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Synthesis and evaluation of new alpha-halovinyl amino acids as amino acid decarboxylase inactivators.

机译：合成和评估新的α-卤代戊基氨基酸作为氨基酸脱羧酶灭活剂。

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摘要

From the medicinal point of view, several amino acid decarboxylases (Arg DC, DOPA DC, Glu DC, His DC, Lys DC, Orn DC, SAM DC) are important targets for the development of specific and potent inactivators. Higher amino acid analogues, in which the alpha-hydrogen of amino acid is replaced by a chlorovinyl or fluorovinyl group, are potential mechanism-based enzyme inhibitors for their cognate amino acid decarboxylases. This dissertation describes, to our knowledge, the first syntheses and enzymatic evaluation of these two families of quaternary amino acids.;Our synthetic approach to quaternary alpha-chloro and alpha-bromovinyl amino acids is based upon addition of the appropriate phenylselenenyl halide to suitably protected alpha-vinyl amino acids, followed by selenide oxidation and pyrolysis. Under conditions of kinetic control (PhSeX, MeCN, 2 ∼ 3 hours), primarily the (+/-)-(E)-alpha-(2-chlorovinyl) amino acids are obtained. At longer times for the PhSeX addition step, the (+/-)-alpha-(1-chlorovinyl) regioisomer is seen, comprising 50 ∼ 100% of the alpha-halovinyl amino acids mixture.;The direct alpha-(1-chloro) vinylation using 2,2-dichlorovinyl phenyl sulfone was accomplished as a potential synthetic route to (+/-)-alpha-(1-chlorovinyl) amino acids. As proof of principle, free (+/-)-alpha-(1-chlorovinyl)alanine and (+/-)-alpha-(1-chlorovinyl)glutamate have been synthesized using this chemistry.;A series of (+/-)-(Z)-alpha-(2-fluorovinyl) amino acids was synthesized from alpha-formyl amino acids via a Horner-Wadsworth-Emmons reaction with very high stereoselectivity. The resultant alpha-fluorovinyl sulfone functionality was transformed into an alpha-fluorovinyl stannane group with high stereoselectivity for all quaternary amino acids examined. Protodestannylation and deprotection were accomplished to give six (+/-)-(Z)-alpha-(2-fluorovinyl) amino acids (Ala, DOPA, Glu, Lys, Phe, m-Tyr).;A coupled continuous UV assay was used to evaluate inhibitory effects of (+/-)-alpha-vinyllysine and (+/-)-alpha-vinylarginine. Time-dependent inhibition was observed for both compounds. (+/-)-(E)-alpha-(2-Chlorovinyl)lysine, (+/-)-alpha-vinyllysine, (+/-)-(Z)-alpha-(2-fluorovinyl)lysine, (+/-)-alpha-vinylglutamate, and (+/-)-(Z)-alpha-(2-fluorovinyl)glutamate were tested with their cognate amino acids decarboxylases with a radioactive time-point