Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, 847 Monroe Avenue Suite 327, Memphis, TN 38163, USA.
Bioorg Med Chem Lett. 2009 Feb 1;19(3):917-21. doi: 10.1016/j.bmcl.2008.11.112. Epub 2008 Dec 6.
Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective and neuroprotective agents. Although quite a few potent inhibitors of the equilibrative nucleoside transporters are known, largely missing are the concentrative nucleoside transporter inhibitors. Phloridzin (3, K(i)=16.00 microM) is a known moderate inhibitor of the concentrative nucleoside transporters. We have synthesized and evaluated analogs of phloridzin at the hCNT3 nucleoside transporter. Within the series of synthesized analogs compound 16 (K(i)=2.88 microM), possessing a ribofuranose sugar unit instead of a glucopyranose as present in phloridzin, exhibited the highest binding affinity at the hCNT3 transporter. Phloridzin and compound 16 have also been shown to be selective for the hCNT3 transporter as compared with the hENT1 transporter. Compound 16 can serve as a new lead which after further modifications could yield selective and potent hCNT3 inhibitors.
核苷转运体抑制剂作为抗癌、抗病毒、心脏保护和神经保护剂具有潜在的治疗应用。尽管已经有相当数量的平衡核苷转运体的有效抑制剂，但仍缺乏集中核苷转运体抑制剂。根皮苷（3，K(i)=16.00 microM）是一种已知的集中核苷转运体的中等抑制剂。我们已经在 hCNT3 核苷转运体上合成并评估了根皮苷的类似物。在所合成的类似物系列中，化合物 16（K(i)=2.88 microM），其具有呋喃核糖单元而不是根皮苷中存在的吡喃葡萄糖，在 hCNT3 转运体上表现出最高的结合亲和力。与 hENT1 转运体相比，根皮苷和化合物 16 也被证明对 hCNT3 转运体具有选择性。化合物 16 可以作为一个新的先导化合物，经过进一步修饰可能产生选择性和有效的 hCNT3 抑制剂。
