B3CD | 142423-15-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: B3CD
• 英文别名: 25-hydroxy-vitamin D3-3β-(2)-bromoacetate；25-Hydroxyvitamin D3-bromoacetate；[(1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexyl] 2-bromoacetate
• CAS: 142423-15-2
• 化学式: C₂₉H₄₅BrO₃
• 分子量: 521.578
• InChiKey: CQUVVXAVZUUZDH-TVIDHFRVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  骨化二醇 、 溴乙酸 在 吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 B3CD
  参考文献：
  名称：

  Effect of a Vitamin D3 derivative (B3CD) with postulated anti-cancer activity in an ovarian cancer animal model

  摘要：

  本研究的目的是采用小鼠卵巢癌异种移植模型来检验骨化二醇衍生物 B3CD 是否有资格作为体内潜在抗癌药物的假设。此外，与对照细胞系相比，体外分析了 B3CD 对铂耐药人卵巢癌细胞系活力和增殖的选择性。 B3CD 显示针对一组卵巢和其他癌细胞系、内皮细胞和对照细胞筛选的细胞系特异性细胞毒性。通过 BrdU 掺入分析确定，亚细胞毒性浓度的 B3CD 对 SKOV-3 卵巢癌细胞的增殖作用比对原代成纤维细胞的作用更强。用 0.5 µM B3CD 处理会导致 SKOV-3 细胞中染色质高度浓缩和细胞核碎片化，但原代成纤维细胞中则不然。 B3CD 在低药物浓度 (≤0.5 µM) 下诱导 SKOV-3 卵巢癌细胞死亡，这是由 p38 MAPK 信号通路介导的：B3CD 在 SKOV-3 细胞中诱导 p38 MAPK 表达和激活，p38 信号传导的抑制抵消了 B3CD 诱导的细胞体外死亡。卵巢癌细胞动物模型（人 SKOV-3 细胞衍生的裸鼠异种移植物）显示，少数 B3CD 治疗小鼠的肿瘤生长加速，而大多数 B3CD 治疗小鼠表现出肿瘤生长延迟或肿瘤完全消退。 B3CD 在体外和体内均具有抗卵巢癌特性。我们建议进一步开发维生素 D3 的非钙血症溴乙酰氧基衍生物作为潜在的抗癌疗法。

  DOI：

  10.1007/s10637-009-9284-y

文献信息

• Chemotherapeutic Effect of Calcidiol Derivative B3CD in a Neuroblastoma Xenograft Model
  作者：Thilo S. Lange、Yongping Zou、Rakesh K. Singh、Kyu K. Kim、Katrin Kristjansdottir、Giselle L. S. Sholler、Laurent Brard

  DOI：10.1111/j.1747-0285.2010.00988.x

  日期：——

  Bromoacetoxy‐calcidiol (B3CD), a pro‐apoptotic and cytotoxic agent in neuroblastoma (NB) cell lines, displayed therapeutic potential in vivo as an anticancer drug in a NB xenograft mouse model. Tumors of all animals treated intraperitoneally with B3CD went into regression within 10–30 days of treatment, while tumors in control animals grew aggressively. The response mechanisms of NB cells to B3CD in vitro were studied and included differential targeting of cell cycle key regulators p21 and cyclin D1 on the transcriptional and expression level leading to arrest in G0/G1 phase. In contrast to the effect in ovarian cancer cells, B3CD‐induced cell death in SMS‐KCNR NB cells was only marginally mediated by the p38 MAPK signaling pathway. Signaling induced by exogenous recombinant EGF leads to a partial restoration of the negative effects of B3CD on SMS‐KCNR cell proliferation and survival. Upon combinational treatment of SMS‐KCNR cells with B3CD and recombinant EGF, the EGF receptor (EGF‐R) was highly activated. We suggest future studies to include analysis of the effects of B3CD in combination therapy with pharmacological inhibitors of cell cycle regulators or with EGF‐R‐targeting inhibitors, ‐toxins or ‐antibodies in vitro and their translation into in vivo models of tumor development.
• Effect of a Vitamin D3 derivative (B3CD) with postulated anti-cancer activity in an ovarian cancer animal model
  作者：Thilo S. Lange、Ashley R. Stuckey、Katina Robison、Kyu Kwang Kim、Rakesh K. Singh、Christina A. Raker、Laurent Brard

  DOI：10.1007/s10637-009-9284-y

  日期：2010.10

  The objective of the present study was to test the hypothesis that Calcidiol derivative B3CD qualifies as a potential anti-cancer drug in vivo employing an ovarian cancer xenograft model in mice. In addition, the selectivity of B3CD on viability and proliferation of platinum-resistant human ovarian cancer cell lines in comparison to control cell lines was analyzed in vitro. B3CD displayed cell line-specific cytotoxicity screened against a panel of ovarian and other carcinoma cell lines, endothelial and control cells. B3CD, at sub-cytotoxic concentrations, revealed stronger effects on the proliferation of SKOV-3 ovarian cancer cells vs. primary fibroblasts as determined by BrdU incorporation analysis. Treatment with B3CD at 0.5 µM resulted in highly condensed chromatin and fragmented nuclei in SKOV-3 cells but not in primary fibroblasts. B3CD induced cell death at low drug concentrations (≤0.5 µM) in SKOV-3 ovarian cancer cells is mediated by the p38 MAPK signaling pathway: B3CD induced p38 MAPK expression and activation in SKOV-3 cells and inhibition of p38 signaling counteracted B3CD induced cell death in vitro. An ovarian cancer cell animal model (human SKOV-3 cell derived xenografts in nude mice) revealed that tumor growth in few B3CD treated mice accelerated while the majority of B3CD treated mice displayed delayed tumor growth or full tumor regression. B3CD possesses anti-ovarian cancer properties in vitro and in vivo. We propose the further development of non-calcemic bromoacetoxy derivatives of vitamin D3 as potential anti-cancer therapeutics.

  本研究的目的是采用小鼠卵巢癌异种移植模型来检验骨化二醇衍生物 B3CD 是否有资格作为体内潜在抗癌药物的假设。此外，与对照细胞系相比，体外分析了 B3CD 对铂耐药人卵巢癌细胞系活力和增殖的选择性。 B3CD 显示针对一组卵巢和其他癌细胞系、内皮细胞和对照细胞筛选的细胞系特异性细胞毒性。通过 BrdU 掺入分析确定，亚细胞毒性浓度的 B3CD 对 SKOV-3 卵巢癌细胞的增殖作用比对原代成纤维细胞的作用更强。用 0.5 µM B3CD 处理会导致 SKOV-3 细胞中染色质高度浓缩和细胞核碎片化，但原代成纤维细胞中则不然。 B3CD 在低药物浓度 (≤0.5 µM) 下诱导 SKOV-3 卵巢癌细胞死亡，这是由 p38 MAPK 信号通路介导的：B3CD 在 SKOV-3 细胞中诱导 p38 MAPK 表达和激活，p38 信号传导的抑制抵消了 B3CD 诱导的细胞体外死亡。卵巢癌细胞动物模型（人 SKOV-3 细胞衍生的裸鼠异种移植物）显示，少数 B3CD 治疗小鼠的肿瘤生长加速，而大多数 B3CD 治疗小鼠表现出肿瘤生长延迟或肿瘤完全消退。 B3CD 在体外和体内均具有抗卵巢癌特性。我们建议进一步开发维生素 D3 的非钙血症溴乙酰氧基衍生物作为潜在的抗癌疗法。