Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States.
J Org Chem. 2013 Jul 19;78(14):6992-7000. doi: 10.1021/jo400826f. Epub 2013 Jul 1.
Ring-substituted derivatives of 2-(4-aminophenyl)benzothiazole, 1a, 1b-g, are under development as antitumor agents. One derivative, 1f, has reached phase 1 clinical trials as the prodrug 2f, Phortress (NSC 710305). These amines are activated by CYP450 1A1, apparently into hydroxylamines 8a-g that are likely metabolized into esters that ionize into nitrenium ions responsible for cellular damage. Previously we showed that 9a, the acetic acid ester of 8a, generates the long-lived (530 ns) nitrenium ion 11a by hydrolysis or photolysis in water. In this study, azide trapping shows that 9b-g generate 11b-g via rate-limiting N-O heterolysis. Ion lifetimes, estimated from azide/solvent selectivities, range from 250 to 1150 ns with identical lifetimes for 11a and 11f. Differences in biological activity of the amines are likely not due to differences in the chemistry of the cations but to differences in metabolic activation/deactivation of individual amines. Unlike the nitrenium ions, lifetimes of the esters are strongly dependent on the 3'-Me substituent. Esters containing 3'-Me (9b, 9f, 9g) have lifetimes of 5-10 s compared to 400-800 s for esters without 3'-Me (9a, 9c, 9d, 9e). This restricts 3'-Me esters to cells/tissues in which activation occurs, concentrating their effects in tumor cells if metabolism is restricted to those cells.
作为抗肿瘤药物，2-(4-氨基苯基)苯并噻唑的环取代衍生物，1a、1b-g，正在开发中。其中一种衍生物 1f 已作为前药 2f（Phortress，NSC 710305）进入 1 期临床试验。这些胺类化合物由 CYP450 1A1 激活，显然转化为羟基胺 8a-g，这些羟基胺可能代谢成酯，然后离子化为负责细胞损伤的氮宾离子。此前我们表明，9a，即 8a 的乙酸酯，通过水解或光解在水中生成长寿命（530 ns）的氮宾离子 11a。在这项研究中，通过叠氮化物捕获表明 9b-g 通过限速的 N-O 异裂生成 11b-g。从叠氮化物/溶剂选择性估计的离子寿命范围为 250 至 1150 ns，11a 和 11f 的离子寿命相同。胺的生物学活性差异可能不是由于阳离子的化学差异，而是由于单个胺的代谢激活/失活的差异。与氮宾离子不同，酯的寿命强烈依赖于 3'-Me 取代基。含有 3'-Me（9b、9f、9g）的酯的寿命为 5-10 s，而不含 3'-Me（9a、9c、9d、9e）的酯的寿命为 400-800 s。这限制了 3'-Me 酯在发生激活的细胞/组织中，从而在代谢仅限于这些细胞的情况下，将其作用集中在肿瘤细胞中。
