(6-((bis(pyridin-2-ylmethyl)amino)methyl)pyridin-3-yl)methanol | 769952-03-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (6-((bis(pyridin-2-ylmethyl)amino)methyl)pyridin-3-yl)methanol
• 英文别名: 3-Pyridinemethanol, 6-[[bis(2-pyridinylmethyl)amino]methyl]-；[6-[[bis(pyridin-2-ylmethyl)amino]methyl]pyridin-3-yl]methanol
• CAS: 769952-03-6
• 化学式: C₁₉H₂₀N₄O
• 分子量: 320.394
• InChiKey: DVKGFWUMRRBWGX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  62.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (6-((bis(pyridin-2-ylmethyl)amino)methyl)pyridin-3-yl)methanol 在 氯化亚砜 、 tetrakis(actonitrile)copper(I) hexafluorophosphate 作用下， 以 氯仿 、 乙腈 为溶剂， 反应 18.01h， 生成 [5-(2-{6-[(Bis-pyridin-2-ylmethyl-amino)-methyl]-pyridin-3-yl}-ethyl)-pyridin-2-ylmethyl]-bis-pyridin-2-ylmethyl-amine
  参考文献：
  名称：

  双核铜配合物对 DNA 的高效和特异性链断裂：具有连接的三（2-吡啶基甲基）胺部分的配合物的比较反应性

  摘要：

  化合物 [Cu(II)(2)(D(1))(H(2)O)(2)](ClO(4))(4) (D(1) = 双核配体与两个 tris(2-吡啶基甲基）胺单元通过 -CH(2)CH(2)- 桥在其 5-吡啶基位置共价连接）选择性促进寡核苷酸链上 DNA 的切割，该链从磨损的双链结构的 3' 侧延伸至两个残基的位点从交界处移位。反应的最低要求包括与切割位点相邻的 3' 突出端的 n（即第一个未配对）位置的鸟嘌呤和 5' 突出端的 n 位置的腺嘌呤。识别和链断裂与切割位点的核碱基无关。还原剂和分子氧的必要存在表明负责裂解的中间体是通过双核络合物的铜 (I) 形式激活分子氧而产生的。对自由基猝灭剂缺乏敏感性和高水平的断裂位点选择性表明一种不涉及可扩散自由基物种的机制。与单核类似物 [Cu(II)(TMPA)(H(2)O)](ClO(4))(2)（TMPA = tris（ 2-吡啶基甲基）胺）和 [Cu(OP)(2)](2+)（OP

  DOI：

  10.1021/ja020039z
• 作为产物：
  描述：

  2,5-吡啶-二羧酸二甲酯 在 selenium(IV) oxide 、 sodium tetrahydroborate 、 碳酸氢钠 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 乙腈 为溶剂， 反应 39.0h， 生成 (6-((bis(pyridin-2-ylmethyl)amino)methyl)pyridin-3-yl)methanol
  参考文献：
  名称：

  基因靶向的聚吡啶基三链体形成寡核苷酸杂交体的开发。

  摘要：

  据报道，点击化学方法可靶向DNA氧化，其中叠氮化物修饰的三脚架配体与炔烃-TFO偶联。在协调的Cu II存在下，这些杂种可以有效地靶向和切割富含嘌呤的遗传元件。

  DOI：

  10.1002/cbic.202000408

文献信息

• [EN] COMPOUNDS<br/>[FR] COMPOSÉS
  申请人：UNIV OSLO

  公开号：WO2018033719A1

  公开（公告）日：2018-02-22

  The invention provides compounds for use in a method of treating and/or preventing a bacterial infection in a human or non-human mammal, said method comprising administration of said compound in combination with (either simultaneously, separately, or sequentially) a β-lactam antibiotic, wherein said compound has the general formula I: (I) (wherein: Q is a lipophilic, zinc chelating moiety which is selective for Zn2+ ions and which comprises at least one, preferably two or more (e.g 2, 3 or 4), optionally substituted, unsaturated heterocyclic rings, e.g. 5 or 6-membered heterocyclic rings (such rings preferably include at least one heteroatom selected from N, S and O, preferably N); wherein any optional substituents may be selected from C1-6 alkyl, C1-6 alkoxy, halogen, nitro, cyano, amine, and substituted amine; each L, which may be the same or different, is a covalent bond or a linker; each W, which may be the same or different, is a non-peptidic hydrophilic group which comprises one or more hydroxy groups; and x is an integer from 1 to 3) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.

