(8S,20R)-de-A,B-20-[3-(cyclopropyl-N-t-Boc-amine)propyl]pregnan-8-one | 1357161-56-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (8S,20R)-de-A,B-20-[3-(cyclopropyl-N-t-Boc-amine)propyl]pregnan-8-one
• 英文别名: tert-butyl N-[(4R)-4-[(1R,3aR,7aR)-7a-methyl-4-oxo-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]pentyl]-N-cyclopropylcarbamate
• CAS: 1357161-56-8
• 化学式: C₂₃H₃₉NO₃
• 分子量: 377.568
• InChiKey: ABVUPBNRDACCAH-YQYRJILISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.59
• 重原子数：
  27.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  46.61
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (8S,20R)-de-A,B-20-[3-(cyclopropyl-N-t-Boc-amine)propyl]pregnan-8-one 在 氢氟酸 、 苯基锂 作用下， 以 四氢呋喃 、 二丁醚 、 水 、 乙腈 为溶剂， 反应 29.0h， 生成 N-cyclopropyl-(20R)-2-methylene-19,25,26,27-tetranor-25-aza-1α-hydroxyvitamin D
  参考文献：
  名称：

  Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase

  摘要：

  Selective inhibitors of CYP24A1 represent an important synthetic target in a search for novel vitamin D compounds of therapeutic value. In the present work, we show the synthesis and biological properties of two novel side chain modified 2-methylene-19-nor-1,25(OH)(2)D-3 analogs, the 22-imidazole-1-yl derivative 2 (VIMI) and the 25-N-cyclopropylamine compound 3 (CPA1), which were efficiently prepared in convergent syntheses utilizing the Lythgoe type Horner-Wittig olefination reaction. When tested in a cell-free assay, both compounds were found to be potent competitive inhibitors of CYP24A1, with the cyclopropylamine analog 3 exhibiting an 80-1 selective inhibition of CYP24A1 over CYP27B1. Addition of 3 to a mouse osteoblast culture sustained the level of 1,25(OH)(2)D-3, further demonstrating its effectiveness in CYP24A1 inhibition. Importantly, the in vitro effects on human promyeloid leukemia (HL-60) cell differentiation by 3 were nearly identical to those of 1,25(OH)(2)D-3 and in vivo the compound showed low calcemic activity. Finally, the results of preliminary theoretical studies provide useful insights to rationalize the ability of analog 3 to selectively inhibit the cytochrome P450 isoform CYP24A1. (C) 2011 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2011.11.007
• 作为产物：
  描述：

  (4R)-4-((1R,4S,7aR)-7a-methyl-4-((triethylsilyl)oxy)octahydro-1H-inden-1-yl)pentanal 在 4-二甲氨基吡啶 重铬酸吡啶 、 四丁基氟化铵 、 4-甲基苯磺酸吡啶 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 11.0h， 生成 (8S,20R)-de-A,B-20-[3-(cyclopropyl-N-t-Boc-amine)propyl]pregnan-8-one
  参考文献：
  名称：

  [EN] N-CYCLOPROPYL-(20R)-2-METHYLENE-19,26,27-TRINOR-25-AZA-VITAMIN D ANALOGS AND THEIR USES
  [FR] ANALOGUES DE N-CYCLOPROPYL-(20R)-2-MÉTHYLÈNE-19,26,27-TRINOR-25-AZA-VITAMINE D ET LEURS UTILISATIONS

  摘要：

  这项发明揭示了N-环丙基-(20R)-2-亚甲基-19,26,27-三去-25-氮杂维生素D类似物，具体为N-环丙基-(20R)-2-亚甲基-19,26,27-三去-25-氮-1α-羟基维生素D3及其药用。该化合物表现出相对较高的结合活性和明显的抑制未分化细胞增殖并诱导它们分化为单核细胞的活性，因此可作为抗癌剂，特别适用于治疗或预防白血病、结肠癌、乳腺癌、皮肤癌或前列腺癌。

