methyl N^α-(4-aminobenzoyl)-N^δ-phthaloyl-L-ornithinate | 158090-74-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl N^α-(4-aminobenzoyl)-N^δ-phthaloyl-L-ornithinate
• 英文别名: methyl 2-L<(4-aminobenzoyl)amino>-5-phthalimidopentanoate；methyl L-2-[(4-aminobenzoyl)amino]-5-phthalimidopentanoate；methyl (2S)-2-[(4-aminobenzoyl)amino]-5-(1,3-dioxoisoindol-2-yl)pentanoate
• CAS: 158090-74-5
• 化学式: C₂₁H₂₁N₃O₅
• 分子量: 395.415
• InChiKey: KJDGQBDSLGGLFJ-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl N^α-(4-aminobenzoyl)-N^δ-phthaloyl-L-ornithinate 在 盐酸 、 氢气 、 镍 、 sodium cyanoborohydride 作用下， 以 甲醇 、 水 、 溶剂黄146 为溶剂， 20.0 ℃ 、103.42 kPa 条件下， 反应 16.0h， 生成 methyl (2S)-2-[[4-[(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methylamino]benzoyl]amino]-5-(1,3-dioxoisoindol-2-yl)pentanoate
  参考文献：
  名称：

  新型二氢叶酸还原酶吡咯并[2,3- d ]嘧啶和噻吩并[2,3- d ]嘧啶抑制剂的合成及抗叶酸活性

  摘要：

  三个以前未描述的二氢叶酸还原酶（DHFR）抑制剂，N α - 〔4-〔Ñ - [（2,4- diaminopyrrolo [2,3- d ]嘧啶-5-基）甲基]氨基]苯甲酰基] - ñ δ -hemiphthaloyl -L鸟氨酸（7） ，ñ α - 〔4-〔ñ - [（2,4- diaminothieno [2,3- d ]嘧啶-5-基）甲基]氨基]苯甲酰基] - ñ δ -hemiphthaloyl-L -鸟氨酸（8）和N- [4- [ N -[（2,4-二氨基噻吩并[2,3 - d ]嘧啶-5-基）甲基]氨基]苯甲酰基] -L-谷氨酸（12），合成，并评估其抗叶酸活性。的能力7和8结合到DHFR和抑制CCRF-CEM人淋巴细胞性白血病细胞在培养物中的生长在与相应的蝶啶类似物相比受到显着减少，Ñ α - （4-氨基-4- deoxypteroyl） - ñ δ -半甲基丙二酰基-L-鸟

  DOI：

  10.1002/jhet.5570410523
• 作为产物：
  描述：

  Methyl N^δ-Phthaloyl-L-ornithinate Hydrochloride 在 platinum(IV) oxide 氢气 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 溶剂黄146 为溶剂， 25.0 ℃ 、344.73 kPa 条件下， 反应 27.25h， 生成 methyl N^α-(4-aminobenzoyl)-N^δ-phthaloyl-L-ornithinate
  参考文献：
  名称：

  氨基蝶呤和3'，5-二氯氨基蝶呤的Nω-半邻苯二甲酰基-α，ω-二氨基链烷酸类似物的合成和生物活性。

  摘要：

  Nα-（4-氨基-4-脱氧蝶酰基）-Nδ-（半邻苯二甲酰基）-L-鸟氨酸（PT523）的类似物，在对氨基苯甲酰基部分具有3'，5'-二氯取代，或具有一个或多个或多个合成了氨基酸部分中的CH2基团，并将其作为二氢叶酸还原酶（DHFR）活性和细胞生长的抑制剂进行了测试。用L-2,4-二氨基丁酸或L-赖氨酸替代PT523中的L-鸟氨酸不会降低与人重组DHFR的结合力，但会导致针对SCC25人和SCC VII鼠鳞状细胞癌以及针对MCF-7的活性丧失人类乳腺癌的文化。PT523的效力比甲氨蝶呤（MTX），氨基蝶呤（AMT）或曲美脲（TMQ）强几倍。3'，5'-二氯取代不会降低DHFR结合或细胞毒性。从2到PT523的新合成路线 研究了4-二氨基-6-（羟甲基）蝶啶和甲基Nα-（4-氨基苯甲酰基）-N-邻苯二甲酰基-L-鸟氨酸盐，但没有发现其优于前述方法。在有关PT523和MTX竞争性抑制（6R）-5

