Slusarczyk Magdalena, Ferla Salvatore, Brancale Andrea, McGuigan Christopher
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Bioorg Med Chem. 2018 Feb 1;26(3):551-565. doi: 10.1016/j.bmc.2017.11.037. Epub 2017 Dec 2.
A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P-N bond cleavage and free nucleoside 5'-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.
合成了一个由13种不同的6-取代-5-氟尿苷核苷类似物的磷酰胺酯前药（ProTides）组成的新家族，并将其作为潜在的抗癌药物进行评估。此外，使用细胞病变效应抑制试验评估了对基孔肯雅病毒（CHIKV）的抗病毒活性。尽管羧肽酶Y试验支持了基于具有此类C6修饰的5-氟尿苷构建的ProTides的假定激活机制，但Hint对接研究表明，Hint磷酰胺酶型酶的底物活性受损，该酶可能通过P-N键断裂和游离核苷5'-单磷酸传递负责磷酰胺酯的生物激活。我们的观察结果可能在一定程度上支持并解释了一系列6-取代-5-氟尿苷磷酰胺酯（ProTides）通常表现出的较差的体外生物活性，并将为新型磷酰胺酯前药的设计提供指导。