  公开号：

  WO2012158794A1

文献信息

• [EN] N-CYCLOPROPYL-(20R)-2-METHYLENE-19,26,27-TRINOR-25-AZA-VITAMIN D ANALOGS AND THEIR USES<br/>[FR] ANALOGUES DE N-CYCLOPROPYL-(20R)-2-MÉTHYLÈNE-19,26,27-TRINOR-25-AZA-VITAMINE D ET LEURS UTILISATIONS
  申请人：WISCONSIN ALUMNI RES FOUND

  公开号：WO2012158794A1

  公开（公告）日：2012-11-22

  This invention discloses N-cyclopropyl-(20R)-2 -methylene-19,26,27-trinor-25-aza-vitamin D analogs, and specifically N-cyclopropyl-(20R)-2-methylene-19,26,27-trinor-25-aza-1α-hydroxyvitamin D3 and pharmaceutical uses therefor. This compound exhibits relatively high binding activity and pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent especially for the treatment or prevention of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer.

  这项发明揭示了N-环丙基-(20R)-2-亚甲基-19,26,27-三去-25-氮杂维生素D类似物，具体为N-环丙基-(20R)-2-亚甲基-19,26,27-三去-25-氮-1α-羟基维生素D3及其药用。该化合物表现出相对较高的结合活性和明显的抑制未分化细胞增殖并诱导它们分化为单核细胞的活性，因此可作为抗癌剂，特别适用于治疗或预防白血病、结肠癌、乳腺癌、皮肤癌或前列腺癌。
• N-Cyclopropyl-(20R)-2-Methylene-19,26,27-Trinor-25-Aza-Vitamin D Analogs and Their Uses
  申请人：Hector DeLuca F.

  公开号：US20120309713A1

  公开（公告）日：2012-12-06

  This invention discloses N-cyclopropyl-(20R)-2-methylene-19,26,27-trinor-25-aza-vitamin D analogs, and specifically N-cyclopropyl-(20R)-2-methylene-19,26,27-trinor-25-aza-1α-hydroxyvitamin D 3 and pharmaceutical uses therefor. This compound exhibits relatively high binding activity and pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent especially for the treatment or prevention of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer.
• US8987235B2
  申请人：——

  公开号：US8987235B2

  公开（公告）日：2015-03-24
• Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase
  作者：Grazia Chiellini、Simona Rapposelli、Jinge Zhu、Ilaria Massarelli、Marilena Saraceno、Anna Maria Bianucci、Lori A. Plum、Margaret Clagett-Dame、Hector F. DeLuca

  DOI：10.1016/j.steroids.2011.11.007

  日期：2012.2

  Selective inhibitors of CYP24A1 represent an important synthetic target in a search for novel vitamin D compounds of therapeutic value. In the present work, we show the synthesis and biological properties of two novel side chain modified 2-methylene-19-nor-1,25(OH)(2)D-3 analogs, the 22-imidazole-1-yl derivative 2 (VIMI) and the 25-N-cyclopropylamine compound 3 (CPA1), which were efficiently prepared in convergent syntheses utilizing the Lythgoe type Horner-Wittig olefination reaction. When tested in a cell-free assay, both compounds were found to be potent competitive inhibitors of CYP24A1, with the cyclopropylamine analog 3 exhibiting an 80-1 selective inhibition of CYP24A1 over CYP27B1. Addition of 3 to a mouse osteoblast culture sustained the level of 1,25(OH)(2)D-3, further demonstrating its effectiveness in CYP24A1 inhibition. Importantly, the in vitro effects on human promyeloid leukemia (HL-60) cell differentiation by 3 were nearly identical to those of 1,25(OH)(2)D-3 and in vivo the compound showed low calcemic activity. Finally, the results of preliminary theoretical studies provide useful insights to rationalize the ability of analog 3 to selectively inhibit the cytochrome P450 isoform CYP24A1. (C) 2011 Elsevier Inc. All rights reserved.