Lewandowska Marta, Ruszkowski Piotr, Chojnacka Kinga, Kleczewska Natalia, Hoffmann Marcin, Kacprzak Karol, Celewicz Lech
Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland.
Department of Pharmacology, Poznań University of Medical Sciences, Rokietnicka St 5 a, 60-806 Poznań, Poland.
Bioorg Med Chem. 2016 May 15;24(10):2330-41. doi: 10.1016/j.bmc.2016.04.003. Epub 2016 Apr 1.
Two series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3'-O-(t-butoxycarbonyl)-5-fluoro-2'-deoxyuridine (3'-BOC-FdU) (9a-9j) and 5-fluoro-2'-deoxyuridine (FdU) (10a-10j) were synthesized by means of phosphorylation of 3'-BOC-FdU (4) with 4-chlorophenyl phosphoroditriazolide (7), followed by a reaction with the appropriate amine. Phosphoramidates 9a-9j were converted to the corresponding 10a-10j by removal of the 3'-t-butoxycarbonyl protecting group (BOC) under acidic conditions. The synthesized phosphoramidates 9a-9j and 10a-10j were evaluated for their cytotoxic activity in five human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), liver (HepG2), osteosarcoma (143B) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Two phosphoramidates 9b and 9j with the N-ethyl and N-(methoxy-(S)-alaninyl) substituents, respectively, displayed remarkable activity in all the investigated cancer cells, and the activity was considerably higher than that of the parent nucleoside 4 and FdU. Among phosphoramidates 10a-10j compound 10c with the N-(2,2,2-trifluoroethyl) substituent showed the highest activity. Phosphoramidate 10c was more active than the FdU in all the cancer cell lines tested.
通过用4-氯苯基磷酰三叠氮化物（7）对3'-O-（叔丁氧羰基）-5-氟-2'-脱氧尿苷（3'-BOC-FdU）（4）进行磷酸化，然后与适当的胺反应，合成了两系列新型的3'-O-（叔丁氧羰基）-5-氟-2'-脱氧尿苷（3'-BOC-FdU）（9a - 9j）和5-氟-2'-脱氧尿苷（FdU）（10a - 10j）的4-氯苯基N-烷基磷酰胺酯。在酸性条件下去除3'-叔丁氧羰基保护基（BOC），将磷酰胺酯9a - 9j转化为相应的10a - 10j。使用磺酰罗丹明B（SRB）测定法，对合成的磷酰胺酯9a - 9j和10a - 10j在五种人类癌细胞系：宫颈癌细胞（HeLa）、鼻咽癌细胞（KB）、乳腺癌细胞（MCF-7）、肝癌细胞（HepG2）、骨肉瘤细胞（143B）以及正常人皮肤成纤维细胞系（HDF）中进行细胞毒性活性评估。两种分别带有N-乙基和N-（甲氧基-（S）-丙氨酰基）取代基的磷酰胺酯9b和9j在所有研究的癌细胞中均表现出显著活性，且该活性明显高于母体核苷4和FdU。在磷酰胺酯10a - 10j中，带有N-（2,2,2-三氟乙基）取代基的化合物10c表现出最高活性。在所有测试的癌细胞系中，磷酰胺酯10c比FdU更具活性。
