2,8-dimethyl-2,7-nonadienyl-5,5-bisphosphonic acid | 891822-45-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: 2,8-dimethyl-2,7-nonadienyl-5,5-bisphosphonic acid
• 英文别名: (2,8-Dimethyl-5-phosphononona-2,7-dien-5-yl)phosphonic acid
• CAS: 891822-45-0
• 化学式: C₁₁H₂₂O₆P₂
• 分子量: 312.24
• InChiKey: RVXKJZPVVOOYLJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  115
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2,8-dimethyl-2,7-nonadienyl-5,5-bisphosphonic acid 、 特戊酸氯甲酯 在 sodium iodide 作用下， 以47%的产率得到[[5-[Bis(2,2-dimethylpropanoyloxymethoxy)phosphoryl]-2,8-dimethylnona-2,7-dien-5-yl]-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate
  参考文献：
  名称：

  Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation

  摘要：

  Nitrogenous bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically for treatment of bone disease. Because many of their effects may be mediated by depletion of geranylgeranyl diphosphate, our group has sought compounds that do this more directly through inhibition of geranylgeranyl diphosphate synthase and we have discovered a number of isoprenoid-containing bisphosphonates that selectively inhibit this enzyme. These compounds have a high negative charge at physiological pH which is necessary for inhibition of the enzyme but may limit their ability to enter cells. Therefore, chemical modifications that mask this charge may enhance their cellular potency. We now have synthesized novel pivaloyloxymethyl-modified isoprenoid bisphosphonates and investigated their ability to inhibit protein geranylgeranylation within cells. We have found that addition of pivaloyloxymethyl moieties to isoprenoid bisphosphonates increases their potency towards cellular geranylgeranylation even though this modification decreases their in vitro inhibition of geranylgeranyl diphosphate synthase. Pivaloyloxymethyl modifications more effectively increase the cellular activity of the more polar isoprenoid bisphosphonates. These results reveal structural relationships between in vitro and cellular activity which may serve as the basis for future development of more potent and/or druglike inhibitors of geranylgeranyl diphosphate synthase. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.02.016
• 作为产物：
  描述：

  tetraethyl 2,8-dimethyl-2,7-nonadienyl-5,5-bisphosphonate 在 2,3,5-三甲基吡啶 、 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 生成 2,8-dimethyl-2,7-nonadienyl-5,5-bisphosphonic acid
  参考文献：
  名称：

  Synthesis and biological activity of isoprenoid bisphosphonates

  摘要：

  Bisphosphonates have been used in the clinic to treat osteoporosis and to reduce bone resorption and the accompanying pathological bone fractures that attend a number of malignancies including multiple myeloma and cancers of the prostate, breast, and lung. There is also evidence that some bisphosphonates have direct anticancer activity. Expansion of the current class of bisphosphonates may lead to compounds that more selectively and potently target these cancers through inhibition of the mevalonate pathway. To this end, a set of dialkyl bisphosphonates bearing isoprenoid chains of varying lengths has been synthesized. Some of these compounds were found to have biological activity on post-translational processing of the oncogenic small GTPases, Ras and Rapla, in human-derived K562 leukemia cells. Most importantly, these compounds impair protein geranylgeranylation and not protein farnesylation. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.02.010

文献信息

• Synthesis and biological activity of isoprenoid bisphosphonates
  作者：Larry W. Shull、Andrew J. Wiemer、Raymond J. Hohl、David F. Wiemer

  DOI：10.1016/j.bmc.2006.02.010

  日期：2006.6

  Bisphosphonates have been used in the clinic to treat osteoporosis and to reduce bone resorption and the accompanying pathological bone fractures that attend a number of malignancies including multiple myeloma and cancers of the prostate, breast, and lung. There is also evidence that some bisphosphonates have direct anticancer activity. Expansion of the current class of bisphosphonates may lead to compounds that more selectively and potently target these cancers through inhibition of the mevalonate pathway. To this end, a set of dialkyl bisphosphonates bearing isoprenoid chains of varying lengths has been synthesized. Some of these compounds were found to have biological activity on post-translational processing of the oncogenic small GTPases, Ras and Rapla, in human-derived K562 leukemia cells. Most importantly, these compounds impair protein geranylgeranylation and not protein farnesylation. (c) 2006 Elsevier Ltd. All rights reserved.
• Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation
  作者：Andrew J. Wiemer、Jose S. Yu、Larry W. Shull、Rocky J. Barney、Brian M. Wasko、Kimberly M. Lamb、Raymond J. Hohl、David F. Wiemer

  DOI：10.1016/j.bmc.2008.02.016

  日期：2008.4.1

  Nitrogenous bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically for treatment of bone disease. Because many of their effects may be mediated by depletion of geranylgeranyl diphosphate, our group has sought compounds that do this more directly through inhibition of geranylgeranyl diphosphate synthase and we have discovered a number of isoprenoid-containing bisphosphonates that selectively inhibit this enzyme. These compounds have a high negative charge at physiological pH which is necessary for inhibition of the enzyme but may limit their ability to enter cells. Therefore, chemical modifications that mask this charge may enhance their cellular potency. We now have synthesized novel pivaloyloxymethyl-modified isoprenoid bisphosphonates and investigated their ability to inhibit protein geranylgeranylation within cells. We have found that addition of pivaloyloxymethyl moieties to isoprenoid bisphosphonates increases their potency towards cellular geranylgeranylation even though this modification decreases their in vitro inhibition of geranylgeranyl diphosphate synthase. Pivaloyloxymethyl modifications more effectively increase the cellular activity of the more polar isoprenoid bisphosphonates. These results reveal structural relationships between in vitro and cellular activity which may serve as the basis for future development of more potent and/or druglike inhibitors of geranylgeranyl diphosphate synthase. (C) 2008 Elsevier Ltd. All rights reserved.