Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK.
Angew Chem Int Ed Engl. 2020 Aug 17;59(34):14677-14685. doi: 10.1002/anie.202006814. Epub 2020 Jul 7.
Monosaccharides are added to the hydrophilic face of a self-assembled asymmetric Fe metallohelix, using CuAAC chemistry. The sixteen resulting architectures are water-stable and optically pure, and exhibit improved antiproliferative selectivity against colon cancer cells (HCT116 p53 ) with respect to the non-cancerous ARPE-19 cell line. While the most selective compound is a glucose-appended enantiomer, its cellular entry is not mainly glucose transporter-mediated. Glucose conjugation nevertheless increases nuclear delivery ca 2.5-fold, and a non-destructive interaction with DNA is indicated. Addition of the glucose units affects the binding orientation of the metallohelix to naked DNA, but does not substantially alter the overall affinity. In a mouse model, the glucose conjugated compound was far better tolerated, and tumour growth delays for the parent compound (2.6 d) were improved to 4.3 d; performance as good as cisplatin but with the advantage of no weight loss in the subjects.
单糖通过铜催化的叠氮-炔环加成（CuAAC）化学被添加到自组装的不对称 Fe 金属螺旋的亲水面。所得的 16 种结构具有良好的水稳定性和光学纯度，与非癌性 ARPE-19 细胞系相比，对结肠癌细胞（HCT116 p53）表现出更好的抗增殖选择性。虽然最具选择性的化合物是葡萄糖附加的对映异构体，但它的细胞进入不是主要由葡萄糖转运蛋白介导的。然而，葡萄糖的结合增加了核内递送 ca 2.5 倍，并表明与 DNA 存在非破坏性相互作用。葡萄糖单元的添加会影响金属螺旋与裸露 DNA 的结合取向，但不会显著改变整体亲和力。在小鼠模型中，葡萄糖结合的化合物耐受性更好，母体化合物（2.6d）的肿瘤生长延迟改善至 4.3d；其性能与顺铂相当，但受试动物体重没有减轻。
