(4-amino-1-hydroxybutylidene)bisphosphonic acid disodium salt

• 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: (4-amino-1-hydroxybutylidene)bisphosphonic acid disodium salt
• 英文别名: alendronate；Ale sodium；disodium alendronate；sodium alendronate；disodium salt of alendronic acid；Alendronatedisodium；sodium;(4-amino-1-hydroxy-1-phosphonatobutyl)phosphonic acid
• 化学式: C₄H₁₁NO₇P₂*2Na
• 分子量: 293.061
• InChiKey: CAKRAHQRJGUPIG-UHFFFAOYSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  -5.53
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  167
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(3,5-di-O-acetyl-β-D-2-deoxyribofuranosyl)-4-(1,2,4-triazol-1-yl)-5-fluoropyrimidin-2(1H)-one 、 (4-amino-1-hydroxybutylidene)bisphosphonic acid disodium salt 在 三乙胺 、 ammonium hydroxide 、 水 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 72.0h， 以55%的产率得到
  参考文献：
  名称：

  N4-[Alkyl-(hydroxyphosphono)phosphonate]-cytidine—New drugs covalently linking antimetabolites (5-FdU, araU or AZT) with bone-targeting bisphosphonates (alendronate or pamidronate)

  摘要：

  Amino-bisphosphonates (alendronate, pamidronate) were covalently linked in a three step synthesis, with protected and triazolylated derivatives of therapeutically used nucleoside analogs (5-FdU, araC, AZT) by substitution of their triazolyl residue. From the deprotected and chromatographically purified reaction mixtures N-4-[alkyl-(hydroxyphosphono) phosphonate]-cytidine combining two differently cytotoxic functions were obtained. This new family of bisphosphonates (BPs) contains as novelty an alkyl side chain with a cytotoxic nucleoside. The BPs moiety allows for a high binding to hydroxyapatite which is a prerequisite for bone targeting of the drugs. In vitro binding of 5-FdU-alendronate (5-FdU-ale) to hydroxyapatite showed a sixfold increased binding of these BPs as compared to 5-FdU.Exploratory cytotoxic properties of 5-FdU-ale were tested on a panel of human tumor cell lines resulting in growth inhibition ranging between 5% and 38%. The determination of IC50-concentrations of the conjugate in Lewis lung carcinoma and murine macrophages showed an incubation time dependent growth inhibition with higher sensitivity towards the tumor cells. We assume that the antimetabolite-BPs can be cleaved into different active metabolites that may exert cytotoxic and other therapeutic effects. However, the underlying mechanisms of these promising new antimetabolite-BPs conjugates remain to be evaluated in future experiments. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.04.015

文献信息

• Biological assessment of novel bisphosphonate-containing 99mTc/Re-organometallic complexes
  作者：Célia Fernandes、Sofia Monteiro、Patrícia Mendes、Lurdes Gano、Fernanda Marques、Sandra Casimiro、Luís Costa、João D.G. Correia、Isabel Santos

  DOI：10.1016/j.jorganchem.2013.10.038

  日期：2014.6

  Aimed at finding complexes of the same family with improved bone-seeking properties and adequate tumor cell uptake profile, we have synthesized novel complexes of the type fac-[M(CO)3(k3-L)]+ (M = 99mTc/Re, Tc3/Re3–Tc5/Re5) stabilized by bifunctional chelators with different molecular weight, overall charge, (lipo)hydrophilic nature and different positions of BP attachment. Biodistribution studies in

  骨寻求放射性药物如放射性标记的二膦酸盐（BPS）结合骨基质中增加的骨转换的区域，metastization站点的特性，选择性地递送γ辐射或β -用于分别骨成像或骨疼痛减轻，粒子。最近的临床前研究表明，含氮的BP也可能具有直接的抗肿瘤活性。我们最近推出了一套99m Tc-有机金属复合物，可将γ射线和BP同时递送至骨组织。为了找到具有改善的寻骨特性和足够的肿瘤细胞摄取特征的同一家族的复合物，我们合成了fac- [M（CO）3（k3 - L）] +（M  =  99m Tc / Re，Tc3 / Re3 – Tc5 / Re5）通过具有不同分子量，总电荷，（脂）亲水性质和BP连接位置的双功能螯合剂稳定。在正常小鼠中进行的生物分布研究表明，其中BP单元（阿仑膦酸盐）位于吡唑基环的4位的Tc3表现出最有利的药代动力学特征，具有快速的血液清除，高的骨吸收（在1时为17.1±3.6％IA / g h pi），并且比黄金标准99m
• [EN] LLP2A-BISPHOSPHONATE CONJUGATES FOR OSTEOPOROSIS TREATMENT<br/>[FR] CONJUGUÉS LLP2A-BISPHOSPHONATE POUR LE TRAITEMENT DE L'OSTÉOPOROSE
  申请人：UNIV CALIFORNIA

  公开号：WO2013032527A1

  公开（公告）日：2013-03-07

  The present invention provides compounds and pharmaceutical compositions of a peptidomimetic ligand, e.g. LLP2A, conjugated with a bisphosphonate drug, e.g. Alendronate. The compounds and pharmaceutical compositions of the present invention are useful in the treatment of osteoporosis and for the promotion of bone growth due to their specificity for the α4β1 integrin on mesenchymal stem cells and for the surface of bone.

