tetraisopropyl 2-(3-pyridinyl)ethylidene-1,1-bisphosphonate | 144677-11-2

• 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: tetraisopropyl 2-(3-pyridinyl)ethylidene-1,1-bisphosphonate
• 英文别名: tetraisopropyl 2-(3'-pyridyl)ethylidenebisphosphonate；3-[2,2-Bis[di(propan-2-yloxy)phosphoryl]ethyl]pyridine
• CAS: 144677-11-2
• 化学式: C₁₉H₃₅NO₆P₂
• 分子量: 435.438
• InChiKey: AALGZLOEPGAGNQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  28
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  84
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tetraisopropyl 2-(3-pyridinyl)ethylidene-1,1-bisphosphonate 在 sodium hydride 、 N-溴代丁二酰亚胺(NBS) 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以93%的产率得到tetraisopropyl 1-bromo-2-(3-pyridinyl)ethylidene-1,1-bisphosphonate
  参考文献：
  名称：

  Synthesis and Biological Evaluation of α-Halogenated Bisphosphonate and Phosphonocarboxylate Analogues of Risedronate

  摘要：

  alpha-Halogenated. analogues of the anti-resorptive bisphosphonate risedronate (5, Ris) and its phosphonocarboxylate cognate (7, 3-PEHPC were synthesized and compared with 5, 7, and the corresponding desoxy analogues in bone mineral affinity and mevalonate pathway inhibition assays. The Ris (5e-h) and 3-PEHPC (7e-h) analogues had decreased bone mineral affinity, confirming that the alpha-OH group in 5 and 7 enhances bone affinity. The 5 alpha-halo-analogues potently inhibited farnesyl pyrophosphate synthase (FPPS) with IC50 values from 16 ((alpha-F) to 340 (alpha-Br) nM (5, 6 nM). In contrast, 7 alpha-halo-analogues were ineffective versus FPPS (IC50 > 600 mu M), but inhibited Rab geranylgeranyl transferase (RGGT) IC50 = 16-35 mu M) similarly to 7 itself (IC50 = 24 mu M). The alpha-F analogue 7e was 1-2 times as active as 7 in J774 cell viability and Rab11 prenylation inhibition assays.

  DOI：

  10.1021/jm0702884
• 作为产物：
  描述：

  亚甲基二磷酸四异丙酯 在 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 以44%的产率得到tetraisopropyl 2-(3-pyridinyl)ethylidene-1,1-bisphosphonate
  参考文献：
  名称：

  Synthesis and Biological Evaluation of α-Halogenated Bisphosphonate and Phosphonocarboxylate Analogues of Risedronate

  摘要：

  alpha-Halogenated. analogues of the anti-resorptive bisphosphonate risedronate (5, Ris) and its phosphonocarboxylate cognate (7, 3-PEHPC were synthesized and compared with 5, 7, and the corresponding desoxy analogues in bone mineral affinity and mevalonate pathway inhibition assays. The Ris (5e-h) and 3-PEHPC (7e-h) analogues had decreased bone mineral affinity, confirming that the alpha-OH group in 5 and 7 enhances bone affinity. The 5 alpha-halo-analogues potently inhibited farnesyl pyrophosphate synthase (FPPS) with IC50 values from 16 ((alpha-F) to 340 (alpha-Br) nM (5, 6 nM). In contrast, 7 alpha-halo-analogues were ineffective versus FPPS (IC50 > 600 mu M), but inhibited Rab geranylgeranyl transferase (RGGT) IC50 = 16-35 mu M) similarly to 7 itself (IC50 = 24 mu M). The alpha-F analogue 7e was 1-2 times as active as 7 in J774 cell viability and Rab11 prenylation inhibition assays.

  DOI：

  10.1021/jm0702884

文献信息

• Determination of the Microscopic Equilibrium Dissociation Constants for Risedronate and Its Analogues Reveals Two Distinct Roles for the Nitrogen Atom in Nitrogen-Containing Bisphosphonate Drugs
  作者：Andrea M. Hounslow、John Carran、Richard J. Brown、Dominik Rejman、G. Michael Blackburn、Donald J. Watts

  DOI：10.1021/jm7015792

  日期：2008.7.1

  Microscopic equilibrium dissociation constants, k(a)s, were determined for four nitrogen-containing bisphosphonates (N-BP): risedronate and its analogues 2-(2-aminophenyl)-1-hydroxyethylidene-1,1-bisphosphonate,NE 11807, and NE 97220. The proportion of each and of analogues 2-(3'-(N-ethyl)pyridinium)ethylidenebisphosphonate and 2-(3-piperinidyl)- 1-hydroxyethylidene-1, 1-bisphosphonate, having a positively charged nitrogen and three negative charges on the bisphosphonate group ("carbocation analogue") at pH 7.5, was calculated. When set in order of increasing potency at inhibiting farnesyl diphosphate (FDP) synthase (their intracellular target), the N-BPs are also ranked in order of decreasing mole fraction of carbocation analogue. However, only a weak correlation exists between potency for inhibiting FDP synthase and potency for inhibiting Dictyostelium discoideum growth. It is concluded that, although high potency for inhibiting FDP synthase is favored when the nitrogen atom in a N-BP is uncharged, N-BPs having a positively charged nitrogen can still be potent inhibitors of Dictyostelium growth owing to favorable interaction with a second, unidentified target.
• NOVEL METHYLENEBISPHOSPHONIC ACID DERIVATIVES
  申请人：LEIRAS OY

  公开号：EP0563107B1

  公开（公告）日：2000-05-03
• US5393748A
  申请人：——

  公开号：US5393748A

  公开（公告）日：1995-02-28
• Synthesis and Biological Evaluation of α-Halogenated Bisphosphonate and Phosphonocarboxylate Analogues of Risedronate
  作者：Mong S. Marma、Zhidao Xia、Charlotte Stewart、Fraser Coxon、James E. Dunford、Rudi Baron、Boris A. Kashemirov、Frank H. Ebetino、James T. Triffitt、R. Graham G. Russell、Charles E. McKenna

  DOI：10.1021/jm0702884

  日期：2007.11.1

  alpha-Halogenated. analogues of the anti-resorptive bisphosphonate risedronate (5, Ris) and its phosphonocarboxylate cognate (7, 3-PEHPC were synthesized and compared with 5, 7, and the corresponding desoxy analogues in bone mineral affinity and mevalonate pathway inhibition assays. The Ris (5e-h) and 3-PEHPC (7e-h) analogues had decreased bone mineral affinity, confirming that the alpha-OH group in 5 and 7 enhances bone affinity. The 5 alpha-halo-analogues potently inhibited farnesyl pyrophosphate synthase (FPPS) with IC50 values from 16 ((alpha-F) to 340 (alpha-Br) nM (5, 6 nM). In contrast, 7 alpha-halo-analogues were ineffective versus FPPS (IC50 > 600 mu M), but inhibited Rab geranylgeranyl transferase (RGGT) IC50 = 16-35 mu M) similarly to 7 itself (IC50 = 24 mu M). The alpha-F analogue 7e was 1-2 times as active as 7 in J774 cell viability and Rab11 prenylation inhibition assays.