(E,E)-(4,8,12-trimethyl-3,7,11-tridecatrienylidene)bisphosphonic acid | 145572-63-0

• 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: (E,E)-(4,8,12-trimethyl-3,7,11-tridecatrienylidene)bisphosphonic acid
• 英文别名: (2E, 6E)-farnesylbisphosphonate；[(3E,7E)-4,8,12-trimethyl-1-phosphonotrideca-3,7,11-trienyl]phosphonic acid
• CAS: 145572-63-0
• 化学式: C₁₆H₃₀O₆P₂
• 分子量: 380.358
• InChiKey: QBAOBDKNTDWTHR-YFVJMOTDSA-N

物化性质

• 沸点：
  601.1±65.0 °C(Predicted)
• 密度：
  1.220±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  24
• 可旋转键数：
  10
• 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：

  特戊酸氯甲酯 、 (E,E)-(4,8,12-trimethyl-3,7,11-tridecatrienylidene)bisphosphonic acid 在 sodium iodide 作用下， 以40%的产率得到tetrapivaloyloxymethyl (3E,7E)-4,8,12-trimethyltrideca-3,7,11-triene-1,1-diyldiphosphonate
  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：

  反,反-法呢基溴 在 2,3,5-三甲基吡啶 、 盐酸 、 sodium hydroxide 、 三甲基溴硅烷 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 (E,E)-(4,8,12-trimethyl-3,7,11-tridecatrienylidene)bisphosphonic acid
  参考文献：
  名称：

  法呢基焦磷酸酯的膦酸酯和双膦酸酯类似物可作为法呢基蛋白转移酶的潜在抑制剂。

  摘要：

  制备了法呢基焦磷酸的几种膦酸酯和双膦酸酯类似物，以检查其抑制法呢基蛋白转移酶（FPTase）的能力。法呢醛或香叶醛与亚甲基二膦酸四乙酯的霍纳-沃兹沃思-埃蒙斯缩合反应得到所需的乙烯基膦酸酯，而甲基膦酸二甲酯阴离子与萜类溴化物烷基化得到相应的饱和膦酸酯。亚甲基二膦酸四乙酯与法呢基溴的烷基化反应得到预期的双膦酸烷基酯，其通过制备亚硒酸苯基酯，氧化为亚硒酸酯并消除而转化为其α，β-不饱和衍生物。以类似的方式，通过与法呢基溴反应，将膦酰基乙酸三乙酯转化为法呢基焦磷酸酯类似物。制备相应的酸后，测试每种化合物对FPTase的抑制作用，浓度最高可达10 microM。这些化合物对FPTase活性的影响变化很大，范围从抑制到令人惊讶地增强。

  DOI：

  10.1016/s0968-0896(98)00034-0

文献信息

• 1,1-Bisphosphonate Squalene Synthase Inhibitors: Interplay Between the Isoprenoid Subunit and the Diphosphate Surrogate
  作者：David R. Magnin、John K. Dickson、Janette V. Logan、R. Michael Lawrence、Ying Chen、Richard B. Sulsky、Carl P. Ciosek、Scott A. Biller、Thomas W. Harrity、Kern G. Jolibois、Lori K. Kunselman、Lois C. Rich、Dorothy A. Slusarchyk

  DOI：10.1021/jm00014a012

  日期：1995.7

  Inhibitors of squalene synthase have the potential to be superior cholesterol-lowering agents. We previously disclosed that lipophilic 1,1-bisphosphonates I are potent squalene synthase inhibitors and orally active cholesterol-lowering agents in animal models (Ciosek, C. P., Jr.; et al. J. Biol. Chem. 1993, 268, 24832-24837). In this paper, we describe modifications to the bisphosphonate moiety, in

  角鲨烯合酶的抑制剂有可能成为优异的降胆固醇药。我们先前曾披露亲脂性1,1-双膦酸酯I在动物模型中是有效的角鲨烯合酶抑制剂和口服活性降胆固醇剂（Ciosek，CP，Jr .; et al.J.Biol.Chem.1993，268，24832-24837 ）。在本文中，我们描述了对双膦酸酯部分的修饰，以尝试减少这些抑制剂中所含的酸性功能。当与自然存在的法呢基部分的近似模拟物配对时（R1 =法呢基乙基），而与较短的异戊二烯替代物配对时（R1 =香叶基乙基），用甲基（II，R2 = CH3）取代一个酸性基团会产生有效的抑制剂或4-联苯丙基）。相反，所有三种相应的双膦酸酯I都是有效的角鲨烯合酶抑制剂。当R2为CH2OH或CH2OCH3时，用较短的异戊二烯替代物可恢复抑制能力。提出这些R 2基团充当酶的活性位点的氢键受体。描述了这些化合物在大鼠中作为胆固醇生物合成抑制剂的特性，并详细说明了这些化合物和相关化合物的合成途径。
• Synthesis of pyrophosphonic acid analogues of farnesyl pyrophosphate
  作者：A.R.P.M. Valentijn、O. van den Berg、G.A. van der Marel、L.H. Cohen、J.H. van Boom

