A rhodium(III) complex for high-affinity DNA base-pair mismatch recognition
A rhodium(III) complex for high-affinity DNA base-pair mismatch recognition
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DOI：
10.1073/pnas.0537194100
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发表时间：
2003-04-01
影响因子：
11.1
通讯作者：
Barton, JK
中科院分区：
文献类型：
--
作者：
Junicke, H;Hart, JR;Barton, JK
铑（III）配合物rac-[Rh(bpy)(2)phzi](3+) （bpy, 2,2'-联吡啶；phzi，苯并[A]吩嗪-5,6-醌二亚胺）被设计为一种立体要求高的插入物，靶向双螺旋DNA中不稳定的错配位点。该配合物很容易由非那嗪醌与相应的二胺配合物缩合而成。光激活后，该复合体促进DNA双链内单碱基错配位点的直接链断裂。与母体错配特异性试剂[Rh(bpy)(2)(chrysi)](3+) [chrysi -5,6-醌二亚胺（chrysi）]一样，错配选择性取决于与错配相关的螺旋不稳定。与亲本蝶复合体不同，phzi类似物具有高亲和力和高效率的结合和裂解。在31聚寡核苷酸双链中，CA、CC和CT错配的特异性结合常数分别为0.3、1和6 × 10(7) M-1；位点特异性光裂解在纳摩尔浓度下是明显的。此外，特异性（定义为错配位点与良好配对位点的结合亲和力之比）得以维持。亲和性的增加归因于与杂环芳香族配体堆叠相关的错配位点的更大稳定性。高亲和力复合体也应用于从错配修复缺陷细胞系与错配修复精通细胞系中获得的DNA的差异切割。在错配特异性探针的光裂解和错配修复缺陷之间发现了一致。因此，这种不匹配特异性靶向为新的化疗设计提供了一种潜在的策略。
A rhodium(III) complex, rac-[Rh(bpy)(2)phzi](3+) (bpy, 2,2'-bipyridine; phzi, benzo[a]phenazine-5,6-quinone diimine) has been designed as a sterically demanding intercalator targeted to destabilized mismatched sites in double-helical DNA. The complex is readily synthesized by condensation of the phenazine quinone with the corresponding diammine complex. Upon photoactivation, the complex promotes direct strand scission at single-base mismatch sites within the DNA duplex. As with the parent mismatch-specific reagent, [Rh(bpy)(2)(chrysi)](3+) [chrysene-5,6-quinone diimine (chrysi)], mismatch selectivity depends on the helix destabilization associated with mispairing. Unlike the parent chrysi complex, the phzi analogue binds and cleaves with high affinity and efficiency. The specific binding constants for CA, CC, and CT mismatches within a 31-mer oligonucleotide duplex are 0.3, 1, and 6 x 10(7) M-1, respectively; site-specific photocleavage is evident at nanomolar concentrations. Moreover, the specificity, defined as the ratio in binding affinities for mispaired vs. well paired sites, is maintained. The increase in affinity is attributed to greater stability in the mismatched site associated with stacking by the heterocyclic aromatic ligand. The high-affinity complex is also applied in the differential cleavage of DNA obtained from cell lines deficient in mismatch repair vs. those proficient in mismatch repair. Agreement is found between photocleavage by the mismatch-specific probes and deficiency in mismatch repair. This mismatch-specific targeting, therefore, offers a potential strategy for new chemotherapeutic design.