assay. Lineweaver-Burk analysis was used to test each assay and to obtain values of Km for each natural substrate (L-lysine/LDC Km = 1.9 mM, L-glutamate/GAD Km = 1.3 mM) and Kitz-Wilson analysis were used to obtain KI, kinact, and t 1/2. Extended dialysis showed the inhibition of lysine decarboxylase to be essentially irreversible.;In the case of the best lysine decarboxylase inactivator found, (+/-)-(Z)-alpha-(2-fluorovinyl)lysine, non-pseudofirst order kinetics (ln (Et/Eo) vs. preincubation time) were observed. A Kitz-Wilson analysis of these data using tangents to the inactivation curves provided KI = 1.3 mM, kinact = 0.15 min--1 , t1/2 = 5 minutes. Consistent with the notion that this compound is a "suicide substrat", the product of its enzymatic decarboxylation was observed by 19F NMR and the ratio of turnover product observed to total enzyme inactivated is approximately 46. That the observed 19F NMR signal was due to product has been confirmed by independent synthesis of (Z)-alpha-(2-fluorovinyl)cadaverine.
机译：从医学角度来看，几种氨基酸脱羧酶（Arg DC，DOPA DC，Glu DC，His DC，Lys DC，Orn DC，SAM DC）是开发特定且有效的灭活剂的重要目标。其中氨基酸的α-氢被氯乙烯基或氟乙烯基取代的高级氨基酸类似物是其同源氨基酸脱羧酶的潜在的基于机理的酶抑制剂。据我们所知，本论文描述了这两个季氨基酸家族的首次合成和酶促评估。我们合成季α-氯和α-溴乙烯基氨基酸的合成方法是基于在适当保护下添加适当的苯基硒烯基卤化物α-乙烯基氨基酸，然后进行硒化物氧化和热解。在动力学控制的条件下（PhSeX，MeCN，2-3小时），主要获得（+/-）-（E）-α-（2-氯乙烯基）氨基酸。在PhSeX加成步骤的更长时间内，可以看到（+/-）-α-（1-氯乙烯基）区域异构体，包含50〜100％的α-卤代戊基氨基酸混合物。 ）使用2,2-二氯乙烯基苯基砜进行乙烯基化反应，作为（+/-）-α-（1-氯乙烯基）氨基酸的潜在合成途径。作为原理上的证明，已经使用这种化学方法合成了游离的（+/-）-α-（1-氯乙烯基）谷氨酸和（+/-）-α-（1-氯乙烯基）谷氨酸。 ）-（Z）-α-（2-氟乙烯基）氨基酸是由α-甲酰基氨基酸经Horner-Wadsworth-Emmons反应合成的，具有很高的立体选择性。所得的α-氟乙烯基砜官能团被转化为对所检查的所有季氨基酸具有高立体选择性的α-氟乙烯基锡烷基。进行原脱甲烯基化和脱保护，得到六个（+/-）-（Z）-α-（2-氟乙烯基）氨基酸（Ala，DOPA，Glu，Lys，Phe，m-Tyr）。用于评估（+/-）-α-乙烯基赖氨酸和（+/-）-α-乙烯基精氨酸的抑制作用。两种化合物均观察到时间依赖性抑制作用。 （+/-）-（E）-α-（2-氯丙啶基）赖氨酸，（+/-）-α-乙烯基赖氨酸，（+/-）-（Z）-α-（2-氟乙烯基）赖氨酸，（+用放射性时间点测定法用它们的同源氨基酸脱羧酶测试了-）-α-乙烯基谷氨酸和（+/-）-（Z）-α-（2-氟乙烯基）谷氨酸。使用Lineweaver-Burk分析测试每种测定并获得每种天然底物的Km值（L-赖氨酸/ LDC Km = 1.9 mM，L-谷氨酸/ GAD Km = 1.3 mM），并使用Kitz-Wilson分析获得KI，运动系数和t 1/2。长时间的透析显示，赖氨酸脱羧酶的抑制作用基本上是不可逆的。在发现最佳赖氨酸脱羧酶灭活剂的情况下，（+/-）-（Z）-α-（2-氟乙烯基）赖氨酸是非拟一级动力学（观察到ln（Et / Eo）与预孵育时间的关系。使用灭活曲线的切线对这些数据进行Kitz-Wilson分析，可得出KI = 1.3 mM，运动= 0.15 min-1，t1 / 2 = 5分钟。与该化合物是“自杀底物”的观点一致，通过19F NMR观察到了其酶促脱羧的产物，观察到的周转产物与总酶失活的比率约为46。观察到的19F NMR信号是由于产物（Z）-α-（2-氟乙烯基）尸胺的独立合成已证实。

著录项

  • 作者

    Jahng, Wan Jin.;

  • 作者单位

    The University of Nebraska - Lincoln.;

  • 授予单位 The University of Nebraska - Lincoln.;
  • 学科 Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2000
  • 页码 323 p.
  • 总页数 323
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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