  本发明提供了一种肽类模拟配体化合物和制药组合物，例如LLP2A，与双磷酸盐药物，例如阿伦膦酸，结合。本发明的化合物和制药组合物由于对间充质干细胞上的α4β1整合素和骨表面的特异性，对骨质疏松症的治疗和促进骨生长具有用处。
• Spectrofluorimetric Determination of Alendronate by Conjugation with the Rhodamine B Sulfonyl Group
  作者：Yun-Seong Jeong、Ji-Hye Park、Geun-Woo Jin、Jong-Sang Park

  DOI：10.5012/bkcs.2011.32.5.1777

  日期：2011.5.20

  sensitive analytical methods. 3-8 NadDPA-2Zn 2+ , a fluorescent chemosensor (FCS), which is used for the recognition of certain molecules or ions, was identified as a new analytical tool for the determination of alendronate in our previous study. 9 However, analysis using NadDPA-2Zn 2+ is not very effective as a method because of its low sensitivity(limit of quantitation (LOQ) = 0.104 μg/ mL), due to

  治疗范围内的阿仑膦酸盐浓度对于静脉内和经皮给药非常低，其定量估计相当困难。因此，医学和临床需要一种灵敏而简单的方法来测定患者血液中阿仑膦酸盐的浓度。为此，许多研究人员试图开发各种灵敏的分析方法。3-8 NadDPA-2Zn 2+ 是一种荧光化学传感器（FCS），用于识别某些分子或离子，在我们之前的研究中被确定为测定阿仑膦酸盐的新分析工具。9 然而，使用 NadDPA-2Zn 2+ 的分析方法由于其低灵敏度（定量限 (LOQ) = 0.104 μg/mL）而不是很有效，因为石脑油的荧光活性
• Prostaglandin E2-bisphosphonate conjugates: potential agents for treatment of osteoporosis
  作者：Laurent Gil、Yongxin Han、Evan E. Opas、Gideon A. Rodan、Réjean Ruel、J.Gregory Seedor、Peter C. Tyler、Robert N. Young

  DOI：10.1016/s0968-0896(99)00045-0

  日期：1999.5

  Conjugates of bisphosphonates (potential bone resorption inhibitors) and prostaglandin E-2 (a bone formation enhancer) were prepared and evaluated for their ability to bind to bone and to liberate, enzymatically, free PGE(2). The conjugate 3, an amide at C-1 of PGE(2) proved to be too stable in vivo while conjugate 6, a thioester, was too labile. Several PGE(2), C-15 ester-linked conjugates (18, 23, 24 and 31) were prepared and conjugate 23 was found to bind effectively to bone in vitro and in vivo and to liberate PGE(2) at an acceptable rate. A 4-week study in a rat model of osteoporosis showed that 23 was better tolerated and more effective as a bone growth stimulant than daily maximum tolerated doses of free PGE(2). (C) 1999 Elsevier Science Ltd. All rights reserved.
• Dual delivery of nucleic acids and PEGylated-bisphosphonates via calcium phosphate nanoparticles
  作者：Sofia Bisso、Simona Mura、Bastien Castagner、Patrick Couvreur、Jean-Christophe Leroux

  DOI：10.1016/j.ejpb.2019.06.013

  日期：2019.9

  Despite many years of research and a few success stories with gene therapeutics, efficient and safe DNA delivery remains a major bottleneck for the clinical translation of gene-based therapies. Gene transfection with calcium phosphate (CaP) nanoparticles brings the advantages of low toxicity, high DNA entrapment efficiency and good endosomal escape properties. The macroscale aggregation of CaP nanoparticles can be easily prevented through surface coating with bisphosphonate conjugates. Bisphosphonates, such as alendronate, recently showed promising anticancer effects. However, their poor cellular permeability and preferential bone accumulation hamper their full application in chemotherapy. Here, we investigated the dual delivery of plasmid DNA and alendronate using CaP nanoparticles, with the goal to facilitate cellular internalization of both compounds and potentially achieve a combined pharmacological effect on the same or different cell lines. A pH-sensitive poly(ethyleneglycol)-alendronate conjugate was synthetized and used to formulate stable plasmid DNA-loaded CaP nano-particles. These particles displayed good transfection efficiency in cancer cells and a strong cytotoxic effect on macrophages. The in vivo transfection efficiency, however, remained low, calling for an improvement of the system, possibly with respect to the extent of particle uptake and their physical stability.