Rhodium metalloinsertors are a unique set of metal complexes that bind specifically to DNA base pair mismatches in vitro and kill mismatch repair (MMR)-deficient cells at lower concentrations than their MMR-proficient counterparts. A family of metalloinsertors containing rhodium-oxygen ligand coordination, termed "Rh-O" metalloinsertors, has been prepared and shown to have a significant increase in both overall potency and selectivity toward MMR-deficient cells regardless of structural changes in the ancillary ligands. Here we describe DNA-binding and cellular studies with the second generation of Rh-O metalloinsertors in which an ancillary ligand is varied in both steric bulk and lipophilicity. These complexes, of the form [Rh(L)(chrysi)(PPO)]2+, all include the O-containing PPO ligand (PPO = 2-(pyridine-2-yl)propan-2-ol) and the aromatic inserting ligand chrysi (5,6-chrysene quinone diimine) but differ in the identity of their ancillary ligand L, where L is a phenanthroline or bipyridyl derivative. The Rh-O metalloinsertors in this family all show micromolar binding affinities for a 29-mer DNA hairpin containing a single CC mismatch. The complexes display comparable lipophilic tendencies and p Ka values of 8.1-9.1 for dissociation of an imine proton on the chrysi ligand. In cellular proliferation and cytotoxicity assays with MMR-deficient cells (HCT116O) and MMR-proficient cells (HCT116N), the complexes containing the phenanthroline-derived ligands show highly selective cytotoxic preference for the MMR-deficient cells at nanomolar concentrations. Using mass spectral analyses, it is shown that the complexes are taken into cells through a passive mechanism and exhibit low accumulation in mitochondria, an off-target organelle that, when targeted by parent metalloinsertors, can lead to nonselective cytotoxicity. Overall, these Rh-O metalloinsertors have distinct and improved behavior compared to previous generations of parent metalloinsertors, making them ideal candidates for further therapeutic assessment.

中文翻译：

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对错配修复缺陷癌症具有选择性毒性的一系列铑配合物

Rhodium metalloinsertors 是一组独特的金属配合物，可在体外与 DNA 碱基对错配特异性结合，并以比其 MMR 熟练对应物更低的浓度杀死错配修复 (MMR) 缺陷细胞。已经制备了一系列包含铑-氧配体配位的金属插入物，称为“Rh-O”金属插入物，并显示出对 MMR 缺陷细胞的整体效力和选择性都有显着增加，而不管辅助配体的结构变化如何。在这里，我们描述了第二代 Rh-O 金属插入器的 DNA 结合和细胞研究，其中辅助配体在空间体积和亲脂性方面都不同。这些复合物，形式为 [Rh(L)(chrysi)(PPO)]2+，都包括含 O 的 PPO 配体 (PPO = 2-(pyridine-2-yl)propan-2-ol) 和芳香插入配体 chrysi (5,6-chrysene quinone diimine) 但它们的辅助配体的身份不同L，其中L是菲咯啉或联吡啶衍生物。该家族中的 Rh-O 金属插入物均显示出对包含单个 CC 错配的 29 聚体 DNA 发夹的微摩尔结合亲和力。对于 chrysi 配体上的亚胺质子的解离，这些复合物显示出类似的亲脂性倾向和 8.1-9.1 的 p Ka 值。在对 MMR 缺陷细胞 (HCT116O) 和 MMR 精通细胞 (HCT116N) 进行的细胞增殖和细胞毒性测定中，含有菲咯啉衍生配体的复合物在纳摩尔浓度下对 MMR 缺陷细胞显示出高度选择性的细胞毒性偏好。使用质谱分析，结果表明，复合物通过被动机制进入细胞，并在线粒体中表现出低积累，线粒体是一种脱靶细胞器，当被母体金属插入物靶向时，可导致非选择性细胞毒性。总体而言，与前几代母金属插入物相比，这些 Rh-O 金属插入物具有独特且改进的行为，使其成为进一步治疗评估的理想候选者。