brefeldin A 4,7-O-dinicotinate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: brefeldin A 4,7-O-dinicotinate
• 英文别名: [(1R,2R,3E,7S,11E,13S,15S)-7-methyl-5-oxo-2-(pyridine-3-carbonyloxy)-6-oxabicyclo[11.3.0]hexadeca-3,11-dien-15-yl] pyridine-3-carboxylate
• 化学式: C₂₈H₃₀N₂O₆
• 分子量: 490.556
• InChiKey: MECQQPZSSPRKEX-MAJMIXDQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  105
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  brefeldin A 7-O-nicotinate 在 4-二甲氨基吡啶 、 水 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 aq. phosphate buffer 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 64.0h， 生成 brefeldin A 4,7-O-dinicotinate
  参考文献：
  名称：

  Synthesis and Cytotoxic Evaluation of Acylated Brefeldin A Derivatives as Potential Anticancer Agents

  摘要：

  Brefeldin A has attracted considerable attention because of its potential function in cancer prevention. However, its therapeutic use is limited by its poor bioavailability. The modifications on brefeldin A were difficult because of its low stability and selectivity toward two hydroxyl groups within the same molecule. In this study, we report the selective acylation of brefeldin A under mild conditions and the preparation of a series of monoacylated and diacylated brefeldin A derivatives. Their cytotoxicity, antitumor activity against TE‐1 cell, and molecular properties of adsorption, distribution, metabolism, and elimination were evaluated. Brefeldin A 7‐O‐benzoate, brefeldin A 4,7‐O‐dibenzoate, and brefeldin A 7‐O‐biotin carboxylate showed the most potent cytotoxic activity, with GI50 values of 0.39, 0.46, and 0.50 μm, respectively. Molecular docking of these analogs revealed that the derivatives were well tolerated at the interface between ARF1 and its guanine nucleotide exchange factor ARNO. Our results may serve as a basis for the development of novel potential anticancer agents from brefeldin A derivatives.

  DOI：

  10.1111/cbdd.12154

文献信息

• Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug <b>CHNQD-01255</b> with Potent Anti-Hepatocellular Carcinoma Efficacy <i>In Vivo</i>
  作者：Yao-Yao Jiang、Yang Gao、Jian-Yu Liu、Ying Xu、Mei-Yan Wei、Chang-Yun Wang、Yu-Cheng Gu、Chang-Lun Shao

  DOI：10.1021/acs.jmedchem.2c00532

  日期：2022.9.22

  Brefeldin A (BFA), a well-known natural Arf-GEFs inhibitor, is effective against hepatocellular carcinoma (HCC), while the poor solubility, serious toxicity, and short half-life limit its potential. Herein, distinct corresponding prodrugs of BFA, including esters 1–15, carbonates 16–24 and 30–32, and carbamates 25–29, were synthesized and evaluated. CHNQD-01255 (16) with improved aqueous solubility

  Brefeldin A (BFA) 是一种众所周知的天然 Arf-GEFs 抑制剂，对肝细胞癌 (HCC) 有效，但溶解度差、毒性严重和半衰期短限制了其潜力。在此，合成和评估了不同的相应BFA前药，包括酯1-15、碳酸酯16-24和30-32，以及氨基甲酸酯25-29 。具有改善的水溶性 (15–20 mg/mL)的 CHNQD-01255 ( 16 ) 表现出良好的药代动力学特征。它通过在体内快速转化为 BFA 表现出预期的效果, 并实现了足够高的血浆暴露量、延长的半衰期以及 BFA 的生物利用度提高 ( F = 18.96%)。同时，CHNQD-01255在异种移植模型中以 45 mg/kg (po) 的剂量显着抑制肿瘤生长 (TGI = 61.0%)。值得注意的是，CHNQD-01255 (MTD > 750 mg/kg, po) 的改进安全性被证实优于 BFA (MTD < 506