Haratipour Pouya, Minard Corinne, Nakhjiri Maryam, Negahbani Amirsoheil, Kashemirov Boris A, McKenna Charles E
Department of Chemistry, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, U.S.A.
Phosphorus Sulfur Silicon Relat Elem. 2019;194(4-6):329-330. doi: 10.1080/10426507.2018.1540482. Epub 2019 Mar 1.
Individual diastereomers of CXY bisphosphonate analogues of dNTPs or NTPs are useful chemical stereoprobes to investigate interactions within the chiral active site environment of enzymes such as polymerases and kinases. We previously reported synthetic access to β,γ-CHX-dGTPs (X = F or Cl) via a bisphosphonate synthon with an (R)-methyl mandelate auxiliary and have extended this approach to dTTP and dATP analogues. As removal of the chiral auxiliary by (Pd/C) hydrogenolysis is incompatible with the cytosine heterocycle and also with X = Br, we have now designed bisphosphonate synthons using (R)-(+)-α-ethylbenzylamine or methyl (R)-(-)-phenylglycine auxiliaries and equipped with an o-nitrobenzyl ester protecting group allowing photochemical deprotection. These new synthons have made possible the first syntheses of individual dCTP and monobromo-substituted dNTP β,γ-CHX diastereomers.
脱氧核苷三磷酸（dNTP）或核苷三磷酸（NTP）的CXY双膦酸酯类似物的各个非对映异构体是有用的化学立体探针，可用于研究诸如聚合酶和激酶等酶的手性活性位点环境中的相互作用。我们之前报道了通过带有（R）-扁桃酸甲酯辅助基团的双膦酸酯合成子合成β,γ-CHX-dGTPs（X = F或Cl），并且已将此方法扩展至dTTP和dATP类似物。由于通过（Pd/C）氢解去除手性辅助基团与胞嘧啶杂环不相容，并且与X = Br也不相容，我们现在设计了使用（R）-（+）-α-乙苄胺或（R）-（-）-苯基甘氨酸甲酯辅助基团并带有邻硝基苄酯保护基团的双膦酸酯合成子，该保护基团允许光化学脱保护。这些新的合成子使得首次合成各个dCTP以及单溴取代的dNTPβ,γ-CHX非对映异构体成为可能。
