Maleki Ali, Taheri-Ledari Reza, Eivazzadeh-Keihan Reza, de la Guardia Miguel, Mokhtarzadeh Ahad
Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran.
Department of Analytical Chemistry, University of Valencia, Dr. Moliner 50, 46100, Burjassot, Valencia, Spain.
Curr Org Synth. 2019;16(5):765-771. doi: 10.2174/1570179416666190423114704.
Bacteria could become resistant to β-lactam antibiotics through production of β- lactamase enzymes like metallo-β-lactamase. 2-(2-mercaptoacetamido)-3-phenylpropanoic acid was reported as a model inhibitor for this enzyme. In order to elucidate the mechanism of action in the body's internal environment, preparation of a labeled version of 2-(2-mercaptoacetamido)-3-phenylpropanoic acid finds importance. In this regard, we report a convenient synthetic pathway for preparation of carbon-14 labeled 2-(2- mercaptoacetamido)-3-phenylpropanoic acid.
This study was initiated by using non-radioactive materials. Then, necessary characterization was performed after each of the reactions. Finally, the synthesis steps were continued to produce the target labeled product. For labeled products, the process was started from benzoic acid-[carboxyl- 14C] which has been prepared from barium 14C-carbonate. Chromatography column and NMR spectroscopy were used for purifications and identification of desired products, respectively. Barium [14C]carbonate was purchased from Amersham Pharmacia Biotech and was converted to [14C]benzyl bromide. Radioactivity was determined using liquid scintillation spectrometer.
We used [14C]PhCH2Br which was previously prepared from [14C]BaCO3, H2SO4, PhMgI, LAH and HBr, respectively. To neutralize the [14C]phenylalanine in acidic condition and to reach an isoelectric point of phenylalanine (pH = 5.48), Pb(OH)2 was used. Next, thioacetic acid and bromo acetic acid were used to prepare (acetylthio) acetic acid. A peptide coupling reagent was used in this stage to facilitating amide bond formation reaction between [14C]methyl-2-amino-3-phenyl propanoate hydrochloride and (acetylthio) acetic acid.
Carbon-14 labeled 2-(2-mercaptoacetamido)-3-phenylpropanoic acid via radioactive phenylalanine was obtained with overall chemical yield 73% and radioactivity 65.3 nCi. The labeled target product will be used for in vivo pharmacological studies.
细菌可通过产生金属β-内酰胺酶等β-内酰胺酶对β-内酰胺类抗生素产生耐药性。2-(2-巯基乙酰氨基)-3-苯基丙酸被报道为该酶的一种模型抑制剂。为阐明其在体内环境中的作用机制，制备2-(2-巯基乙酰氨基)-3-苯基丙酸的标记版本具有重要意义。在这方面，我们报道了一种制备碳-14标记的2-(2-巯基乙酰氨基)-3-苯基丙酸的简便合成途径。
本研究首先使用非放射性材料开始。然后，在每个反应后进行必要的表征。最后，继续合成步骤以生产目标标记产物。对于标记产物，该过程从由碳酸钡-14C制备的苯甲酸-[羧基-14C]开始。分别使用色谱柱和核磁共振光谱对所需产物进行纯化和鉴定。碳酸钡-14C购自安玛西亚 Pharmacia Biotech，并转化为苄基溴-14C。使用液体闪烁光谱仪测定放射性。
我们使用了先前分别由碳酸钡-14C、硫酸、苯基溴化镁、氢化铝锂和氢溴酸制备的苄基溴-14C。为在酸性条件下中和苯丙氨酸-14C并达到苯丙氨酸的等电点（pH = 5.48），使用了氢氧化铅。接下来，使用硫代乙酸和溴乙酸制备(乙酰硫基)乙酸。在该阶段使用肽偶联试剂以促进盐酸-14C-甲基-二氨基-3-苯基丙酸酯与(乙酰硫基)乙酸之间的酰胺键形成反应。
通过放射性苯丙氨酸获得了碳-14标记的2-(2-巯基乙酰氨基)-3-苯基丙酸，总化学产率为73%，放射性为65.3 nCi。该标记的目标产物将用于体内药理学研究。