  DOI：

  10.1021/jm00040a008

文献信息

• Synthesis and Potent Antifolate Activity and Cytotoxicity of B-Ring Deaza Analogues of the Nonpolyglutamatable Dihydrofolate Reductase Inhibitor <i>N</i>^α-(4-Amino-4-deoxypteroyl)-<i>N</i>^δ-hemiphthaloyl-<scp>l</scp>-ornithine (PT523)
  作者：Andre Rosowsky、Joel E. Wright、Chitra M. Vaidya、Henry Bader、Ronald A. Forsch、Clara E. Mota、Jorge Pardo、Cindy S. Chen、Ying-Nan Chen

  DOI：10.1021/jm980477+

  日期：1998.12.1

  Six new B-ring analogues of the nonpolyglutamatable antifolate N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (PT523, 3) were synthesized with a view to determining the effect of modifications at the 5- and/or 8-position on dihydrofolate reductase (DHFR) binding and tumor cell growth inhibition The 5- and 8-deaza analogues were prepared from methyl 2-L-amino-5-phthalimidopentanoate and 4-amino-4-deoxy-N-10-formyl-5-deaza- and -8-deazapteroic acid, respectively. The 5,8-dideaza analogues were prepared from methyl 2-L-[(4-aminobenzoyl)-amino]-5-phthalimidopentanoate and 2,4-diaminoquinazoline-6-carbonitriles. The K-i for inhibition of human DHFR by the 5-deaza and 5-methyl-5-deaza analogues was about the same as that of 3 (0.35 pM), 11-fold lower than that of aminopterin (AMT, 1), and 15-fold lower than that of methotrexate (MTX, 2). However the K-i of the 8-deaza analogue was 27-fold lower than that of 1, and that of the 5,8-dideaza, 5-methyl-5,8-dideaza, and 5-chloro-5,8-dideaza analogues was approximately 50-fold lower. This trend was consistent with the published literature on the corresponding DHFR inhibitors with a glutamate side chain. In colony formation assays against the human head and neck squamous carcinoma cell line SCC25 after 72 h of treatment, the 5- and 8-deaza analogues were approximately as potent as 3, whereas the 5,8-dideaza analogue was 3 times more potent. 5-Methyl and 5-chloro substitution was also favorable, with the 5-methyl-5-deaza analogue being 2.5-fold more potent than the 5-deaza analogue. However the effect of 5-methyl substitution was less pronounced in the 5,8-dideaza analogues than in the 5-deaza analogues. The 5-chloro-5,8-dideaza analogue of 3 was the most active member of the series, with an IC50 = 0.33 nM versus 1.8 nM for 3 and 15 nM for MTX. The 5-methyl-5-deaza analogue of 3 was also tested at the National Cancer Institute against a panel of 50 human tumor cell lines in culture and was consistently more potent than 3, with IC50 values in the low nanomolar to subnanomolar range against most of the tumors. Leukemia and colorectal carcinoma cell lines were generally most sensitive, though good activity was also observed against CNS tumors and carcinomas of the breast and prostate. The results of this study demonstrate that B-ring analogues of 3 inhibit DHFR activity and tumor cell colony formation as well as, or better than, the parent compound. In view of the fact that 3 and its B-ring analogues cannot form polyglutamates, their high cytotoxicity relative to the corresponding B-ring analogues of AMT is noteworthy.
• Synthesis and Biological Activity of N.omega.-Hemiphthaloyl-.alpha.,.omega.-diaminoalkanoic Acid Analogs of Aminopterin and 3',5-Dichloroaminopterin
  作者：Andre Rosowsky、Henry Bader、Joel E. Wright、Khandan Keyomarsi、Larry H. Matherly