  该发明提供了一种化合物，用于治疗和/或预防人类或非人哺乳动物体内的细菌感染，所述方法包括将该化合物与β-内酰胺类抗生素（可以同时、分开或顺序地）结合给药，其中所述化合物具有一般式I：（I）（其中：Q是一个亲脂性、选择性结合Zn2+离子的基团，包括至少一个，最好是两个或更多（例如2、3或4个），可选择地取代的不饱和杂环环，例如5或6元杂环环（这些环最好包括至少一个从N、S和O中选择的杂原子，最好是N）；其中任何可选择的取代基可以选择自C1-6烷基、C1-6烷氧基、卤素、硝基、氰基、胺和取代胺；每个L，可以相同也可以不同，是一个共价键或一个连接基；每个W，可以相同也可以不同，是一个非肽性亲水基团，包括一个或多个羟基；x是1到3之间的整数）或其立体异构体、药学上可接受的盐或前药。
• Synthesis and Preclinical Evaluation of TPA-Based Zinc Chelators as Metallo-β-lactamase Inhibitors
  作者：Christian Schnaars、Geir Kildahl-Andersen、Anthony Prandina、Roya Popal、Sylvie Radix、Marc Le Borgne、Tor Gjøen、Adriana Magalhães Santos Andresen、Adam Heikal、Ole Andreas Økstad、Christopher Fröhlich、Ørjan Samuelsen、Silje Lauksund、Lars Petter Jordheim、Pål Rongved、Ove Alexander Høgmoen Åstrand

  DOI：10.1021/acsinfecdis.8b00137

  日期：2018.9.14

  development of efficient and clinically available MBL inhibitors. At present, no such inhibitor is available, and research is urgently needed to advance this field. We report herein the development, synthesis, and biological evaluation of chemical compounds based on the selective zinc chelator tris-picolylamine (TPA) that can restore the bactericidal activity of Meropenem (MEM) against Pseudomonas aeruginosa

  全球抗菌素耐药性（AMR）的兴起和表达金属β-内酰胺酶（MBL）的多药耐药生物的日益普及，要求开发有效且临床上可用的MBL抑制剂。目前，尚无此类抑制剂，因此迫切需要研究以促进该领域的发展。我们在此报告了基于选择性锌螯合剂三甲基吡啶胺（TPA）的化合物的开发，合成和生物学评估，该化合物可恢复美罗培南（MEM）对铜绿假单胞菌和肺炎克雷伯菌表达碳青霉烯酶维罗纳整合子编码金属的杀菌活性-β-内酰胺酶（VIM-2）和新德里金属-β-内酰胺酶1（NDM-1）。这些佐剂是通过标准化学方法制备的，并在生物学分析中评估了MEM对细菌的增强作用以及对HepG2人肝癌细胞的毒性（IC50）。最佳化合物之一15在所有测试的表达MBL的临床分离株中以50μM的浓度将MEM的最低抑菌浓度（MIC）降低了32-256倍，并且对表达丝氨酸碳青霉烯酶的分离株无活性。用纯化的VIM-2和NDM-1和15进行生化分析可得出抑制动力学，其kinact
• Synthesis and Characterization of PY2- and TPA-Appended Diphenylglycoluril Receptors and Their Bis-CuI Complexes
  作者：Vera S. I. Sprakel、Johannes A. A. W. Elemans、Martin C. Feiters、Baldo Lucchese、Kenneth D. Karlin、Roeland J. M. Nolte

