Piotrowska Dorota G, Balzarini Jan, Andrei Graciela, Schols Dominique, Snoeck Robert, Wróblewski Andrzej E, Gotkowska Joanna
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódź, 90-151, Łódź, Muszyńskiego 1, Poland.
KU Leuven, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
Tetrahedron. 2016 Dec 15;72(50):8294-8308. doi: 10.1016/j.tet.2016.10.073. Epub 2016 Nov 2.
Isoxazolidine analogues of homonucleos(t)ides were synthesized from nucleobase-derived nitrones (uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine) employing 1,3-dipolar cycloadditions with allyl alcohol as well as with alkenylphosphonates (allyl-, allyloxymethyl- and vinyloxymethyl- and vinylphosphonate). Besides reactions with vinylphosphonate the additions proceeded regioselectively to produce mixtures of major cis and minor trans 3,5-disubstituted isoxazolidines (d.e. 28-82%). From vinylphosphonate up to 10% of 3,4-disubstituted isoxazolidines was additionally produced. Vicinal couplings, shielding effects and 2D NOE correlations were employed in configurational assignments as well as in conformational analysis to find out preferred conformations for several isoxazolidines and to observe anomeric effects (pseudoaxial orientation of phosphonylmethoxy groups) for those obtained from vinyloxymethylphosphonate. None of the tested compounds were endowed in vitro with antiviral activity against a variety of DNA and RNA viruses at subtoxic concentrations (up to 250 μM) nor exhibited antiproliferative activity towards L1210, CEM, and HeLa cells (IC = ≥100 μM).
利用1,3 -偶极环加成反应，从碱基衍生的硝酮（尿嘧啶、5 -氟尿嘧啶、5 -溴尿嘧啶、胸腺嘧啶、腺嘌呤）出发，与烯丙醇以及烯基膦酸酯（烯丙基膦酸酯、烯丙氧基甲基膦酸酯、乙烯氧基甲基膦酸酯和乙烯基膦酸酯）反应，合成了同核核苷（酸）的异恶唑烷类似物。除了与乙烯基膦酸酯的反应外，加成反应具有区域选择性，生成主要的顺式和次要的反式3,5 -二取代异恶唑烷的混合物（非对映体过量28 - 82%）。从乙烯基膦酸酯还额外生成了高达10%的3,4 -二取代异恶唑烷。利用邻位偶合、屏蔽效应和二维NOE相关进行构型归属以及构象分析，以找出几种异恶唑烷的优选构象，并观察从乙烯氧基甲基膦酸酯获得的那些异恶唑烷的端基异构效应（膦酰基甲氧基的假轴向取向）。在亚毒性浓度（高达250μM）下，所测试的化合物均未在体外对多种DNA和RNA病毒具有抗病毒活性，也未对L1210、CEM和HeLa细胞表现出抗增殖活性（IC =≥100μM）。
