Novak Michael, Toth Krisztina, Rajagopal Sridharan, Brooks Michael, Hott Lora L, Moslener Matthew
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, USA.
J Am Chem Soc. 2002 Jul 10;124(27):7972-81. doi: 10.1021/ja0121944.
The model ultimate carcinogens 1a-d, related to the metabolites of the food-derived carcinogenic heterocyclic amines Glu-P-1, Glu-P-2, MeIQx, and IQx, spontaneously decompose in neutral aqueous solution to generate the heterocyclic nitrenium ions, 2a-d. The less reactive esters 1a and 1b also undergo acid-catalyzed ester hydrolysis to generate the corresponding hydroxamic acids at pH <2, while the more reactive 2c and 2d are prone to rearrangement in nonaqueous solvents. The reactions of the nitrenium ions with AcO(-), HPO(4)(2-), N(3)(-), and 2'-deoxyguanosine (d-G) were characterized in aqueous solution by using a combination of competitive trapping methods and product isolation and identification. The reactions with N(3)(-) and d-G generally follow patterns previously established for carbocyclic nitrenium ions, but the reactions with AcO(-) and HPO(4)(2-) are unusual. Similar reactions have previously only been reported for heterocyclic 1-alkyl-2-imidazolium ions. The N(3)(-)/solvent selectivities of these ions (5.1 x 10(6) M(-1) for 2a, 2.3 x 10(6) M(-1) for 2b, 1.2 x 10(5) M(-1) for 2c, and 5.2 x 10(4) M(-1) for 2d) are comparable to those of highly selective carbocyclic nitrenium ions. If k(az) for these ions is diffusion limited at ca. 5 x 10(9) M(-1) s(-1) the aqueous solution lifetimes of these ions range from 10 micros (2d) to 1 ms (2a). These ions are also highly selective for trapping by d-G, but comparisons to other nitrenium ions show that they are 10- to 50-fold less selective for trapping by d-G than they would be if both the N(3)(-) and d-G reactions were diffusion limited. This is not a consequence of their heterocyclic structures. Several carbocyclic ions show similar behavior. The relatively inefficient trapping of 2c and 2d by d-G may account for the observation of the unusual minor N-2 d-G adduct that is isolated for both of these nitrenium ions, but has not previously been observed for the reactions of other nitrenium ions with monomeric d-G.
与食物来源的致癌杂环胺Glu-P-1、Glu-P-2、MeIQx和IQx的代谢产物相关的模型终极致癌物1a-d在中性水溶液中自发分解，生成杂环氮鎓离子2a-d。反应活性较低的酯1a和1b在pH<2时也会发生酸催化的酯水解反应，生成相应的异羟肟酸，而反应活性较高的2c和2d在非水溶剂中易于重排。通过竞争性捕获方法与产物分离和鉴定相结合，对氮鎓离子与AcO(-)、HPO(4)(2-)、N(3)(-)和2'-脱氧鸟苷(d-G)在水溶液中的反应进行了表征。与N(3)(-)和d-G的反应通常遵循先前为碳环氮鎓离子建立的模式，但与AcO(-)和HPO(4)(2-)的反应则不同寻常。类似的反应此前仅见诸于杂环1-烷基-2-咪唑鎓离子的报道。这些离子的N(3)(-)/溶剂选择性(2a为5.1×10(6) M(-1)，2b为2.3×10(6) M(-1)，2c为1.2×10(5) M(-1)，2d为5.2×10(4) M(-1))与高选择性碳环氮鎓离子相当。如果这些离子的k(az)在约5×10(9) M(-1) s(-1)时受扩散限制，那么这些离子在水溶液中的寿命范围为10微秒(2d)至1毫秒(2a)。这些离子对d-G捕获也具有高度选择性，但与其他氮鎓离子的比较表明，如果N(3)(-)和d-G反应均受扩散限制，它们对d-G捕获的选择性要低10至50倍。这并非其杂环结构所致。几种碳环离子也表现出类似行为。d-G对2c和2d的捕获效率相对较低，这可能解释了为何在这两种氮鎓离子反应中均分离出异常的次要N-2 d-G加合物，而此前在其他氮鎓离子与单体d-G的反应中尚未观察到这种情况。
