Toward the novel development for the diagnosis and treatment of cancer by the use of peptides that are accumulated into tumor cells.

通过使用积累到肿瘤细胞中的肽来诊断和治疗癌症的新发展。

• 批准号: 13680678
• 负责人: WAKAMIYA Tateaki
• 金额: $ 2.05万
• 依托单位: Kinki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13680678/
• 关键词: magnetic resonance imaging (MRI); diagnosis and treatment of cancer; peptides accumulating into tumor cells; boron neutron capture therapy (BNCT); pentafluorophenvlalanine; p-boronophenylalanine; 4-borono-2,3,5,6-tetrafluorophenylalanine; 2,3,5,6-テ

1) Since commercial 4-fluorophenylalanine [Phe(4F)] is quite expensive, we synthesized this amino acid by conventional method from 4-fluorobenzyl chloride and diethyl acetamidomalonate. However, the content of F atom in this molecule is not enough for measurement by magnetic resonance imaging (MRI). Therefore, pentafluorophenylalanine [Phe(F_5)] was newly synthesized in a similar manner, and subjected to prepare several Phe(F_5)-containing dipeptides. Accumulation of these peptides into tunor cells via specific oligopeptide transporter is being currently undertaken.2) p-Boronophenylalanine (Bpa) is rather expensive than Phe(4F), and the compound enriched with ^<10>B must be prepared by ourselves. To avoid the application of a harmful strategy such as the Snyder or Kirihata method, a novel methodology using p-bromobenzaldehyde as a starting material was elucidated. In the course of this study, we first planned to prepare N-chloroacetyl-Bpa (ClAc-Bpa) for enzymatic optical resolution. However, the synthesis of ClAc-Bpa was quite difficult, and we thus changed the plan toward to prepare common N-acetyl-Bpa (Ac-Bpa). As a result of the present study, we developed a useful method to prepare Ac-Bpa by employing the mild reaction conditions for boronation at para-position on the phenyl ring or halogenation at benzyl-position. Enzymatic optical resolution of this derivative is being currently undertaken.3) During the course of this work, we newly planned to synthesize a chimeral compound between Bpa and Phe(F_5), i.e., 4-borono-2,3,5,6-tetrafluorophenylalanine [Bpa(F_4)], and we are currently undertaking the synthesis of this amino acid. Bpa(F_4)-ol that is obtainable by reduction of the carboxyl group of Bpa(F_4) seems to be a good candidate to promote boron neutron capture therapy (BNCT), i.e., we can check the exact location of cancer cells by MRI, and thus cancer cells can be irradiated accurately by neutron.

1）由于商业4-氟苯丙氨酸[Phe(4F)]相当昂贵，我们通过常规方法由4-氟苄基氯和乙酰氨基丙二酸二乙酯合成该氨基酸。然而，该分子中F原子的含量不足以通过磁共振成像（MRI）测量。因此，以类似的方式重新合成五氟苯丙氨酸[Phe(F_5)]，并制备多种含Phe(F_5)的二肽。目前正在通过特定的寡肽转运蛋白将这些肽积累到肿瘤细胞中。2)对硼苯丙氨酸(Bpa)比Phe(4F)相当昂贵，并且富含^ 10 B的化合物必须由我们自己制备。为了避免使用有害策略（例如 Snyder 或 Kirihata 方法），阐明了一种使用对溴苯甲醛作为起始材料的新方法。在本研究过程中，我们首先计划制备用于酶光学拆分的 N-氯乙酰基-Bpa (ClAc-Bpa)。然而，ClAc-Bpa的合成相当困难，因此我们改变了计划，转向制备普通的N-乙酰基-Bpa（Ac-Bpa）。作为本研究的结果，我们开发了一种有用的方法来制备 Ac-Bpa，该方法采用温和的反应条件，在苯环上对位硼化或在苄基位卤化。目前正在对该衍生物进行酶促光学拆分。 3)在这项工作过程中，我们新计划合成Bpa和Phe(F_5)之间的嵌合化合物，即4-硼基-2,3,5,6-四氟苯丙氨酸[Bpa(F_4)]，目前我们正在进行该氨基酸的合成。通过还原Bpa(F_4)的羧基得到的Bpa(F_4)-ol似乎是促进硼中子捕获疗法(BNCT)的良好候选者，即我们可以通过MRI检查癌细胞的确切位置，从而可以准确地用中子照射癌细胞。