6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one | 1067242-94-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one
• 英文别名: coumarin A；(S)-6-(1-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one；6-[(1S)-1-hydroxy-3-methylbutyl]-7-methoxychromen-2-one
• CAS: 1067242-94-7
• 化学式: C₁₅H₁₈O₄
• 分子量: 262.306
• InChiKey: ZRXJDVGAMZQYJX-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one 在 carbonic anhydrase 作用下， 生成 3-[2-hydroxy-5-[(1S)-1-hydroxy-3-methylbutyl]-4-methoxyphenyl]prop-2-enoic acid
  参考文献：
  名称：

  Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations

  摘要：

  We investigated a series of coumarinyl-substituted aromatic sulfonamides as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medical applications, the cytosolic hCA I, and II, and the transmembrane, tumor-associated hCA IX and XII. Compounds incorporating 7-methoxy-coumarin-4-yl-acetamide-tails and benzenesulfonamide and benzene-1,3-disulfonamide scaffolds showed medium potency inhibition of hCA I (K(I)s of 73-131 nM), effective hCA II inhibition (K(I)s of 9.1-36 nM) and less effective hCA IX and XII inhibition (K(I)s of 55-128 nM). Only one compound, the derivatized 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide with the coumarinyl tail, showed effective inhibition of the transmembrane isoforms, with K(I)s of 5.9-14.2 nM, although it was less effective as hCA I and II inhibitor (K(I)s of 36120 nM). An X-ray crystal structure of hCA II in complex with 4-(7-methoxy-coumarin-4-yl-acetamido)-benzenesulfonamide (K-I of 9.1 nM against hCA II) showed the intact inhibitor coordinated to the zinc ion from the enzyme active site by the sulfonamide moiety, and participating in a edge-to-face stacking with Phe131, in addition to other hydrophobic and hydrophilic interactions with water molecules and amino acid residues from the active site. Thus, sulfonamides incorporating coumarin rings have a distinct inhibition mechanism compared to the coumarins, and may lead to compounds with interesting inhibition profiles against various alpha-CAs found in mammals or parasites, such as Plasmodium falciparum. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.028

文献信息

• CARBONIC ANHYDRASE INHIBITORS WITH ANTIMETASTATIC ACTIVITY
  申请人：Supuran Claudiu

  公开号：US20140148400A1

  公开（公告）日：2014-05-29

  Derivatized coumarin-based pharmaceutical compositions and methods to use them are provided. The compositions are characterized in that they inhibit the activity of tumor-related CAIX and CAXII to a greater degree than they inhibit the activity of CAI and CAII. The compositions can be used to suppress tumor growth and/or suppress tumor metastases in a mammal.

  提供了衍生香豆素类制药组合物及其使用方法。这些组合物的特征在于它们抑制肿瘤相关的CAIX和CAXII的活性，而不是CAI和CAII的活性。这些组合物可用于抑制哺乳动物中的肿瘤生长和/或抑制肿瘤转移。
• 7,8-Disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range
  作者：Alfonso Maresca、Andrea Scozzafava、Claudiu T. Supuran

  DOI：10.1016/j.bmcl.2010.10.094

  日期：2010.12

  Two series of disubstituted coumarins incorporating ether and acetyl/propionyl moieties in positions 6,7- and 7,8- of the heterocyclic ring were synthesized investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). All these coumarins were very weak or ineffective as inhibitors of the housekeeping, offtarget isoforms CA I and II. The 6,7-disubstituted series showed ineffective inhibition also for the transmembrane tumor-associated isoforms CA IX and XII, whereas the corresponding isomeric 7,8-disubstituted coumarins showed nanomolar/subnanomolar inhibition of CA IX/XII. The nature and position of the groups substituting the coumarin ring in the 7,8-positions greatly influenced CA inhibitory properties, with C1-C4 alkyl ethers being the most effective inhibitors. (C) 2010 Elsevier Ltd. All rights reserved.