Głowacka Iwona E, Piotrowska Dorota G, Andrei Graciela, Schols Dominique, Snoeck Robert, Wróblewski Andrzej E
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland.
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Louvain, Belgium.
Monatsh Chem. 2016;147(12):2163-2177. doi: 10.1007/s00706-016-1848-x. Epub 2016 Oct 26.
To study the influence of a linker rigidity and donor-acceptor properties, the P-CH-- fragment in acyclic nucleoside phosphonates (e.g., acyclovir, tenofovir) was replaced by the P-CH-- residue. The respective phosphonates were synthesized in good yields by coupling the straight chain of -aminophosphonates and nucleobase-derived acetic acids with EDC. Based on the H and C NMR data, the unrestricted rotation within the methylene and 1,2-ethylidene linkers in phosphonates from series and was confirmed. For phosphonates containing 1,3-propylidene (series ) fragments, antiperiplanar disposition of the bulky ,-diethylphosphonate and substituted amidomethyl groups was established. The synthesized ANPs P-X-HNC(O)-CHB (X = CH, CHCH, CHCHCH, CHOCHCH) appeared inactive in antiviral assays against a wide variety of DNA and RNA viruses at concentrations up to 100 μM while marginal antiproliferative activity (L1210 cells, IC = 89 ± 16 μM and HeLa cells, IC = 194 ± 19 μM) was noticed for the analog derived from (5-fluorouracyl-1-yl)acetic acid and ,-diethyl (2-aminoethoxy)methylphosphonate.
为了研究连接子刚性和供体-受体性质的影响，将无环核苷膦酸盐（如阿昔洛韦、替诺福韦）中的P-CH₂-片段替换为P-CH₂CH₂-残基。通过将氨基膦酸盐的直链与核苷碱基衍生的乙酸用EDC偶联，以良好的产率合成了相应的膦酸盐。基于¹H和¹³C NMR数据，证实了系列1和2的膦酸盐中亚甲基和1,2-亚乙基连接子内的自由旋转。对于含有1,3-亚丙基（系列3）片段的膦酸盐，确定了庞大的β,β-二乙基膦酸酯和取代的氨甲基基团的反式共平面排列。合成的无环核苷膦酸盐P-X-HNC(O)-CH₂B（X = CH₂、CH₂CH₂、CH₂CH₂CH₂、CH₂OCH₂CH₂）在浓度高达100 μM时对多种DNA和RNA病毒的抗病毒试验中表现为无活性，而对于源自(5-氟尿嘧啶-1-基)乙酸和β,β-二乙基(2-氨基乙氧基)甲基膦酸酯的类似物，观察到了微弱的抗增殖活性（L1210细胞，IC₅₀ = 89 ± 16 μM；HeLa细胞，IC₅₀ = 194 ± 19 μM）。
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