(3β) 3-hydroxy-N-hydroxy-lup-20(29)-en-28-amide

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (3β) 3-hydroxy-N-hydroxy-lup-20(29)-en-28-amide
• 英文别名: betulinic acid hydroxamate；BAH；(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N,9-dihydroxy-5a,5b,8,8,11a-pentamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carboxamide
• 化学式: C₃₀H₄₉NO₃
• 分子量: 471.724
• InChiKey: XNJMICUWXYERTB-FZFNOLFKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  34
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  白桦脂酸 在 吡啶 、 4-二甲氨基吡啶 、 草酰氯 、 三乙胺 、 potassium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 112.0h， 生成 (3β) 3-hydroxy-N-hydroxy-lup-20(29)-en-28-amide
  参考文献：
  名称：

  Betulinic acid derived hydroxamates and betulin derived carbamates are interesting scaffolds for the synthesis of novel cytotoxic compounds

  摘要：

  The betulinic acid-derived hydroxamates 5-18, the amides 19-24, and betulin-derived bis-carbamates 25-28 as well as the carbamates 31-40 and 44-48 were prepared and evaluated for their anti-proliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3-O-acetyl hydroxamic acid 5 EC50 values as low as EC50 = 1.3 mu M were found, N,O-bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC50 = 16-20 mu M). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC50 = 5.9 mu M for A2780 human ovarian carcinoma cells and EC50 > 30 mu M for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19-24 and of betulin derived bis-carbamates 25-28 was low, except for N-ethyl substituted 25. Hexyl substituted 39 showed EC50 = 5.6 mu M (518A2 cells) while for mouse fibroblasts EC50 > 30 was determined. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.10.043

文献信息

• [EN] HYDROXAMATE TRITERPENOID DERIVATIVES<br/>[FR] DÉRIVÉS D'HYDROXAMATE TRITERPÉNOÏDE
  申请人：VIVACELL BIOTECHNOLOGY ESPANA S L

  公开号：WO2018069086A1

  公开（公告）日：2018-04-19

  Triterpenoid derivatives and compositions comprising said triterpenoids derivatives of Formula (I) are described, wherein R=-C(O)NHOH. Said triterpenoids and compositions show capacity to bind PHD2, stabilize HIF-1α and HIF-2α proteins, activate the HIF pathway in different cell types, induce angiogenesis in human endothelial vascular cell, show neuroprotective activity in vitro and in vivo, antidiabetic activity and reduce the levels of lipids in vivo, and increase the plasma levels of Erythropoietin in vivo. The triterpenoid derivatives described act also in a selective manner and do not induce Nrf2 activation, NF-κB inhibition, STAT3 inhibition, and TGR5 activation, which are known activities of the natural triterpenoid precursors. Said triterpenoid derivatives are useful in the treatment of conditions and diseases which are responsive to HIF activation such as stroke, cerebral palsy, traumatic injuries and neurodegenerative diseases; and also IBD, myocardial ischaemia–reperfusion injury, acute lung injury, diabetic and chronic wounds, organ transplantation, acute kidney injury or arterial diseases.

  本文描述了式（I）的三萜衍生物和包含该三萜衍生物的组合物，其中R=-C（O）NHOH。所述三萜衍生物和组合物表现出与PHD2结合的能力，稳定HIF-1α和HIF-2α蛋白，激活不同细胞类型中的HIF通路，诱导人类内皮细胞血管生成，显示体外和体内的神经保护作用，抗糖尿病活性并减少体内脂质水平，增加体内促红细胞生成素的血浆水平。所述三萜衍生物还具有选择性作用，不会诱导Nrf2激活、NF-κB抑制、STAT3抑制和TGR5激活，这是天然三萜衍生物前体的已知活性。所述三萜衍生物在治疗对HIF激活有反应的疾病和病症方面具有用途，例如中风、脑瘫、创伤性损伤和神经退行性疾病；以及炎症性肠病、心肌缺血再灌注损伤、急性肺损伤、糖尿病和慢性创口、器官移植、急性肾损伤或动脉疾病。
• Hydroxamate triterpenoid derivatives
  申请人：VIVACELL BIOTECHNOLOGY ESPANA S.L.

