N-((2,2-dimethyl-2H-chromen-6-yl)methyl)cyclopentanamine | 1342891-31-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: N-((2,2-dimethyl-2H-chromen-6-yl)methyl)cyclopentanamine
• 英文别名: N-[(2,2-dimethylchromen-6-yl)methyl]cyclopentanamine
• CAS: 1342891-31-9
• 化学式: C₁₇H₂₃NO
• 分子量: 257.376
• InChiKey: GBQYDASFNCNDAC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  21.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  吡啶-2-磺酰氯 、 N-((2,2-dimethyl-2H-chromen-6-yl)methyl)cyclopentanamine 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以16%的产率得到N-(cyclopentyl)-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]pyridine-2-sulfonamide
  参考文献：
  名称：

  Design and in Vitro Activities of N-Alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, Novel, Small-Molecule Hypoxia Inducible Factor-1 Pathway Inhibitors and Anticancer Agents

  摘要：

  The hypoxia inducible factor (HIF) pathway is an attractive target for cancer, as it controls tumor adaptation to growth under hypoxia and mediates chemotherapy and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide as a novel, small-molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 mu M in water; log P-7.4 = 3.7). Here we describe the synthesis of 12 N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental log P-7.4 values of 8 of the 12 new analogs ranged from 1.2-3.1. Aqueous solubilities of three analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 mu M, e.g., a solubility improvement of similar to 9000-fold. The pharmacological optimization had limited impact on drug efficacy as the compounds retained IC50 values at or below 5 mu M in our HIF-dependent reporter assay.

  DOI：

  10.1021/jm300752n
• 作为产物：
  描述：

  4-((2-methylbut-3-yn-2-yl)oxy)benzaldehyde 在 N-甲基吡咯烷酮 、 二异丁基氢化铝 、 对甲苯磺酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 生成 N-((2,2-dimethyl-2H-chromen-6-yl)methyl)cyclopentanamine
  参考文献：
  名称：

  Design and in Vitro Activities of N-Alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, Novel, Small-Molecule Hypoxia Inducible Factor-1 Pathway Inhibitors and Anticancer Agents

  摘要：

  The hypoxia inducible factor (HIF) pathway is an attractive target for cancer, as it controls tumor adaptation to growth under hypoxia and mediates chemotherapy and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide as a novel, small-molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 mu M in water; log P-7.4 = 3.7). Here we describe the synthesis of 12 N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental log P-7.4 values of 8 of the 12 new analogs ranged from 1.2-3.1. Aqueous solubilities of three analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 mu M, e.g., a solubility improvement of similar to 9000-fold. The pharmacological optimization had limited impact on drug efficacy as the compounds retained IC50 values at or below 5 mu M in our HIF-dependent reporter assay.

  DOI：

  10.1021/jm300752n

文献信息

• HYPOXIA INDUCIBLE FACTOR-1 PATHWAY INHIBITORS AND USES AS ANTICANCER AND IMAGING AGENTS
  申请人：EMORY UNIVERSITY

  公开号：US20130164218A1

  公开（公告）日：2013-06-27

  This disclosure relates to Hypoxia Inducible Factor-1 pathway inhibitors and uses as anticancer and imaging agents. In certain embodiments, the disclosure contemplates compounds and pharmaceutical compositions disclosed herein.

  本公开涉及缺氧诱导因子-1通路抑制剂及其作为抗癌和成像剂的用途。在某些实施方式中，本公开考虑了在此披露的化合物和药物组成物。
• Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway
  作者：Jalisa Ferguson、Zeus De Los Santos、Narra Devi、Erwin Van Meir、Sarah Zingales、Binghe Wang

  DOI：10.1016/j.bmcl.2017.02.073

  日期：2017.4

  Many forms of solid tumor have a characteristic feature known as hypoxia, which describes a low or nonexistent presence of oxygen in the cellular microenvironment. This decrease in oxygen causes activation of the hypoxia inducible factor (HIF) pathway, which activates the transcription of many genes that cause cell proliferation, metastasis, increased glycolysis and angiogenesis. Increased HIF expression has been linked with poor patient prognosis, increased malignancy, and therapeutic resistance. Previous work in our lab has identified 1 and 2 as inhibitors of the HIF pathway, specifically as disrupters of the p300-HIF-1 alpha complex formation. A library of sulfonamide analogs has been designed and synthesized with the intent of examining the SAR of this series of compounds and improving potency and physicochemical properties as compared with lead compounds 1 and 2. At the end, we have achieved a thorough understanding of the structural features critical for future optimization work. (C) 2017 Elsevier Ltd. All rights reserved.
• Design and Synthesis of Novel Small-Molecule Inhibitors of the Hypoxia Inducible Factor Pathway
  作者：Suazette Reid Mooring、Hui Jin、Narra S. Devi、Adnan A. Jabbar、Stefan Kaluz、Yuan Liu、Erwin G. Van Meir、Binghe Wang

  DOI：10.1021/jm201018g

  日期：2011.12.22

  Hypoxia, a reduction in partial oxygen pressure, is a salient property of solid tumors. Hypoxia drives malignant progression and metastasis in tumors and participates in tumor resistance to radio- and chemotherapies. Hypoxia activates the hypoxia-inducible factor (HIF) family of transcription factors, which induce target genes that regulate adaptive biological processes such as anaerobic metabolism, cell motility, and angiogenesis. Clinical evidence has demonstrated that expression of HIF-1 is strongly associated with poor patient prognosis and activation of HIF-1 contributes to malignant behavior and therapeutic resistance. Consequently, HIF-1 has become an important therapeutic target for inhibition by small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 signaling pathway. Many of these compounds exhibit inhibitory activity in the nanomolar range. Separate mechanistic studies indicate that these inhibitors do not alter HIF-1 levels but interfere with the ability of HIF-1 alpha/HIF-1 beta to interact with cofactors p300/CBP to form an active transcriptional complex.
• US9381260B2
  申请人：——

  公开号：US9381260B2

  公开（公告）日：2016-07-05