L-mannaro-1,4:3,6-di-γ-lactone | 214038-58-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃类
• 英文名称: L-mannaro-1,4:3,6-di-γ-lactone
• 英文别名: L-mannaro-1,4:6,3-dilactone；L-1,4:3,6-mannarodilactone；(3R,3aS,6R,6aS)-3,6-dihydroxy-3,3a,6,6a-tetrahydrofuro[3,2-b]furan-2,5-dione
• CAS: 214038-58-1
• 化学式: C₆H₆O₆
• 分子量: 174.11
• InChiKey: QRFNDAVXJCGLFB-MMPJQOAZSA-N

物化性质

• 沸点：
  558.6±50.0 °C(Predicted)
• 密度：
  1.892±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.6
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  93.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  L-mannaro-1,4:3,6-di-γ-lactone 在 三氟甲磺酸 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 为溶剂， 反应 50.0h， 生成 N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di[(4-bromobenzyl)oxy]-3,4-dihydroxyhexanediamide
  参考文献：
  名称：

  Design and Fast Synthesis of C-Terminal Duplicated Potent C₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors

  摘要：

  tin analysis of the X-ray structure of a complex of HIV-1 protease with a linear C-2-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K-i values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K-i values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.

  DOI：

  10.1021/jm9910371
• 作为产物：
  描述：

  L-甘露糖酸-1,4-内酯 在 硝酸 作用下， 反应 16.0h， 以60%的产率得到L-mannaro-1,4:3,6-di-γ-lactone
  参考文献：
  名称：

  设计和合成新型有效的C2对称HIV-1蛋白酶抑制剂。L-甘露酸作为拟肽支架的用途。

  摘要：

  已经进行了使用衍生的碳水化合物作为C2对称HIV-1蛋白酶抑制剂的研究。在C-2和C-5处对L-甘露酸（6）进行双-O-苄基化，然后与氨基酸和胺偶联，基于C端重复生成C2对称产物。已经发现了有效的HIV蛋白酶抑制剂28 Ki = 0.4 nM和43 Ki = 0.2 nM，并且已经开发出两种合成方法，其中一种可以通过仅三个化学步骤由市售材料制备这些抑制剂。在抑制剂中将-COOMe换成-CONHMe时，观察到效价从IC50 = 5000 nM（23）到IC50 = 15 nM（28）显着增加，导致两者之间净增加一个氢键相互作用-NH-基团和HIV蛋白酶主链（Gly 48/148）。

  DOI：

  10.1021/jm970777b

文献信息

• Design and Synthesis of New Potent <i>C</i>₂-Symmetric HIV-1 Protease Inhibitors. Use of <scp>l</scp>-Mannaric Acid as a Peptidomimetic Scaffold
  作者：Mathias Alterman、Magnus Björsne、Anna Mühlman、Björn Classon、Ingemar Kvarnström、Helena Danielson、Per-Olof Markgren、Ulrika Nillroth、Torsten Unge、Anders Hallberg、Bertil Samuelsson

  DOI：10.1021/jm970777b

  日期：1998.9.1

  C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be

  已经进行了使用衍生的碳水化合物作为C2对称HIV-1蛋白酶抑制剂的研究。在C-2和C-5处对L-甘露酸（6）进行双-O-苄基化，然后与氨基酸和胺偶联，基于C端重复生成C2对称产物。已经发现了有效的HIV蛋白酶抑制剂28 Ki = 0.4 nM和43 Ki = 0.2 nM，并且已经开发出两种合成方法，其中一种可以通过仅三个化学步骤由市售材料制备这些抑制剂。在抑制剂中将-COOMe换成-CONHMe时，观察到效价从IC50 = 5000 nM（23）到IC50 = 15 nM（28）显着增加，导致两者之间净增加一个氢键相互作用-NH-基团和HIV蛋白酶主链（Gly 48/148）。
• Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV
  作者：Karolina Ersmark、Martin Nervall、Hugo Gutiérrez-de-Terán、Elizabeth Hamelink、Linda K. Janka、Jose C. Clemente、Ben M. Dunn、Adolf Gogoll、Bertil Samuelsson、Johan Åqvist、Anders Hallberg

  DOI：10.1016/j.bmc.2005.11.003

  日期：2006.4

  The first macrocyclic inhibitor of the Plasmodium falciparum aspartic proteases plasmepsin I, II, and IV with considerable selectivity over the human aspartic protease cathepsin D has been identified. A series of macrocyclic compounds were designed and synthesized. Cyclizations were accomplished using ring-closing metathesis with the second generation Grubbs catalyst. These compounds contain either

  已经鉴定出恶性疟原虫天冬氨酸蛋白酶纤溶酶I，II和IV的第一种大环抑制剂，其对人天冬氨酸蛋白酶组织蛋白酶D具有相当大的选择性。设计并合成了一系列大环化合物。环化是使用第二代Grubbs催化剂通过闭环复分解完成的。这些化合物包含13元或16元大环，并结合有1，2-二羟基乙烯作为过渡态模拟单元。通过自动对接和分子动力学模拟预测了这类新化合物的结合模式，并通过线性相互作用能（LIE）方法估算了结合亲和力。
• C2-Symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions
  作者：Karolina Ersmark、Isabella Feierberg、Sinisa Bjelic、Johan Hultén、Bertil Samuelsson、Johan Åqvist、Anders Hallberg

  DOI：10.1016/s0968-0896(03)00339-0

  日期：2003.8

  A series of C-2-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results. (C) 2003 Elsevier Ltd. All rights reserved.
• Potent Inhibitors of the <i>Plasmodium </i><i>f</i><i>alciparum</i> Enzymes Plasmepsin I and II Devoid of Cathepsin D Inhibitory Activity
  作者：Karolina Ersmark、Isabella Feierberg、Sinisa Bjelic、Elizabeth Hamelink、Fiona Hackett、Michael J. Blackman、Johan Hultén、Bertil Samuelsson、Johan Åqvist、Anders Hallberg

  DOI：10.1021/jm030933g

  日期：2004.1.1

  The hemoglobin-degrading aspartic proteases plasmepsin I (Plin I) and plasmepsin II (Plin II) of the malaria parasite Plasmodium falciparum have lately emerged as putative drug targets. A series of C-2-symmetric compounds encompassing the 1,2-dihydroxyethylene scaffold and a variety of elongated P1/P1' side chains were synthesized via microwave-assisted palladium-catalyzed coupling reactions. Binding affinity calculations with the linear interaction energy method and molecular dynamics simulations reproduced the experimental binding data obtained in a Plm II assay with very good accuracy. Bioactive conformations of the elongated P1/P1' chains were predicted and agreed essentially with a recent X-ray structure. The compounds exhibited picomolar to nanomolar inhibition constants for the plasmepsins and no measurable affinity to the human enzyme cathepsin D. Some of the compounds also demonstrated significant inhibition of parasite growth in cell culture. To the best of our knowledge, these plasmepsin inhibitors represent the most selective reported to date and constitute promising lead compounds for further optimization.
• 2,3,4,5-TETRAHYDROXYHEXANDISÄUREESTER AUS DILACTONEN DER 2,3,4,5-TETRAHYDROXYHEXANDISÄURE
  申请人：BASF SE

  公开号：EP3258909B1

  公开（公告）日：2019-09-25