Conformationally Preorganized High-Affinity Ligands for Copper Biology with Hinged and Rigid Thiophene Backbones,Inorganic Chemistry

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Conformationally Preorganized High-Affinity Ligands for Copper Biology with Hinged and Rigid Thiophene Backbones
Inorganic Chemistry ( IF 4.3 ) Pub Date : 2023-01-20 , DOI: 10.1021/acs.inorgchem.2c03524
Jiyao Yu ₁ , John Bacsa _{1,

2} , Christoph J Fahrni ₁

Affiliation

Copper-selective ligands are essential tools for probing the affinity of cuproproteins or manipulating the cellular copper availability. They also harbor significant potential as antiangiogenic agents in cancer therapy or as therapeutics to combat copper toxicity in Wilson’s disease. To achieve the high Cu(I) affinities required for competing effectively with cellular cuproproteins, we recently devised a ligand design based on phosphine-sulfide-stabilized phosphine (PSP) donor motifs. Building on this design strategy, we integrated two PSP donors within preorganized ligand architectures composed of either a hinged bithiophene backbone (bithipPS) or a single rigid thiophene bridge (thipPS). Extensive characterization based on X-ray crystal structures, solution NMR data, spectrophotometric titrations, and electrochemical studies established that bithipPS adapts well to the coordination preferences of Cu(I) to form a discrete air-stable mononuclear Cu(I) complex with a dissociation constant of 4 zM. In contrast, the wider bite angle of thipPS introduces some strain upon Cu(I) coordination to yield an almost 10-fold lower affinity with a K_d of 35 zM. As revealed by ICP-MS and two-photon excitation microscopy studies with the Cu(I)-selective fluorescent probe crisp-17, both ligands are effective at removing cellular copper from live mouse fibroblasts with rapid kinetics. Altogether, the stability and redox properties of PSP-ligand–Cu(I) complexes can be effectively tuned by judicious balancing of their geometrical preorganization and conformational flexibility.

中文翻译：

具有铰链和刚性噻吩骨架的用于铜生物学的构象预组织高亲和力配体

铜选择性配体是探测铜蛋白亲和力或操纵细胞铜可用性的重要工具。它们还具有作为癌症治疗中的抗血管生成剂或作为对抗威尔逊氏病中的铜毒性的治疗剂的巨大潜力。为了实现与细胞铜蛋白有效竞争所需的高 Cu(I) 亲和力，我们最近设计了一种基于膦硫化物稳定的膦 (PSP) 供体基序的配体设计。在此设计策略的基础上，我们将两个 PSP 供体集成到由铰链联噻吩主链 (bithipPS) 或单个刚性噻吩桥 (thipPS) 组成的预组织配体结构中。基于 X 射线晶体结构、溶液 NMR 数据、分光光度滴定和电化学研究的广泛表征表明，bithipPS 很好地适应 Cu(I) 的配位偏好，形成具有解离的离散空气稳定单核 Cu(I) 配合物常数 4 zM。相比之下，thipPS 较宽的咬合角会在 Cu(I) 配位上引入一些应变，从而产生几乎低 10 倍的亲和力，且K _d为 35 zM。 ICP-MS 和使用 Cu(I) 选择性荧光探针 crisp-17 进行的双光子激发显微镜研究表明，两种配体都能以快速动力学的方式有效去除活体小鼠成纤维细胞中的细胞铜。总而言之，PSP-配体-Cu(I)配合物的稳定性和氧化还原性质可以通过其几何预组织和构象灵活性的明智平衡来有效调节。

更新日期：2023-01-20

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