pteroyl hydrazide | 197151-68-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: pteroyl hydrazide
• 英文别名: 4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzohydrazide
• CAS: 197151-68-1
• 化学式: C₁₄H₁₄N₈O₂
• 分子量: 326.318
• InChiKey: NVKLRUMUKZSKHW-UHFFFAOYSA-N

物化性质

• 密度：
  1.72±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  160
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  pteroyl hydrazide 在 亚硝酸特丁酯 、 potassium thioacyanate 、 三氟乙酸 作用下， 反应 6.5h， 以83%的产率得到pteroyl azide
  参考文献：
  名称：

  与谷氨酰基-γ-谷氨酸类似的膦酸假肽：合成和与蝶酰基叠氮化物偶联导致有效的叶酰多-γ-谷氨酸合成酶抑制剂。

  摘要：

  已经研究了几种类似于γ-谷氨酰基肽Glu-γ-Glu的复杂次膦酸酯磷酸肽的途径。由于需要升高的温度，发现通过向被保护的乙烯基甘氨酸中添加磷基基团来形成γ-膦酰基谷氨酸衍生物具有有限的价值。研究了三价磷（P（III））的烷基化和共轭加成反应。次膦酸的双三甲基甲硅烷基酯的原位生成被证明是具有中等结构复杂性的次膦酸酯的有效途径。但是，这种化学方法不能扩展到在所需次膦酸酯的N-末端侧掺入氨基酸部分。使用P（III）化学方法和脱卤化氢成功合成了目标次膦酸酯磷酸肽，得到α，β-不饱和次膦酸酯，然后共轭添加二乙基乙酰胺基丙二酸酯和酸介导的水解得到所需的次膦酸酯磷酸肽。未保护的次膦酸酯磷酸肽与衍生自叶酸和甲氨蝶呤的两个酰基叠氮化物的偶联导致感兴趣的相应的蝶酰基磷酸肽，因为叶酰聚谷氨酸合成酶催化反应中四面体中间体的可能模拟。

  DOI：

  10.1021/jo010283t
• 作为产物：
  描述：

  pteroyl azide 在 1,1,2,3-四甲基胍 、 肼 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 反应 30.5h， 生成 pteroyl hydrazide
  参考文献：
  名称：

  Efficient Syntheses of Pyrofolic Acid and Pteroyl Azide, Reagents for the Production of Carboxyl-Differentiated Derivatives of Folic Acid

  摘要：

  Reaction of folic acid (1) with excess trifluoroacetic anhydride provides access to both the previously unknown N-10-(trifluoroacetyl)pyrofolic acid (8) and pyrofolic acid (9). Reaction of either of these materials with hydrazine selectively affords pteroyl hydrazide (13), which may be oxidized to pteroyl azide (27) on a large scale (62% overall from 1 without the need for chromatography). Treatment of 27 with differentially protected glutamates provides a convenient and high-yielding synthesis of differentially protected, optically pure folates.

  DOI：

  10.1021/ja971568j

文献信息

• Folate-modified cholesterol-bearing pullulan as a drug carrier
  申请人：Sunamoto Junzo

  公开号：US20070042970A1

  公开（公告）日：2007-02-22

  Folate modified cholesterol-bearing pullulan (FA-CHP) was synthesized by the reaction of folic acid γ-2-aminoethylamide and 4-nitorophenyl chloroformate-activated cholesterol-bearing pullulan, wherein folate and pullulan are connected through a NH—CH 2 —CH 2 —NH group. Approximately 0.5-1 folates are connected per about 100 glycoside units of pullulan. Then, several combinations of FA-CHP, cholesterol-bearing pullulan (CHP) and doxorubicin (DOX) mixture were tested for cancer selective cytotoxicity. A mixture of FA-CHP, CHP and DOX of 1:4:0.02 (weight ratio) gave sharp and selective damage to cells of a human epidermoid cancer KB known as expressing a high level of folate receptor. The same mixture inhibited the growth of HuH7 cells, which is a human hepatocellular carcinoma and is unknown as a folate receptor.

