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首页> 外文期刊>Chemical research in toxicology >Overcoming the Genotoxicity of a Pyrrolidine Substituted Arylindenopyrimidine As a Potent Dual Adenosine A(2A)/A(1) Antagonist by Minimizing Bioactivation to an Iminium Ion Reactive Intermediate.
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Overcoming the Genotoxicity of a Pyrrolidine Substituted Arylindenopyrimidine As a Potent Dual Adenosine A(2A)/A(1) Antagonist by Minimizing Bioactivation to an Iminium Ion Reactive Intermediate.

机译：通过最大限度地减少对Iminium离子活性中间体的生物活化作用，克服吡咯烷取代的Arylindenopyrimidine作为强力双重腺苷A（2A）/ A（1）拮抗剂的遗传毒性。

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摘要

2-Amino-4-phenyl-8-pyrrolidin-1-ylmethyl-indeno[1,2-d]pyrimidin-5-one (1) is a novel and potent selective dual A(2A)/A(1) adenosine receptor antagonist from the arylindenopyrimidine series that was determined to be genotoxic in both the Ames and Mouse Lymphoma L5178Y assays only following metabolic activation. Compound 1 was identified as a frame-shift mutagen in Salmonella typhimurium tester strain TA1537 as indicated by a significant dose-dependent increase in revertant colonies as compared to the vehicle control. The metabolic activation-dependent irreversible covalent binding of radioactivity to DNA, recovery of 1 and its enamine metabolite from acid hydrolysis of covalently modified DNA, and protection of covalent binding to DNA by both cyanide ion and methoxylamine suggest that the frame-shift mutation in TA1537 strain involved covalent binding instead of simple intercalation to DNA. Compound 1 was bioactivated to endocyclic iminium ion, aldehyde, epoxide, and alpha,beta-unsaturated keto reactive intermediates from the detection of cyano, oxime, and glutathione conjugates by data-dependent high resolution accurate mass measurements. Collision-induced dissociation of these conjugates provided evidence for bioactivation of the pyrrolidine ring of 1. The epoxide and alpha,beta-unsaturated keto reactive intermediates were unlikely to cause the genotoxicity of 1 because the formation of their glutathione adducts did not ameliorate the binding of compound related material to DNA. Instead, the endocyclic iminium ions and amino aldehydes were likely candidates responsible for genotoxicity based on, first, the protection afforded by both cyanide ion and methoxylamine, which reduced the potential to form covalent adducts with DNA, and, second, analogues of 1 designed with low probability to form these reactive intermediates were not genotoxic. It was concluded that 1 also had the potential to be mutagenic in humans based on observing the endocyclic iminium ion following incubation with a human liver S9 preparation and the commensurate detection of DNA adducts. An understanding of this genotoxicity mechanism supported an evidence-based approach to selectively modify the structure of 1 which resulted in analogues being synthesized that were devoid of a genotoxic liability. In addition, potency and selectivity against both adenosine A(2A) and A(1) receptors were maintained.
机译：2-Amino-4-phenyl-8-pyrrolidin-1-ylmethyl-indeno [1,2-d] pyrimidin-5-one（1）是一种新型且有效的选择性双重A（2A）/ A（1）腺苷受体仅在代谢激活后，才在Ames和小鼠淋巴瘤L5178Y分析中确定具有毒理作用的arylindenopyrimidine系列拮抗剂。化合物1被鉴定为鼠伤寒沙门氏菌测试株TA1537中的移码诱变剂，与媒介物对照相比，回复菌落的剂量依赖性显着增加表明。放射性与DNA的代谢活化相关的不可逆共价结合，共价修饰的DNA的酸水解回收1及其烯胺代谢物以及氰化物离子和甲氧基胺对DNA的共价结合的保护表明TA1537中的移码突变该菌株涉及共价结合而不是简单地插入DNA。通过依赖于数据的高分辨率精确质量检测，通过检测氰基，肟和谷胱甘肽共轭物，将化合物1生物活化为环内亚胺离子，醛，环氧化物和α，β-不饱和酮反应性中间体。这些缀合物的碰撞诱导解离为1的吡咯烷环的生物活化提供了证据。环氧化物和α，β-不饱和酮反应性中间体不太可能引起1的遗传毒性，因为它们的谷胱甘肽加合物的形成并未改善与1的结合。与DNA相关的化合物。相反，内环亚胺离子和氨基醛可能是造成基因毒性的候选物，首先是由于氰化物离子和甲氧基胺提供的保护作用，这降低了与DNA形成共价加合物的可能性，其次，由1设计的1的类似物形成这些反应性中间体的可能性很小，没有遗传毒性。结论是，在与人肝S9制剂孵育并相应检测DNA加合物后，观察到内环亚胺鎓离子后，1在人体内也可能具有致突变性。对这种遗传毒性机制的理解支持了一种基于证据的方法来选择性地修饰1的结构，从而导致合成的类似物没有遗传毒性。此外，保持了针对腺苷A（2A）和A（1）受体的效力和选择性。

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