(3S,6R)-3-amino-6-(3-hydroxypropyl)-3,6-dihydropyridin-2(3H)-one hydrochloride

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3S,6R)-3-amino-6-(3-hydroxypropyl)-3,6-dihydropyridin-2(3H)-one hydrochloride
• 英文别名: (2R,5S)-5-amino-2-(3-hydroxypropyl)-2,5-dihydro-1H-pyridin-6-one;hydrochloride
• 化学式: C₈H₁₄N₂O₂*ClH
• 分子量: 206.672
• InChiKey: HUHRHMHSUCLRNU-HHQFNNIRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.44
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  75.4
• 氢给体数：
  4
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3S,6R)-3-amino-6-(3-hydroxypropyl)-3,6-dihydropyridin-2(3H)-one hydrochloride 、 磷酸吡哆醛 在 transaminase BioA 、 2-巯基乙醇 作用下， 反应 2.0h， 生成
  参考文献：
  名称：

  Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis

  摘要：

  BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal S'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 angstrom resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.

  DOI：

  10.1021/ja204036t
• 作为产物：
  描述：

  tert-butyl {(3S,6R)-6-[3-(tert-butyldimethylsilyloxy)propyl]-2-oxo-3,6-dihydro-pyridin-3-yl}carbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 以88%的产率得到(3S,6R)-3-amino-6-(3-hydroxypropyl)-3,6-dihydropyridin-2(3H)-one hydrochloride
  参考文献：
  名称：

  Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis

  摘要：

  BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal S'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 angstrom resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.

  DOI：

  10.1021/ja204036t

文献信息

• Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in <i>Mycobaterium tuberculosis</i>
  作者：Ce Shi、Todd W. Geders、Sae Woong Park、Daniel J. Wilson、Helena I. Boshoff、Orishadipe Abayomi、Clifton E. Barry、Dirk Schnappinger、Barry C. Finzel、Courtney C. Aldrich

  DOI：10.1021/ja204036t

  日期：2011.11.16

  BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal S'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 angstrom resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.