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 | 113857-87-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 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
• 英文名称: (S)-2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid
• 英文别名: N^α-(4-amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine；N(α)-(4-amino-4-deoxypteroyl)-N(δ)-(hemiphthaloyl)-L-ornithine；N(α)-(4-amino-4-deoxypteroyl)-N(δ)-hemiphthaloyl-L-ornithine；Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-L-ornithine；N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine；PT523；Talotrexin；2-[[(4S)-4-carboxy-4-[[4-[(2,4-diaminopteridin-6-yl)methylamino]benzoyl]amino]butyl]carbamoyl]benzoic acid
• CAS: 113857-87-7
• 化学式: C₂₇H₂₇N₉O₆
• 分子量: 573.568
• InChiKey: NYQPLPNEESYGNO-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  248
• 氢给体数：
  7
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  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 在 次氯酸叔丁酯 作用下， 以 溶剂黄146 为溶剂， 反应 4.0h， 以12 mg的产率得到N^α-(4-amino-4-3',5'-dichlorodeoxypteroyl)-N^δ-hemiphthaloyl-L-ornithine
  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
• 作为产物：
  描述：

  在 sodium hydroxide 、 bovine carboxypeptidase A 、 zinc(II) chloride 作用下， 以 水 为溶剂， 反应 0.83h， 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

文献信息

• MEDICINAL COMPOSITIONS CONTAINING ANTI-Fas ANTIBODY
  申请人：Sankyo Company, Limited

  公开号：EP1180369A1

  公开（公告）日：2002-02-20

  The present invention provides a novel pharmaceutical composition containing an anti-Fas antibody which is useful as an agent for prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis. More particularly, the present invention provides a pharmaceutical composition containing an anti-human Fas antibody having apoptosis inducing activity and a compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity, as active ingredients. According to the present invention, the amount of the anti-Fas antibody to be used can be reduced in an agent for prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis, and thereby, the possibility that the patient becomes tolerant to anti-Fas antibody as a result of the production of antibodies against the anti-Fas antibody in the patient's body or the like can be decreased, and thus there can be provided a pharmaceutical composition of the present invention useful as an excellent agent for prophylaxis and/or treatment which can be used for a long time.

  本发明提供了一种含有抗 Fas 抗体的新型药物组合物，该药物组合物可用于预防和/或治疗自身免疫性疾病或类风湿性关节炎。 更具体地说，本发明提供了一种药物组合物，它含有一种具有诱导细胞凋亡活性的抗人 Fas 抗体和一种具有叶酸拮抗剂活性或二氢叶酸还原酶抑制活性的化合物作为活性成分。 根据本发明，在预防和/或治疗自身免疫性疾病或类风湿性关节炎的药剂中，可以减少抗 Fas 抗体的用量，从而降低患者因体内产生抗 Fas 抗体的抗体等而对 Fas 抗体产生耐受性的可能性，因此可以提供本发明的药物组合物，该药物组合物可作为预防和/或治疗的优良药剂长期使用。
• Amphiphilic drug-drug conjugates for cancer therapy, compositions and methods of preparation and uses thereof
  申请人：Shanghai Jiao Tong University

  公开号：US10463743B2

  公开（公告）日：2019-11-05

  The invention provides novel amphiphilic drug-drug conjugates useful as cancer therapeutics, and compositions and methods thereof.

  本发明提供了可用于癌症治疗的新型两亲性药物共轭物及其组合物和方法。
• Pharmaceutical compositions containing anti-fas antibody
  申请人：SANKYO COMPANY, LIMITED

  公开号：US20020103212A1

  公开（公告）日：2002-08-01

  A pharmaceutical composition containing an anti-human Fas antibody having apoptosis inducing activity and a compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity, as active ingredients for the prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis. According to the present invention, the amount of the anti-Fas antibody to be used can be reduced and thereby the possibility that a patient may become tolerant to anti-Fas antibody as a result of the production of antibodies against the anti-Fas antibody in the patient's body or the like can be decreased, and thus is provided a pharmaceutical composition which can be used for a long time.

  一种药物组合物，含有一种具有诱导细胞凋亡活性的抗人 Fas 抗体和一种具有叶酸拮抗剂活性或二氢叶酸还原酶抑制活性的化合物作为活性成分，用于预防和/或治疗自身免疫性疾病或类风湿性关节炎。根据本发明，可以减少抗 Fas 抗体的用量，从而降低患者因体内产生抗 Fas 抗体的抗体等而对 Fas 抗体产生耐受性的可能性，因此提供了一种可以长期使用的药物组合物。
• Combinations of antibodies selective for a tumor necrosis factor-related apoptosis-inducing ligand receptor and other therapeutic agents
  申请人：——

  公开号：US20030133932A1

  公开（公告）日：2003-07-17

  An antibody of the invention interacts with human DR5 or with human DR4 to produce agonistic or antagonistic effects downstream of the receptor including inhibition of cell proliferation and apoptosis. Methods and uses for the antibodies, optionally in combination with various therapeutic agents, are detailed, including treatment of apoptosis-related disease and treatment of dysregulated cell growth.

  本发明的抗体与人类 DR5 或人类 DR4 相互作用，在受体下游产生激动或拮抗作用，包括抑制细胞增殖和凋亡。详细介绍了抗体的方法和用途，可选择与各种治疗剂结合使用，包括治疗细胞凋亡相关疾病和治疗细胞生长失调。
• J. Med. Chem. 1988, 31, 1332-1337
  作者：

  DOI：——

  日期：——