  DOI：10.1021/jm00040a008

  日期：1994.7

  carcinoma in culture. PT523 was several times more potent than methotrexate (MTX), aminopterin (AMT), or trimetrexate (TMQ). 3',5'-Dichloro substitution did not decrease either DHFR binding or cytotoxicity. A new synthetic route to PT523 from 2,4-diamino-6-(hydroxymethyl)pteridine and methyl N alpha-(4-aminobenzoyl)-N delta-phthaloyl-L-ornithinate was investigated but was not found superior to previously

  Nα-（4-氨基-4-脱氧蝶酰基）-Nδ-（半邻苯二甲酰基）-L-鸟氨酸（PT523）的类似物，在对氨基苯甲酰基部分具有3'，5'-二氯取代，或具有一个或多个或多个合成了氨基酸部分中的CH2基团，并将其作为二氢叶酸还原酶（DHFR）活性和细胞生长的抑制剂进行了测试。用L-2,4-二氨基丁酸或L-赖氨酸替代PT523中的L-鸟氨酸不会降低与人重组DHFR的结合力，但会导致针对SCC25人和SCC VII鼠鳞状细胞癌以及针对MCF-7的活性丧失人类乳腺癌的文化。PT523的效力比甲氨蝶呤（MTX），氨基蝶呤（AMT）或曲美脲（TMQ）强几倍。3'，5'-二氯取代不会降低DHFR结合或细胞毒性。从2到PT523的新合成路线 研究了4-二氨基-6-（羟甲基）蝶啶和甲基Nα-（4-氨基苯甲酰基）-N-邻苯二甲酰基-L-鸟氨酸盐，但没有发现其优于前述方法。在有关PT523和MTX竞争性抑制（6R）-5
• Synthesis and antifolate activity of new pyrrolo[2,3-<i>d</i>]pyrimidine and thieno[2,3-<i>d</i>]pyrimidine inhibitors of dihydrofolate reductase
  作者：Chitra Vaidya、Joel E. Wright、Andre Rosowsky

  DOI：10.1002/jhet.5570410523

  日期：2004.9

  inhibitors, Nα-[4-[N-[(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)methyl]amino]benzoyl]-Nδ-hemiphthaloyl-L-ornithine (7), Nα- [4- [N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]amino]benzoyl]- Nδ-hemiphthaloyl-L-ornithine (8), and N-[4-[N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]amino]benzoyl]-L-glutamic acid (12), were synthesized and their antifolate activity was assessed. The ability of 7

  三个以前未描述的二氢叶酸还原酶（DHFR）抑制剂，N α - 〔4-〔Ñ - [（2,4- diaminopyrrolo [2,3- d ]嘧啶-5-基）甲基]氨基]苯甲酰基] - ñ δ -hemiphthaloyl -L鸟氨酸（7） ，ñ α - 〔4-〔ñ - [（2,4- diaminothieno [2,3- d ]嘧啶-5-基）甲基]氨基]苯甲酰基] - ñ δ -hemiphthaloyl-L -鸟氨酸（8）和N- [4- [ N -[（2,4-二氨基噻吩并[2,3 - d ]嘧啶-5-基）甲基]氨基]苯甲酰基] -L-谷氨酸（12），合成，并评估其抗叶酸活性。的能力7和8结合到DHFR和抑制CCRF-CEM人淋巴细胞性白血病细胞在培养物中的生长在与相应的蝶啶类似物相比受到显着减少，Ñ α - （4-氨基-4- deoxypteroyl） - ñ δ -半甲基丙二酰基-L-鸟