methyl 6-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl)pentan-3-yl)-2-methylphenoxy)hexanoate | 1445854-33-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl 6-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl)pentan-3-yl)-2-methylphenoxy)hexanoate
• 英文别名: Methyl 6-[4-[3-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]pentan-3-yl]-2-methylphenoxy]hexanoate；methyl 6-[4-[3-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]pentan-3-yl]-2-methylphenoxy]hexanoate
• CAS: 1445854-33-0
• 化学式: C₃₂H₄₈O₅
• 分子量: 512.73
• InChiKey: LUWNHOOVESLIPO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.5
• 重原子数：
  37
• 可旋转键数：
  16
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 6-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl)pentan-3-yl)-2-methylphenoxy)hexanoate 在 羟胺 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 48.0h， 以29%的产率得到N-hydroxy-6-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl)pentan-3-yl)-2-methylphenoxy)hexanamide
  参考文献：
  名称：

  Optimization of histone deacetylase inhibitor activity in non-secosteroidal vitamin D-receptor agonist hybrids

  摘要：

  The combination of (1 alpha,25)-dihydroxyvitamin D-3 (1,25D) and histone deacetylase inhibitor (HDACi) trichostatin A is highly antiproliferative in numerous cancer cell lines. We have previously prepared novel non-secosteroidal hybrid molecules which simultaneously act as both vitamin D receptor (VDR) agonists and HDACi. These molecules function as cytostatic and cytotoxic agents in 1,25D-resistant SCC4 squamous carcinoma cells. Here we have extended the scope of the hybrids by making several modifications to the diarylpentane core and to the aliphatic spacer unit to develop molecules with increased potency towards HDACs while maintaining VDR agonist activity. Notably, hybrid DK-366 (33a), a direct analog of first-generation hybrids but lacking a methyl group on one aryl ring possesses low micromolar potency for HDAC3 and HDAC6 and is a highly effective antiproliferative agent in SCC4 cells. Chain extended hybrids such as DK-367 (33c) possess even greater HDAC potency and are also highly antiproliferative. These results show that we can optimize HDACi potency in hybrid molecules without sacrificing VDR agonism. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.05.011
• 作为产物：
  描述：

  3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-hydroxy-3-methylphenyl]pentane 、 6-溴己酸甲酯 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 12.0h， 以77%的产率得到methyl 6-(4-(3-(4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl)pentan-3-yl)-2-methylphenoxy)hexanoate
  参考文献：
  名称：

  Optimization of histone deacetylase inhibitor activity in non-secosteroidal vitamin D-receptor agonist hybrids

  摘要：

  The combination of (1 alpha,25)-dihydroxyvitamin D-3 (1,25D) and histone deacetylase inhibitor (HDACi) trichostatin A is highly antiproliferative in numerous cancer cell lines. We have previously prepared novel non-secosteroidal hybrid molecules which simultaneously act as both vitamin D receptor (VDR) agonists and HDACi. These molecules function as cytostatic and cytotoxic agents in 1,25D-resistant SCC4 squamous carcinoma cells. Here we have extended the scope of the hybrids by making several modifications to the diarylpentane core and to the aliphatic spacer unit to develop molecules with increased potency towards HDACs while maintaining VDR agonist activity. Notably, hybrid DK-366 (33a), a direct analog of first-generation hybrids but lacking a methyl group on one aryl ring possesses low micromolar potency for HDAC3 and HDAC6 and is a highly effective antiproliferative agent in SCC4 cells. Chain extended hybrids such as DK-367 (33c) possess even greater HDAC potency and are also highly antiproliferative. These results show that we can optimize HDACi potency in hybrid molecules without sacrificing VDR agonism. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.05.011

文献信息

• [EN] BIS-(ARYL/HETEROARYL)-METHYLENE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND THEIR USE FOR TREATING CANCER<br/>[FR] COMPOSÉS DE BIS(ARYL/HÉTÉROARYL)MÉTHYLÈNE, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT ET LEUR UTILISATION POUR LE TRAITEMENT DU CANCER
  申请人：UNIV MCGILL

  公开号：WO2013091082A1

  公开（公告）日：2013-06-27

  The present disclosure relates to novel bis-(aryl/heteroaryl)-methylene compounds of formula (I) having vitamin D receptor agonist and histone deacetylase (HDAC) inhibitory efficacy as well as to methods for reducing or inhibiting the proliferation of cancer cells or for treating cancer cells.

  本公开涉及具有维生素D受体激动剂和组蛋白去乙酰化酶（HDAC）抑制活性的新型双（芳基/杂芳基）亚甲基化合物（I）的公式，以及用于减少或抑制癌细胞增殖或治疗癌细胞的方法。
• BIS-(ARYL/HETEROARYL)-METHYLENE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND THEIR USE FOR TREATING CANCER
  申请人：The Royal Institution For The Advancement of Learning/McGill University

  公开号：US20140315965A1

  公开（公告）日：2014-10-23

  The present disclosure relates to novel compounds having vitamin D receptor agonist and histone deacetylase inhibitory efficacy as well as methods for reducing or inhibiting the proliferation of cancer cells or for treating cancer.

  本公开涉及具有维生素D受体激动剂和组蛋白去乙酰化酶抑制剂功效的新化合物，以及用于减少或抑制癌细胞增殖或治疗癌症的方法。
• US9428447B2
  申请人：——

  公开号：US9428447B2

  公开（公告）日：2016-08-30
• Optimization of histone deacetylase inhibitor activity in non-secosteroidal vitamin D-receptor agonist hybrids
  作者：Dainis Kaldre、Tian-Tian Wang、Joshua Fischer、John H. White、James L. Gleason

  DOI：10.1016/j.bmc.2015.05.011

  日期：2015.8

  The combination of (1 alpha,25)-dihydroxyvitamin D-3 (1,25D) and histone deacetylase inhibitor (HDACi) trichostatin A is highly antiproliferative in numerous cancer cell lines. We have previously prepared novel non-secosteroidal hybrid molecules which simultaneously act as both vitamin D receptor (VDR) agonists and HDACi. These molecules function as cytostatic and cytotoxic agents in 1,25D-resistant SCC4 squamous carcinoma cells. Here we have extended the scope of the hybrids by making several modifications to the diarylpentane core and to the aliphatic spacer unit to develop molecules with increased potency towards HDACs while maintaining VDR agonist activity. Notably, hybrid DK-366 (33a), a direct analog of first-generation hybrids but lacking a methyl group on one aryl ring possesses low micromolar potency for HDAC3 and HDAC6 and is a highly effective antiproliferative agent in SCC4 cells. Chain extended hybrids such as DK-367 (33c) possess even greater HDAC potency and are also highly antiproliferative. These results show that we can optimize HDACi potency in hybrid molecules without sacrificing VDR agonism. (C) 2015 Elsevier Ltd. All rights reserved.