  公开号：US10766855B2

  公开（公告）日：2020-09-08

  Triterpenoid derivatives and compositions comprising said triterpenoids derivatives of Formula (I) are described, wherein R═—C(O)NHOH. Said triterpenoids and compositions show capacity to bind PHD2, stabilize HIF-1α and HIF-2α proteins, activate the HIF pathway in different cell types, induce angiogenesis in human endothelial vascular cell, show neuroprotective activity in vitro and in vivo, antidiabetic activity and reduce the levels of lipids in vivo, and increase the plasma levels of Erythropoietin in vivo. The triterpenoid derivatives described act also in a selective manner and do not induce Nrf2 activation, NF-κB inhibition, STAT3 inhibition, and TGR5 activation, which are known activities of the natural triterpenoid precursors. Said triterpenoid derivatives are useful in the treatment of conditions and diseases which are responsive to HIF activation such as stroke, cerebral palsy, traumatic injuries and neurodegenerative diseases; and also IBD, myocardial ischaemia-reperfusion injury, acute lung injury, diabetic and chronic wounds, organ transplantation, acute kidney injury or arterial diseases.

  描述了式 (I) 的三萜类衍生物和包含所述三萜类衍生物的组合物，其中 R═-C(O)NHOH.所述三萜类化合物和组合物具有结合 PHD2 的能力，可稳定 HIF-1α 和 HIF-2α 蛋白，激活不同类型细胞中的 HIF 通路，诱导人内皮血管细胞的血管生成，在体外和体内显示神经保护活性，具有抗糖尿病活性，降低体内血脂水平，提高体内红细胞生成素的血浆水平。所述三萜类衍生物还具有选择性作用，不会诱导 Nrf2 激活、NF-κB 抑制、STAT3 抑制和 TGR5 激活，这些都是天然三萜类前体的已知活性。所述三萜类衍生物可用于治疗对 HIF 活化有反应的病症和疾病，如中风、脑瘫、创伤性损伤和神经退行性疾病；以及肠道疾病、心肌缺血再灌注损伤、急性肺损伤、糖尿病和慢性伤口、器官移植、急性肾损伤或动脉疾病。
• Betulinic acid derived hydroxamates and betulin derived carbamates are interesting scaffolds for the synthesis of novel cytotoxic compounds
  作者：Jana Wiemann、Lucie Heller、Vincent Perl、Ralph Kluge、Dieter Ströhl、René Csuk

  DOI：10.1016/j.ejmech.2015.10.043

  日期：2015.12

  The betulinic acid-derived hydroxamates 5-18, the amides 19-24, and betulin-derived bis-carbamates 25-28 as well as the carbamates 31-40 and 44-48 were prepared and evaluated for their anti-proliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3-O-acetyl hydroxamic acid 5 EC50 values as low as EC50 = 1.3 mu M were found, N,O-bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC50 = 16-20 mu M). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC50 = 5.9 mu M for A2780 human ovarian carcinoma cells and EC50 > 30 mu M for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19-24 and of betulin derived bis-carbamates 25-28 was low, except for N-ethyl substituted 25. Hexyl substituted 39 showed EC50 = 5.6 mu M (518A2 cells) while for mouse fibroblasts EC50 > 30 was determined. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors
  作者：Alberto Minassi、Federica Rogati、Cristina Cruz、M. Eugenia Prados、Nuria Galera、Carla Jinénez、Giovanni Appendino、M. Luz Bellido、Marco A Calzado、Diego Caprioglio、Eduardo Muñoz

  DOI：10.1021/acs.jnatprod.8b00514

  日期：2018.10.26

  Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular endpoints with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-kappa B, STAT3, Nrf2, TGRS) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (Sb) was selected for further studies, and evaluation of its effect on HIF-la expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.