Gilchrist Alexander M, Wu Xin, Hawkins Bryson A, Hibbs David E, Gale Philip A
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
School of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
iScience. 2023 Jan 23;26(2):105988. doi: 10.1016/j.isci.2023.105988. eCollection 2023 Feb 17.
Synthetic anion transporters show potential in treating life-threatening diseases like cystic fibrosis and cancer. However, with increasingly complex transporter architectures designed to control anion binding and transport, it is important to consider solubility and deliverability during transporter design. The fluorination of synthetic anion transporters has been shown to tune the transporter lipophilicity, transport rates, and binding strength. In this work, we expand on our previously reported tetrapodal (thio)urea transporters with a series of fluorinated tetrapodal anion transporters. The effects of fluorination on tuning the lipophilicity, solubility, deliverability, and anion transport selectivity of the tetrapodal scaffold were investigated using anion-binding and transport assays. The primary mode of anion transport was H/X cotransport, with the most fluorinated tetrathiourea () displaying the highest transport activity in the 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) assay. Intriguingly, inversion of the transmembrane Cl vs NO transport selectivity compared with previously reported tripodal (thio)urea transporters was observed under a modified HPTS assay.
合成阴离子转运体在治疗诸如囊性纤维化和癌症等危及生命的疾病方面显示出潜力。然而，随着旨在控制阴离子结合和转运的转运体结构越来越复杂，在转运体设计过程中考虑溶解性和递送性很重要。合成阴离子转运体的氟化已被证明可调节转运体的亲脂性、转运速率和结合强度。在这项工作中，我们通过一系列氟化四足阴离子转运体扩展了我们之前报道的四足（硫）脲转运体。使用阴离子结合和转运测定法研究了氟化对调节四足支架的亲脂性、溶解性、递送性和阴离子转运选择性的影响。阴离子转运的主要模式是H/X共转运，在8-羟基芘-1,3,6-三磺酸（HPTS）测定中，氟化程度最高的四硫脲（ ）显示出最高的转运活性。有趣的是，在改良的HPTS测定中，与之前报道的三足（硫）脲转运体相比，观察到跨膜Cl与NO 转运选择性发生了反转。
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