-(膦酰基烷基)尿嘧啶衍生物的合成、抗病毒、细胞毒性和细胞生长抑制活性评估

Synthesis, antiviral, cytotoxic and cytostatic evaluation of -(phosphonoalkyl)uracil derivatives.

作者信息

Rygielska-Tokarska Dorota, Andrei Graciela, Schols Dominique, Snoeck Robert, Głowacka Iwona E

机构信息

1Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland.

2Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Louvain, Belgium.

出版信息

Monatsh Chem. 2016;147(6):1081-1090. doi: 10.1007/s00706-016-1701-2. Epub 2016 Mar 1.

ABSTRACT

A series of -(phosphonoalkyl)uracils was prepared in a two-step reaction sequence from -aminoalkylphosphonates and ()-3-ethoxyacryloyl isocyanate followed by the uracil ring closure. Under standard conditions (NCS; NBS; I/CAN) all -(phosphonoalkyl)uracils were transformed into the respective 5-halogeno derivatives to be later benzoylated at N3. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses. One compound was slightly active against human cytomegalovirus in HEL cell cultures (EC = 45 μM) while another showed weak activity against varicella-zoster virus (TK VZV strain OKA and TK VZV strain 07-1) with EC = 43 and 53 µM, respectively. In addition, several compounds exhibited noticeable inhibitory effects on the proliferation of human cervical carcinoma cells (HeLa) at a concentration lower than 200 μM.

摘要

通过两步反应序列，由氨基烷基膦酸酯和（）-3-乙氧基丙烯酰异氰酸酯制备了一系列β-（膦酰基烷基）尿嘧啶，随后进行尿嘧啶环闭合反应。在标准条件下（NCS；NBS；I/CAN），所有β-（膦酰基烷基）尿嘧啶均转化为相应的5-卤代衍生物，随后在N3位进行苯甲酰化。对所有化合物进行了体外抗多种DNA和RNA病毒活性的评估。一种化合物在HEL细胞培养物中对人巨细胞病毒有轻微活性（EC₅₀ = 45 μM），而另一种化合物对水痘-带状疱疹病毒（TK VZV株OKA和TK VZV株07-1）表现出较弱活性，EC₅₀分别为43和53 μM。此外，几种化合物在浓度低于200 μM时对人宫颈癌细胞（HeLa）的增殖表现出显著的抑制作用。