  叶酸修饰的胆固醇载体泊洛聚糖（FA-CHP）是通过叶酸γ-2-氨基乙酰胺和4-硝基苯基氯甲酸酯活化的胆固醇载体泊洛聚糖反应合成的，其中叶酸和泊洛聚糖通过一个NH—CH2—CH2—NH基团连接。每约100个葡糖苷单元中连接了大约0.5-1个叶酸。然后，对叶酸修饰的胆固醇载体泊洛聚糖（FA-CHP）、胆固醇载体泊洛聚糖（CHP）和阿霉素（DOX）混合物进行了多种组合的癌症选择性细胞毒性测试。FA-CHP、CHP和DOX的混合物比例为1:4:0.02（重量比）对人表皮癌KB细胞具有高叶酸受体表达水平的细胞造成了明显和选择性的损伤。同样的混合物抑制了HuH7细胞的生长，这是一种人类肝细胞癌，并且未知是否具有叶酸受体。
• Synthesis, characterization, and anticancer activity of folate γ-ferrocenyl conjugates
  作者：Diego L. Bertuzzi、Gabriel Perli、Carolyne B. Braga、Catia Ornelas

  DOI：10.1039/c9nj04954a

  日期：——

  Novel folate γ-ferrocene conjugates were synthesized through a regiospecific route, and showed selectivity and enhanced cytotoxicity against Frα-positive malignant cells.

  通过一个特定的路线合成了新型的叶酸γ-二茂铁共轭物，并且表现出对Frα阳性的恶性细胞的选择性和增强的细胞毒性。
• Design and structure activity relationship of tumor-homing histone deacetylase inhibitors conjugated to folic and pteroic acids
  作者：Quaovi H. Sodji、James R. Kornacki、John F. McDonald、Milan Mrksich、Adegboyega K. Oyelere

  DOI：10.1016/j.ejmech.2015.04.014

  日期：2015.5

  Histone deacetylase (HDAC) inhibition has recently emerged as a novel therapeutic approach for the treatment of various pathological conditions including cancer. Currently, two HDAC inhibitors (HDACi) - Vorinostat and Romidepsin - have been approved for the treatment of cutaneous T-cell lymphoma. However, HDACi remain ineffective against solid tumors and are associated with adverse events including cardiotoxicity. Targeted delivery may enhance the therapeutic indices of HDACi and enable them to be efficacious against solid tumors. We showed herein that morphing of folic and pteroic acids into the surface recognition group of HDACi results in hydroxamate and benzamide HDACi which derived tumor homing by targeting folate receptor (FR), a receptor commonly overexpressed in solid tumors. We observed a correlation between the potency of HDAC1 inhibition and cytotoxicity as only the potent pteroate hydroxamates, 11d and 11e, displayed antiproliferative activity against two representative FR-expression cancer cells. Our observation further supports the previous results which suggest that for a drug to be successfully targeted using the FR, it must be extremely potent against its primary target as the FR has a low delivery efficiency. Published by Elsevier Masson SAS.
• Folic acid conjugates of a bleomycin mimic for selective targeting of folate receptor positive cancer cells
  作者：Arjan Geersing、Reinder H. de Vries、Gerrit Jansen、Marianne G. Rots、Gerard Roelfes

  DOI：10.1016/j.bmcl.2019.05.047

  日期：2019.8

  A major challenge in the application of cytotoxic anti-cancer drugs is their general lack of selectivity, which often leads to systematic toxicity due to their inability to discriminate between malignant and healthy cells. A particularly promising target for selective targeting are the folate receptors (FR) that are often over-expressed on cancer cells. Here, we report on a conjugate of the pentadentate nitrogen ligand N4Py to folic acid, via a cleavable disulphide linker, which shows selective cytotoxicity against folate receptor expressing cancer cells.
• Site-specific folate conjugation to a cytotoxic protein
  作者：Bryan D. Smith、Joshua J. Higgin、Ronald T. Raines

  DOI：10.1016/j.bmcl.2011.04.081

  日期：2011.9

  Conjugation to folic acid is known to enhance the uptake of molecules by human cells that over-produce folate receptors. Variants of bovine pancreatic ribonuclease (RNase A) that have attenuated affinity for the endogenous ribonuclease inhibitor protein (RI) are toxic to mammalian cells. Here, the random acylation of amino groups in wild-type RNase A with folic acid is shown to decrease its catalytic activity dramatically, presumably because of the alteration to a key active-site residue, Lys41. To effect site-specific coupling, N-delta-bromoacetyl-N-alpha-pteroyl-L-ornithine, which is a folate analogue with an electrophilic bromoacetamido group, was synthesized and used to S-alkylate Cys88 of the G88C variant of RNase A. The pendant folate moiety does not decrease enzymatic activity, enables RI-evasion, and endows toxicity for cancer cells that over-produce the folate receptor. These data reveal a propitious means for targeting proteins and other molecules to cancer cells. (C) 2011 Elsevier Ltd. All rights reserved.