NSC 375974 | 87967-98-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: NSC 375974
• 英文别名: 1,4-dihydro-2,6-dimethyl-4-(5'-methyl-3'-phenylisoxazol-4'-yl)-3,5-pyridinedicarboxylic acid diethyl ester；2,6-dimethyl-4-(5-methyl-3-phenylisoxazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester；diethyl 2,6-dimethyl-4-(5-methyl-3-phenylisoxazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate；Diethyl 2,6-dimethyl-4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate
• CAS: 87967-98-4
• 化学式: C₂₃H₂₆N₂O₅
• 分子量: 410.47
• InChiKey: IOQVTCYDCVHJGZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  90.7
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  NSC 375974 在 硫酸 、 硝酸 作用下， 以 水 为溶剂， 反应 0.17h， 以98%的产率得到2,6-dimethyl-4-(5-methyl-3-phenylisoxazol-4-yl)-pyridine-3,5-dicarboxylic acid diethyl ester
  参考文献：
  名称：

  Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter

  摘要：

  A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510 nM at MDR-1. Three of the dimeric IDHPs possessed <1.5 mu M activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog 4c containing an m-Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole 5 and pyridine 6, also were examined, indicating that the triazole - incorporated as part of the click assembly as a spacer - contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p-Br IDHPs 4d, 4e and 4f with tethers of from n = 2 to 5 ethylenedioxy units, had sub-micromolar affinities with 4d being the most efficacious at 193 nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.04.008
• 作为产物：
  描述：

  (5-甲基-3-苯基-4-异恶唑)甲醇 在 ammonium hydroxide 、 magnesium sulfate 、 pyridinium chlorochromate 作用下， 以 甲醇 、 二氯甲烷 、 苯 为溶剂， 反应 2.0h， 生成 NSC 375974
  参考文献：
  名称：

  Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter

  摘要：

  A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510 nM at MDR-1. Three of the dimeric IDHPs possessed <1.5 mu M activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog 4c containing an m-Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole 5 and pyridine 6, also were examined, indicating that the triazole - incorporated as part of the click assembly as a spacer - contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p-Br IDHPs 4d, 4e and 4f with tethers of from n = 2 to 5 ethylenedioxy units, had sub-micromolar affinities with 4d being the most efficacious at 193 nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.04.008

文献信息

• Fluorescent probes of the isoxazole–dihydropyridine scaffold: MDR-1 binding and homology model
  作者：Monika I. Szabon-Watola、Sarah V. Ulatowski、Kathleen M. George、Christina D. Hayes、Scott A. Steiger、Nicholas R. Natale

  DOI：10.1016/j.bmcl.2013.11.068

  日期：2014.1

  Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis. (C) 2013 Elsevier Ltd. All rights reserved.
• Natale, Nicholas R.; Quincy, David A., Synthetic Communications, 1983, vol. 13, # 10, p. 817 - 822
  作者：Natale, Nicholas R.、Quincy, David A.

  DOI：——

  日期：——
• NATALE, N. R.;QUINCY, D. A., SYNTH. COMMUN., 1983, 13, N 10, 817-822
  作者：NATALE, N. R.、QUINCY, D. A.

  DOI：——

  日期：——
• Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter
  作者：Scott A. Steiger、Chun Li、Donald S. Backos、Philip Reigan、N.R. Natale

  DOI：10.1016/j.bmc.2017.04.008

  日期：2017.6

  A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510 nM at MDR-1. Three of the dimeric IDHPs possessed <1.5 mu M activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog 4c containing an m-Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole 5 and pyridine 6, also were examined, indicating that the triazole - incorporated as part of the click assembly as a spacer - contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p-Br IDHPs 4d, 4e and 4f with tethers of from n = 2 to 5 ethylenedioxy units, had sub-micromolar affinities with 4d being the most efficacious at 193 nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity. (C) 2017 Elsevier Ltd. All rights reserved.