  DOI：10.1016/0040-4020(94)01083-c

  日期：1995.2

  The synthesis of four new analogues (i.e.3–6) of farnesyl pyrophosphate (FPP), which may function as inhibitor of squalene synthase, is described. Compounds 3 and 4 were readily accessible by reaction of farnesal with diethyl phosphite or dimethyl lithiomethylphosphonate, respectively, followed by condensation of the resulting alcohols with diethyl phosphonomethyl triflate. The preparation of 5 and

  描述了法呢基焦磷酸酯（FPP）的四个新类似物（即3–6）的合成，它们可能是角鲨烯合酶的抑制剂。通过将法呢醛与亚磷酸二乙酯或亚硫基甲基膦酸二甲酯反应，然后将所得的醇与三氟甲磺酸膦酸二乙酯缩合，可以容易地获得化合物3和4。通过分别用法呢基溴将双（二乙基膦酰基甲基）醚或亚甲基双膦酸四乙酯烷基化来完成5和6的制备。
• Bisphosphonate squalene synthetase inhibitors
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0513761A2

  公开（公告）日：1992-11-19

  Compounds which are inhibitors of cholesterol biosynthesis (by inhibiting de novo squalene biosynthesis), and thus are useful as hypocholesterolemic agents and antiatherosclerotic agents are provided which have the structure and analogs thereof, wherein R¹, R², R³ and R⁴ are the same or different and are H, lower alkyl, a metal ion or a prodrug ester;    R⁵ is H, halogen or lower alkyl;    Zq is substituted alkenyl, substituted alkynyl, mixed alkenyl-alkynyl or substituted phenylalkyl, or substituted biphenylalkyl, alkylphenylalkyl or alkyl, including all stereoisomers thereof. New methods for using such compounds to inhibit cholesterol biosynthesis are also provided.

  所提供的化合物是胆固醇生物合成的抑制剂（通过抑制角鲨烯的新生物合成），因此可用作降胆固醇药和抗动脉粥样硬化药，其结构为 及其类似物，其中 R¹、R²、R³ 和 R⁴ 相同或不同，并且是 H、低级烷基、金属离子或原药酯； R⁵ 是 H、卤素或低级烷基； Zq 是取代的烯基、取代的炔基、混合烯基-炔基或取代的苯基烷基，或取代的联苯烷基、 烷基苯烷基或烷基，包括其所有立体异构体。 还提供了使用此类化合物抑制胆固醇生物合成的新方法。
• Use of phosphonomethylphosphinate squalene synthetase inhibitors for the manufacture of a medicament for the lowering cholesterol
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0514124A2

  公开（公告）日：1992-11-19

  A method is provided for inhibiting cholesterol biosynthesis by inhibiting de novo squalene production employing methylene phosphonoalkylphosphinate compounds.

  提供了一种利用亚甲基膦酰基膦化合物抑制角鲨烯从头生成，从而抑制胆固醇生物合成的方法。
• Squalene synthetase inhibitory composition and use thereof
  申请人：TAKEDA CHEMICAL INDUSTRIES, LTD.

  公开号：EP0541037A2

  公开（公告）日：1993-05-12

  There is provided a squalene inhibitory composition containing 1,1-bisphosphonic acid compound, a lower alkyl ester thereof or a salt thereof, which is useful as a treating agent for hypercholesterolemia. There are also provided novel compounds having squalene synthetase inhibitory activity and a pharmaceutical composition for treating hypercholesterolemia containing a 1,1-bisphosphonic compound, a lower alkyl ester thereof or a salt thereof.

  提供了一种角鲨烯抑制剂组合物，其中含有 1，1-二膦酸化合物、其低级烷基酯或其盐，可用作高胆固醇血症的治疗剂。还提供了具有角鲨烯合成酶抑制活性的新型化合物，以及一种治疗高胆固醇血症的药物组合物，该组合物含有1,1-二膦酸化合物、其低级烷基酯或其盐。