to HPLC studies. The compound 4 showed pH-dependent hydrolysis kinetics that is consistent with the uncatalyzed decomposition of the neutral form and the acid catalyzed decomposition of the protonated form. The pK_a of the compound was determined by the kinetic method to be 3.84 ± 0.08. The ester 4 undergoes acid catalyzed ester hydrolysis to generate the corresponding hydroxamic acid at pH 1.6.