甲基-2-氧代丙基亚硝胺的α-乙酰氧基衍生物：合成、水解速率及细菌诱变性

Alpha-acetoxy derivatives of methyl-2-oxopropylnitrosamine: synthesis, hydrolysis rate and bacterial mutagenicity.

作者信息

Nagel D L, Mirvish S S, Wallcave L, Walker B

机构信息

Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68105.

出版信息

Cancer Lett. 1987 Sep;36(3):325-32. doi: 10.1016/0304-3835(87)90026-7.

DOI:10.1016/0304-3835(87)90026-7

PMID:3308074

Abstract

N-Methyl-N-2-oxopropylnitrosamine (MOP) induces pancreatic tumors in hamsters. As models for the putative proximate carcinogenic alpha-hydroxy derivatives, we studied N-acetoxymethyl-N-2-oxopropylnitrosamine (AMOP) and N-methyl-N-(1-acetoxy-2-oxopropyl)nitrosamine (MAOP). AMOP was synthesized from aminoacetone by the method of Roller et al. [1975), Tetrahedron Lett., 25, 2065-2068) and MAOP was synthesized by acetoxylation of MOP with lead tetraacetate. The half-lives of AMOP, MAOP and acetoxymethylmethylnitrosamine (ADMN) in aqueous buffer decreased as the pH rose from 5 to 9, with values at pH 5 of 2.8 X 10(4) min for AMOP, 3.2 X 10(3) min for ADMN, and 23 min for MAOP. Mutagenicity was examined in Salmonella typhimurium TA1535, using a pre-incubation at pH 5 without microsomal activation. The mutagenic potency, expressed as revertants/mumole, was 56 for AMOP, 150 for ADMN, and 4.5 X 10(4) for MAOP. Hence, hydrolysis rates at pH 5 were probably important in determining the relative mutagenicity.

摘要

N-甲基-N-2-氧代丙基亚硝胺（MOP）可诱发仓鼠胰腺肿瘤。作为假定的致癌性α-羟基衍生物的模型，我们研究了N-乙酰氧基甲基-N-2-氧代丙基亚硝胺（AMOP）和N-甲基-N-（1-乙酰氧基-2-氧代丙基）亚硝胺（MAOP）。AMOP是根据Roller等人[1975年，《四面体通讯》，25，2065 - 2068]的方法由氨基丙酮合成的，MAOP是通过用四乙酸铅对MOP进行乙酰氧基化合成的。在水性缓冲液中，随着pH从5升至9，AMOP、MAOP和乙酰氧基甲基甲基亚硝胺（ADMN）的半衰期缩短，在pH 5时，AMOP的半衰期为2.8×10⁴分钟，ADMN为3.2×10³分钟，MAOP为23分钟。在鼠伤寒沙门氏菌TA1535中检测致突变性，在pH 5下预孵育且无微粒体激活。以回复突变体/微摩尔表示的致突变效力，AMOP为56，ADMN为150，MAOP为4.5×10⁴。因此，pH 5时的水解速率可能对确定相对致突变性很重要。