Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.
Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Branišovská 31, České Budějovice, 37005, Czech Republic.
Eur J Med Chem. 2022 Sep 5;239:114559. doi: 10.1016/j.ejmech.2022.114559. Epub 2022 Jun 23.
A series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) has been prepared using the optimized Suzuki cross-coupling reaction as the key synthetic step. The final free phosphonates 15a-h were inactive, due to their inefficient transport across cell membranes, but they inhibited Trypanosoma brucei adenine phosphoribosyltransferase (TbrAPRT1) with K values of 1.7-14.1 μM. The corresponding phosphonodiamidate prodrugs 14a-h exhibited anti-trypanosomal activity in the Trypanosoma brucei brucei cell-based assay with EC values in the range of 0.58-6.8 μM. 7-(4-Methoxy)phenyl-7-deazapurine derivative 14h, containing two phosphonate moieties, was the most potent anti-trypanosomal agent from the series, with EC = 0.58 μM and SI = 16. Finally, phosphonodiamidate prodrugs 14a-h exerted low micromolar cytotoxicity against leukemia and/or cancer cell lines tested.
已经使用优化的 Suzuki 交叉偶联反应作为关键合成步骤，制备了一系列新型 7-芳基-7-脱氮腺嘌呤基 N-支化无环核苷膦酸酯（aza-ANPs）。由于它们跨细胞膜的转运效率低下，最终的游离膦酸盐 15a-h 没有活性，但它们抑制了布氏锥虫腺嘌呤磷酸核糖基转移酶（TbrAPRT1），K 值为 1.7-14.1 μM。相应的膦酸二酰胺前药 14a-h 在基于 Trypanosoma brucei brucei 细胞的测定中表现出抗锥虫活性，EC 值在 0.58-6.8 μM 范围内。含有两个膦酸酯部分的 7-(4-甲氧基)苯基-7-脱氮嘌呤衍生物 14h 是该系列中最有效的抗锥虫剂，EC = 0.58 μM，SI = 16。最后，膦酸二酰胺前药 14a-h 对测试的白血病和/或癌细胞系表现出低微摩尔细胞毒性。
