N^α-(4-amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-L-ornithinyl-L-phenylalanine | 417703-27-6

• 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: N^α-(4-amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-L-ornithinyl-L-phenylalanine
• 英文别名: PT633；2-[[(4S)-5-[[(1S)-1-carboxy-2-phenylethyl]amino]-4-[[4-[(2,4-diaminopteridin-6-yl)methylamino]benzoyl]amino]-5-oxopentyl]carbamoyl]benzoic acid
• CAS: 417703-27-6
• 化学式: C₃₆H₃₆N₁₀O₇
• 分子量: 720.745
• InChiKey: XCNYUZDPGWONSL-SVBPBHIXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  53
• 可旋转键数：
  16
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  278
• 氢给体数：
  8
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  N^α-(4-amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-L-ornithinyl-L-phenylalanine 在 bovine carboxypeptidase A 、 zinc(II) chloride 作用下， 以 various solvent(s) 为溶剂， 反应 0.33h， 生成 2-[[(4S)-4-羧基-4-[[4-[(2,4-二氨基蝶啶-6-基)甲基氨基]苯甲酰基]氨基]丁基]氨基甲酰]苯甲酸
  参考文献：
  名称：

  Synthesis and enzymatic activation of N-[Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithiny]-l-phenylalanine, a candidate for antibody-directed enzyme prodrug therapy (ADEPT)

  摘要：

  N-[N-alpha-(4-Amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithinyl]-L-phenylalanine (1), a carboxypeptidase A (CPA) cleavable prodrug was synthesized for use in an antibody directed strategy to improve the therapeutic selectivity of N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (2), an extremely potent nonpoly-glutamatable DHFR inhibitor which is also highly cytotoxic. Compound I was shown by HPLC analysis to give a >99% yield of 2 upon incubation with bovine CPA (bCPA) for 20 min at 25degreesC. In a spectrophotometric kinetic assay with 50 muM dihydrofolate as the competing substrate in the presence of 65 muM NADPH. 1+bCPA stoichiometrically inhibited recombinant human DHFR (rhDHFR) with a K-i of 0.35 pM. In contrast, I without bCPA was a poor inhibitor of rhDHFR (K-i > 10 muM). In a 72 h growth inhibition assay against cultured CCRF-CEM human leukemic lymphoblasts. the growth inhibitory activities of 1+bCPA, 2+bCPA, and 2 alone were the same (IC50 1.3-1.4 nM), whereas I in the absence of bCPA was > 100-fold less potent (IC50 155 nM). (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00298-x
• 作为产物：
  描述：

  在 sodium hydroxide 作用下， 以 水 为溶剂， 反应 0.5h， 以6.8%的产率得到N^α-(4-amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-L-ornithinyl-L-phenylalanine
  参考文献：
  名称：

  Synthesis and enzymatic activation of N-[Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithiny]-l-phenylalanine, a candidate for antibody-directed enzyme prodrug therapy (ADEPT)

  摘要：

  N-[N-alpha-(4-Amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithinyl]-L-phenylalanine (1), a carboxypeptidase A (CPA) cleavable prodrug was synthesized for use in an antibody directed strategy to improve the therapeutic selectivity of N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (2), an extremely potent nonpoly-glutamatable DHFR inhibitor which is also highly cytotoxic. Compound I was shown by HPLC analysis to give a >99% yield of 2 upon incubation with bovine CPA (bCPA) for 20 min at 25degreesC. In a spectrophotometric kinetic assay with 50 muM dihydrofolate as the competing substrate in the presence of 65 muM NADPH. 1+bCPA stoichiometrically inhibited recombinant human DHFR (rhDHFR) with a K-i of 0.35 pM. In contrast, I without bCPA was a poor inhibitor of rhDHFR (K-i > 10 muM). In a 72 h growth inhibition assay against cultured CCRF-CEM human leukemic lymphoblasts. the growth inhibitory activities of 1+bCPA, 2+bCPA, and 2 alone were the same (IC50 1.3-1.4 nM), whereas I in the absence of bCPA was > 100-fold less potent (IC50 155 nM). (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00298-x

文献信息

• Synthesis and enzymatic activation of N-[Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithiny]-l-phenylalanine, a candidate for antibody-directed enzyme prodrug therapy (ADEPT)
  作者：Joel E Wright、Andre Rosowsky

  DOI：10.1016/s0968-0896(01)00298-x

  日期：2002.3

  N-[N-alpha-(4-Amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithinyl]-L-phenylalanine (1), a carboxypeptidase A (CPA) cleavable prodrug was synthesized for use in an antibody directed strategy to improve the therapeutic selectivity of N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (2), an extremely potent nonpoly-glutamatable DHFR inhibitor which is also highly cytotoxic. Compound I was shown by HPLC analysis to give a >99% yield of 2 upon incubation with bovine CPA (bCPA) for 20 min at 25degreesC. In a spectrophotometric kinetic assay with 50 muM dihydrofolate as the competing substrate in the presence of 65 muM NADPH. 1+bCPA stoichiometrically inhibited recombinant human DHFR (rhDHFR) with a K-i of 0.35 pM. In contrast, I without bCPA was a poor inhibitor of rhDHFR (K-i > 10 muM). In a 72 h growth inhibition assay against cultured CCRF-CEM human leukemic lymphoblasts. the growth inhibitory activities of 1+bCPA, 2+bCPA, and 2 alone were the same (IC50 1.3-1.4 nM), whereas I in the absence of bCPA was > 100-fold less potent (IC50 155 nM). (C) 2002 Elsevier Science Ltd. All rights reserved.