Bortezomib D-mannitol | 444576-08-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Bortezomib D-mannitol
• 英文别名: N-[(2S)-1-[[(1R)-1-[(4R,5R)-4,5-bis[(1R)-1,2-dihydroxyethyl]-1,3,2-dioxaborolan-2-yl]-3-methylbutyl]amino]-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide
• CAS: 444576-08-3
• 化学式: C₂₅H₃₅BN₄O₈
• 分子量: 530.386
• InChiKey: QDMRNLRJDHCHLB-DNNBANOASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.13
• 重原子数：
  38
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  183
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  甘露醇 、 硼替佐米 在 三乙胺 作用下， 以 水 、 叔丁醇 为溶剂， 反应 2.0h， 生成 Bortezomib D-mannitol
  参考文献：
  名称：

  A Sialylated-Bortezomib Prodrug Strategy Based on a Highly Expressed Selectin Target for the Treatment of Leukemia or Solid Tumors

  摘要：

  本研究旨在探索与唾液酸相关的选择素靶向策略在白血病和某些实体肿瘤治疗中的潜力。我们期望它能够“主动”结合肿瘤细胞并杀死它们，从而减少对正常细胞的非特异性毒性。通过将唾液酸中的邻二羟基基团与硼酸中的硼基团反应，合成了BOR-SA前药。选择了两种白血病细胞（RAW264.7和HL60细胞）、一种实体肉瘤细胞模型（S180细胞）及其相应的正常细胞（单核细胞（MO）、中性粒细胞（NE）和成纤维细胞（L929））用于体外细胞实验（细胞毒性、细胞摄取、细胞周期和凋亡实验）。建立了S180肿瘤负载的昆明小鼠模型以进行抗肿瘤药效学实验。体外细胞实验结果显示，与对照组相比，HL60和S180细胞对BOR-SA的摄取增加。BOR-SA诱导了更低的IC50、更高的凋亡比例和肿瘤细胞的细胞周期停滞。体内抗S180肿瘤药效学实验显示，BOR-SA组的小鼠相较于对照组具有更高的肿瘤抑制率、更高的体重和更低的免疫器官毒性。唾液酸介导的选择素靶向策略在相关肿瘤治疗中可能具有很大的潜力。

  DOI：

  10.1007/s11095-019-2714-4

文献信息

• A Sialylated-Bortezomib Prodrug Strategy Based on a Highly Expressed Selectin Target for the Treatment of Leukemia or Solid Tumors
  作者：Mingqi Liu、Xueying Tang、Junqiang Ding、Mengyang Liu、Bowen Zhao、Yihui Deng、Yanzhi Song

  DOI：10.1007/s11095-019-2714-4

  日期：2019.12

  This study aimed to explore the potential of sialic acid - related selectin targeting strategy in the treatment of leukemia and some solid tumors. We expected it could “actively” bind tumor cells and kill them, reducing non-specific toxicity to normal cells. BOR-SA prodrug was synthesized by reacting an ortho-dihydroxy group in SA with a boronic acid group in BOR. Two kinds of leukemia cells (RAW264.7 and HL60 cells), one solid sarcoma cell model (S180 cells) and their corresponding normal cells (monocytes (MO), neutrophil (NE) and fibroblast (L929)) were selected for the in vitro cell experiments (cytotoxicity, cellular uptake, cell cycle and apoptosis experiments). The S180 tumor-bearing Kunming mice model was established for anti-tumor pharmacodynamic experiments. In vitro cell assay results showed that uptake of BOR-SA by HL60 and S180 cells were increased compared with the control group. BOR-SA induced a lower IC50, higher ratio of apoptosis and cell cycle arrest of tumor cells. In vivo anti-S180 tumor pharmacodynamics experiments showed that mice in the BOR-SA group had higher tumor inhibition rate, higher body weight and lower immune organ toxicity compared with the control group. sialic acid-mediated selectin targeting strategy may have great potential in the treatment of related tumors.

  本研究旨在探索与唾液酸相关的选择素靶向策略在白血病和某些实体肿瘤治疗中的潜力。我们期望它能够“主动”结合肿瘤细胞并杀死它们，从而减少对正常细胞的非特异性毒性。通过将唾液酸中的邻二羟基基团与硼酸中的硼基团反应，合成了BOR-SA前药。选择了两种白血病细胞（RAW264.7和HL60细胞）、一种实体肉瘤细胞模型（S180细胞）及其相应的正常细胞（单核细胞（MO）、中性粒细胞（NE）和成纤维细胞（L929））用于体外细胞实验（细胞毒性、细胞摄取、细胞周期和凋亡实验）。建立了S180肿瘤负载的昆明小鼠模型以进行抗肿瘤药效学实验。体外细胞实验结果显示，与对照组相比，HL60和S180细胞对BOR-SA的摄取增加。BOR-SA诱导了更低的IC50、更高的凋亡比例和肿瘤细胞的细胞周期停滞。体内抗S180肿瘤药效学实验显示，BOR-SA组的小鼠相较于对照组具有更高的肿瘤抑制率、更高的体重和更低的免疫器官毒性。唾液酸介导的选择素靶向策略在相关肿瘤治疗中可能具有很大的潜力。
• Bortezomib Aqueous Solubility in the Presence and Absence of D-Mannitol: A Clarification With Formulation Implications
  作者：Antonio Lopalco、Rosa Maria Iacobazzi、Nunzio Denora、Valentino J. Stella

  DOI：10.1016/j.xphs.2020.10.012

  日期：2021.1

  The solubility of bortezomib, a boronic acid, in water and normal saline is often misquoted in the literature. Here we confirm that bortezomib equilibrium solubility in water and normal saline is 0.59 ± 0.07 and 0.52 ± 0.11 mg/mL, respectively. The aqueous solubility is significantly enhanced, 1.92 ± 0.14 and 3.40 ± 0.21 mg/mL, respectively, in the presence of 55 mM and 137 mM D-mannitol in normal saline, as in the commercial formulation, Velcade®, after reconstitution. This is due to reversible ester formation between bortezomib and D-mannitol. Based on the pH-solubility profile curve for bortezomib in the absence of added D-mannitol, bortezomib's pKa value is estimated to be 8.8 ± 0.2. Boric acid, glycine and a combination of the two, used in an alternative formulation to that of Velcade® do not enhance the equilibrium aqueous solubility of bortezomib.