digeranyl bisphosphonate | 878190-51-3

• 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: digeranyl bisphosphonate
• 英文别名: [(6E,11E)-2,6,12,16-tetramethyl-9-phosphonoheptadeca-2,6,11,15-tetraen-9-yl]phosphonic acid
• CAS: 878190-51-3
• 化学式: C₂₁H₃₈O₆P₂
• 分子量: 448.477
• InChiKey: SQERRIVHBWCION-IWGRKNQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  29
• 可旋转键数：
  12
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.62
• 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：

  digeranyl bisphosphonate 、 特戊酸氯甲酯 在 sodium iodide 作用下， 以18%的产率得到tetrapivaloyloxymethyl (E)-1,1-bis(4,8-dimethyl-nona-3,7-dienyl)-1,1-bisphosphonate
  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 (6E,11E)-2,6,12,16-tetramethyl-2,6,11,15-heptadecenyl-9,9-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 digeranyl bisphosphonate
  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

• [EN] LIPOPHILIC BISPHOSPHONATES AND METHODS OF USE<br/>[FR] BISPHOSPHONATES LIPOPHILES ET PROCÉDÉS D'UTILISATION
  申请人：SALK INST FOR BIOLOGICAL STUDI

  公开号：WO2016081281A1

  公开（公告）日：2016-05-26

  Disclosed herein are lipophilic bisphosphonate compounds and embodiments of a method for making the same. The compounds may inhibit FPPS and/or GGPPS enzymes. The compounds are useful for treating a disease, such as cancer, such as those with a KRAS mutation. In some embodiments, the compounds are used to prevent or treat a cancer, such as a lung cancer that has a KRAS mutation.

  本文披露了疏水性双膦酸盐化合物及其制备方法的实施例。这些化合物可以抑制FPPS和/或GGPPS酶。这些化合物可用于治疗疾病，如癌症，尤其是具有KRAS突变的癌症。在某些实施例中，这些化合物被用于预防或治疗癌症，如具有KRAS突变的肺癌。
• Geranylgeranyl pyrophosphate synthase inhibitors
  申请人：Wiemer F. David

  公开号：US20060052347A1

  公开（公告）日：2006-03-09

  The invention provides novel pyrophosphate synthase inhibitors of formula I as well as compositions comprising such inhibitors and methods for their use.

  这项发明提供了一种新型的焦磷酸合酶抑制剂，其化学式为I，以及包含这种抑制剂的组合物和使用它们的方法。
• GERANYLGERANYL PYROPHOSPHATE SYNTHASE INHIBITORS
  申请人：University of Iowa Research

  公开号：EP1793832A2

  公开（公告）日：2007-06-13
• METHODS TO MODULATE RAC1 IMPORT AND TO TREAT PULMONARY FIBROSIS
  申请人：University of Iowa Research Foundation

  公开号：US20150005261A1

  公开（公告）日：2015-01-01

  The invention provides methods for treating fibrosis, as well as methods for modulating mitochondrial peroxide production in a cell, and methods for modulating the import of Rac1 into the mitochondria of a cell.
• PREPARATION OF GGA AND DERIVATIVES THEREOF AND THEIR CO-CRYSTALLIZATION WITH UREA OR THIOUREA
  申请人：COYOTE PHARMACEUTICALS, INC.

  公开号：US20150258039A1

  公开（公告）日：2015-09-17

  Provided herein are compositions comprising co-crystals of GGA or a GGA derivative (including salts and tauotomers thereof) with urea or thiourea, and processes related to such co-crystals. Also provided herein are methods, compounds, and compositions related to preparing trans GGA and derivatives thereof, and intermediates thereto.