Design, synthesis, antiviral and cytostatic activity of 蠅-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues
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- 作者：Iwona E. G艂owacka
- 关键词：Cycloaddition ; 1 ; 2 ; 3-Triazoles ; Phosphonates ; Nucleotide analogues ; Antiviral ; Cytostatic
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：15 July 2014
- 年：2014
- 卷：22
- 期：14
- 页码：3629-3641
- 全文大小：880 K
文摘
The efficient synthesis of a new series of polyhydroxylated dibenzyl 蠅-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl 蠅-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50 = 20 渭M—visual CPE score; EC50 = 18 渭M—MTS method; MCC >100 渭M, CC50 >100 渭M) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50 = 9 and 12 渭M, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 = 2.9 and 4 渭M, respectively) and feline herpes virus in CRFK cells (EC50 = 4 渭M) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC 猢?#xA0;4 渭M). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC50 in the 4–50 渭M range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC50 in the 4–7 渭M range).