Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase,ACS Chemical Biology

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Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-12-14 00:00:00 , DOI: 10.1021/acschembio.7b00601
Lawrence D. Harris ₁ , Rajesh K. Harijan ₂ , Rodrigo G. Ducati ₂ , Gary B. Evans _{1,

3} , Brett M. Hirsch ₂ , Vern L. Schramm ₂

Affiliation

Phosphoribosyl transferases (PRTs) are essential in nucleotide synthesis and salvage, amino acid, and vitamin synthesis. Transition state analysis of several PRTs has demonstrated ribocation-like transition states with a partial positive charge residing on the pentose ring. Core chemistry for synthesis of transition state analogues related to the 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) reactant of these enzymes could be developed by stereospecific placement of bis-phosphate groups on an iminoaltritol ring. Cationic character is provided by the imino group and the bis-phosphates anchor both the 1- and 5-phosphate binding sites. We provide a facile synthetic path to these molecules. Cyclic-nitrone redox methodology was applied to the stereocontrolled synthesis of three stereoisomers of a selectively monoprotected diol relevant to the synthesis of transition-state analogue inhibitors. These polyhydroxylated pyrrolidine natural product analogues were bis-phosphorylated to generate analogues of the ribocationic form of 5-phosphoribosyl 1-phosphate. A safe, high yielding synthesis of the key intermediate represents a new route to these transition state mimics. An enantiomeric pair of iminoaltritol bis-phosphates (L-DIAB and D-DIAB) was prepared and shown to display inhibition of Plasmodium falciparum orotate phosphoribosyltransferase and Saccharomyces cerevisiae adenine phosphoribosyltransferase (ScAPRT). Crystallographic inhibitor binding analysis of L- and D-DIAB bound to the catalytic sites of ScAPRT demonstrates accommodation of both enantiomers by altered ring geometry and bis-phosphate catalytic site contacts.

中文翻译：

磷酸二氨基氨基醇对映体的合成及腺嘌呤磷酸核糖基转移酶的结构表征

磷酸核糖基转移酶（PRT）在核苷酸合成和挽救，氨基酸和维生素合成中必不可少。几种PRT的跃迁状态分析表明，核糖化样跃迁状态带有部分正电荷，并存在于戊糖环上。合成这些酶的5-磷酸-α - d-核糖基1-焦磷酸酯（PRPP）反应物相关的过渡态类似物的核心化学方法可以通过将双磷酸酯基立体定向放置在亚氨基糖醇环上来开发。亚胺基和bis提供了阳离子特性-磷酸酯锚定1-和5-磷酸酯结合位点。我们提供了通往这些分子的简便合成途径。将环硝基氧化还原方法应用于与过渡态类似物抑制剂的合成有关的选择性单保护二醇的三种立体异构体的立体控制合成。这些多羟基化的吡咯烷天然产物类似物被双磷酸化以产生5-磷酸核糖基1-磷酸核糖形式的类似物。关键中间体的安全，高产合成代表了通往这些过渡态模拟物的新途径。制备了对映体对的亚氨基二糖醇双磷酸酯（L-DIAB和D-DIAB），并显示出对恶性疟原虫的抑制作用乳清酸磷酸核糖基转移酶和酿酒酵母腺嘌呤磷酸核糖基转移酶（ScAPRT）。与ScAPRT催化位点结合的L-和D-DIAB的晶体学抑制剂结合分析表明，通过改变环的几何形状和双磷酸酯催化位点接触，两种对映异构体均具有适应性。

更新日期：2017-12-14

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