(S)-tert-butyl 3-hydroxy-1-(2-thioethylamino)-1-oxopropan-2-ylcarbamate | 147214-58-2

• 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: (S)-tert-butyl 3-hydroxy-1-(2-thioethylamino)-1-oxopropan-2-ylcarbamate
• 英文别名: N-(N-tert-butoxycarbonyl-L-seryl)cysteamine；t-Butyl [(S)-2-hydroxy-1-[(2-mercaptoethyl)carbamoyl]ethyl]carbamate；tert-butyl N-[(2S)-3-hydroxy-1-oxo-1-(2-sulfanylethylamino)propan-2-yl]carbamate
• CAS: 147214-58-2
• 化学式: C₁₀H₂₀N₂O₄S
• 分子量: 264.346
• InChiKey: BPIBYJSQXCZIKH-ZETCQYMHSA-N

物化性质

• 熔点：
  95-96 °C(Solv: ethyl acetate (141-78-6); hexane (110-54-3))
• 沸点：
  494.0±45.0 °C(Predicted)
• 密度：
  1.181±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  88.7
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl 3-hydroxy-1-(2-thioethylamino)-1-oxopropan-2-ylcarbamate 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 20.0h， 生成
  参考文献：
  名称：

  New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine

  摘要：

  Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.

  DOI：

  10.1021/jm0310232
• 作为产物：
  描述：

  BOC-L-丝氨酸 、 巯基乙胺 在 1-羟基苯并三唑 、 1,2-二氯乙烷 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 以42%的产率得到(S)-tert-butyl 3-hydroxy-1-(2-thioethylamino)-1-oxopropan-2-ylcarbamate
  参考文献：
  名称：

  对抗甲型流感病毒H1N1：苯并呋喃山衍生物作为病毒RNA聚合酶抑制剂的合成，分子建模和生物学评估

  摘要：

  由PA，PB1和PB2三个亚基组成的流感RNA聚合酶复合物是开发新抗病毒药物的有希望的目标。合成了庞大的苯并呋喃化合物文库，并针对流感病毒A / WSN / 33（H1N1）进行了分析。发现大多数新衍生物通过破坏亚基PA和PB1之间形成的复合物来抑制病毒RNA聚合酶复合物而发挥作用。还进行了对接研究，以阐明PA中PB1结合位点内苯并呋喃类的结合方式，并鉴定参与其作用机理的氨基酸。预测的结合姿势与生物学数据完全一致，为合理开发更有效的PA–PB1抑制剂奠定了基础。

  DOI：

  10.1002/cmdc.201300378

文献信息

• DNA gyrase inhibitors and pharmaceutical preparations therefor
  申请人：Hoffmann-LaRoche Inc.

  公开号：US05294609A1

  公开（公告）日：1994-03-15

  Bicyclic derivatives of the formula ##STR1## wherein X.sup.1, X.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7a, R.sup.7b, and R.sup.8 are as defined in the specification. These compounds are antimicrobially active.

  公式为##STR1##的双环衍生物，其中X.sup.1、X.sup.2、R.sup.1、R.sup.2、R.sup.3、R.sup.4、R.sup.5、R.sup.6、R.sup.7a、R.sup.7b和R.sup.8的定义如规范中所述。这些化合物具有抗微生物活性。
• Process for the preparation of DNA gyrase inhibitors
  申请人：Hoffmann-La Roche Inc.

  公开号：US05486466A1

  公开（公告）日：1996-01-23

  Bicyclic derivatives of the general formula ##STR1## wherein X.sup.1 is --S-- or --SO--; X.sup.2 is --CO-- or --CS--; R.sup.1 is hydrogen, halogen or lower alkyl optionally substituted by halogen or lower alkoxy; R.sup.2 and R.sup.3 are each independently hydrogen, lower alkyl, halogen, amino, lower alkylamino, di-lower alkylamino, acylamino, lower alkexy, lower alkoxymethoxy or a group OR.sup.4 ; R.sup.4 is hydrogen or an easily hydrolyzable group; R.sup.5 is hydrogen, optionally esterified carboxy or amidated (thio)carboxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted acyl or heterocyclyl; R.sup.6 and R.sup.7a are each independently hydrogen or lower alkyl; R.sup.7b is hydrogen, optionally substituted hydroxy, --NR--A or --N.dbd.B, in which R is hydrogen or lower alkyl, A is hydrogen, optionally substituted alkyl, lower cycloalkyl, iminoyl, (thio)acyl, esterified carboxy or amidated (thio)carboxy and B is lower alkylidene; R.sup.7a and R.sup.7b together represent oxo, lower alkoxycarbonylmethylidene or optionally substituted hydroxyimino; and R.sup.8 is hydrogen, optionally substituted alkyl, optionally esterified carboxy or amidated (thio)carboxy; provided that no more than two of R.sup.1 -R.sup.3 are nitrogen-containing groups; no more than two of R.sup.1 -R.sup.3 are oxygen containing groups and no more than two of R.sup.1 -R.sup.3 are either nitrogen containing or oxygen containing groups; and pharmaceutically acceptable salts of the compounds of formula I carrying an acidic and/or basic substituent. The products are antimicrobially active.

  通式为##STR1##的二环衍生物，其中X.sup.1为--S--或--SO--;X.sup.2为--CO--或--CS--;R.sup.1为氢、卤素或低碳基，可选择地被卤素或低烷氧基取代;R.sup.2和R.sup.3各自独立地为氢、低烷基、卤素、氨基、低烷基氨基、双低烷基氨基、酰胺基、低烷氧基、低烷氧甲氧基或OR.sup.4基；R.sup.4为氢或易水解的基团；R.sup.5为氢、可选择酯化的羧基或酰胺化的(硫)羧基、可选择地被取代的烷基、可选择地被取代的烯基、可选择地被取代的酰基或杂环基；R.sup.6和R.sup.7a各自独立地为氢或低烷基；R.sup.7b为氢、可选择地被取代的羟基、--NR--A或--N.dbd.B，其中R为氢或低烷基，A为氢、可选择地被取代的烷基、低环烷基、亚胺基、(硫)酰基、酯化的羧基或酰胺化的(硫)羧基，B为低烷基亚甲基；R.sup.7a和R.sup.7b共同表示氧、低烷氧羰基甲基或可选择地被取代的羟亚胺基；R.sup.8为氢、可选择地被取代的烷基、可选择酯化的羧基或酰胺化的(硫)羧基；前提是R.sup.1-R.sup.3中最多有两个含氮基团；R.sup.1-R.sup.3中最多有两个含氧基团；R.sup.1-R.sup.3中最多有两个含氮基团或含氧基团；以及携带酸性和/或碱性取代基的通式I化合物的药物可接受的盐。该产品具有抗微生物活性。
• The design, synthesis, and evaluation of two universal doxorubicin-linkers: Preparation of conjugates that retain topoisomerase II activity
  作者：Chengzao Sun、Simon E. Aspland、Carlo Ballatore、Rosario Castillo、Amos B. Smith、Angelo J. Castellino

  DOI：10.1016/j.bmcl.2005.09.046

  日期：2006.1

  The design, synthesis, and evaluation of two N-alkylmaleimide aldehydes have been achieved, which upon reductive alkylation with the C3'-amino group of doxorubicin (DOX) permits the preparation of DOX conjugates via Michael addition of thiol-containing vectors. This method enables the mild, facile, and high-throughput preparation of DOX conjugates that retain the basic C3'-nitrogen, a pre-requisite for topoisomerase II inhibition. Seven DOX-amino acid conjugates were prepared, each displaying similar inhibitory activity as the parent drug. (c) 2005 Elsevier Ltd. All rights reserved.
• The Fight against the Influenza A Virus H1N1: Synthesis, Molecular Modeling, and Biological Evaluation of Benzofurazan Derivatives as Viral RNA Polymerase Inhibitors
  作者：Mafalda Pagano、Daniele Castagnolo、Martina Bernardini、Anna Lucia Fallacara、Ilaria Laurenzana、Davide Deodato、Ulrich Kessler、Beatrice Pilger、Lilli Stergiou、Stephan Strunze、Cristina Tintori、Maurizio Botta

  DOI：10.1002/cmdc.201300378

  日期：2014.1

  The influenza RNA polymerase complex, which consists of the three subunits PA, PB1, and PB2, is a promising target for the development of new antiviral drugs. A large library of benzofurazan compounds was synthesized and assayed against influenza virus A/WSN/33 (H1N1). Most of the new derivatives were found to act by inhibiting the viral RNA polymerase complex through disruption of the complex formed

  由PA，PB1和PB2三个亚基组成的流感RNA聚合酶复合物是开发新抗病毒药物的有希望的目标。合成了庞大的苯并呋喃化合物文库，并针对流感病毒A / WSN / 33（H1N1）进行了分析。发现大多数新衍生物通过破坏亚基PA和PB1之间形成的复合物来抑制病毒RNA聚合酶复合物而发挥作用。还进行了对接研究，以阐明PA中PB1结合位点内苯并呋喃类的结合方式，并鉴定参与其作用机理的氨基酸。预测的结合姿势与生物学数据完全一致，为合理开发更有效的PA–PB1抑制剂奠定了基础。
• New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine
  作者：Peter Angehrn、Stefan Buchmann、Christoph Funk、Erwin Goetschi、Hans Gmuender、Paul Hebeisen、Dirk Kostrewa、Helmut Link、Thomas Luebbers、Raffaello Masciadri、Joergen Nielsen、Peter Reindl、Fabienne Ricklin、Anne Schmitt-Hoffmann、Frank-Peter Theil

  DOI：10.1021/jm0310232

  日期：2004.3.1

  Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.