  DOI：10.1002/ejoc.200500865

  日期：2006.5

  A number of metallohosts mimicking dinuclear copper oxygenases have been designed and synthesized. These metallohosts combine a substrate binding site, i.e. the diphenylglycoluril basket receptor, with two types of metal-binding ligands, viz. tri-coordinating bis(2-ethylpyridine)amine (PY2) and tetra-coordinating tris(2-methylpyridine)amine (TPA). The preparation of the bis-Cu I complexes of the ligand

  已经设计并合成了许多模拟双核铜加氧酶的金属宿主。这些金属宿主将底物结合位点（即二苯基甘脲篮式受体）与两种类型的金属结合配体（即。三配位双(2-乙基吡啶)胺(PY2)和四配位三(2-甲基吡啶)胺(TPA)。配体双Cu I配合物的制备
• Compounds
  申请人：UNIVERSITETET I OSLO

  公开号：US10961223B2

  公开（公告）日：2021-03-30

  The invention provides compounds for use in a method of treating and/or preventing a bacterial infection in a human or non-human mammal, said method comprising administration of said compound in combination with (either simultaneously, separately, or sequentially) a β-lactam antibiotic, wherein said compound has the general formula I: (I) (wherein: Q is a lipophilic, zinc chelating moiety which is selective for Zn2+ ions and which comprises at least one, preferably two or more (e.g 2, 3 or 4), optionally substituted, unsaturated heterocyclic rings, e.g. 5 or 6-membered heterocyclic rings (such rings preferably include at least one heteroatom selected from N, S and O, preferably N); wherein any optional substituents may be selected from C1-6 alkyl, C1-6 alkoxy, halogen, nitro, cyano, amine, and substituted amine; each L, which may be the same or different, is a covalent bond or a linker; each W, which may be the same or different, is a non-peptidic hydrophilic group which comprises one or more hydroxy groups; and x is an integer from 1 to 3) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.

  本发明提供了用于治疗和/或预防人类或非人类哺乳动物细菌感染的方法的化合物，所述方法包括将所述化合物与β-内酰胺类抗生素（同时、分别或依次）联合给药，其中所述化合物具有通式I： (I) (其中：Q 是对 Zn2+ 离子有选择性的亲脂性锌螯合基团，它包括至少一个，最好是两个或更多 （例如 2、3 或 4 个）任选取代的不饱和杂环，例如5或6元杂环（此类环最好包括至少一个选自N、S和O的杂原子，最好是N）；其中任选取代基可选自C1-6烷基、C1-6烷氧基、卤素、硝基、氰基、胺和取代胺；每个 L（可以相同或不同）是共价键或连接体；每个 W（可以相同或不同）是非肽亲水基团，包括一个或多个羟基；以及 x 是 1 至 3 的整数）或其立体异构体、药学上可接受的盐或原药。
• Reversible O2 Binding to a Dinuclear Copper(I) Complex with Linked Tris(2-pyridylmethyl)amine Units: Kinetic-Thermodynamic Comparisons with Mononuclear Analogs
  作者：Dong-Heon Lee、Ning Wei、Narasimha N. Murthy、Zoltan Tyeklar、Kenneth D. Karlin、Susan Kaderli、Bernhard Jung、Andreas D. Zuberbuehler

  DOI：10.1021/ja00155a014

  日期：1995.12

  fajThe kinetics and thermodynamics of reaction of O-2 with copper(I) complexes can provide fundamental information relevant to chemical and biological systems. Using diode-array variable-temperature (180-296 K) stopped-flow kinetic methods, we report detailed information on the O-2 reactivity (in EtCN) of dicopper(I) complex [(D-1)Cu-2(I)(RCN)(2)](2+) (2a) (R = Me or Et) [D-1 = dinucleating ligand with a -CH2CH2- group linking two tris(2-pyridylmethyl)amine (TMPA) units at a 5-pyridyl position of each tetradentate moiety]. A comparative study of mononuclear complex [(TMPAE)Cu(RCN)li (1a') [TMPAE has a -C(O)OCH3 ester substituent in the 5-position of one pyridyl group of TMPA] has been carried out. The results are compared with data from the previously investigated complex [(TMPA)Cu(RCN)](+) (1a). The syntheses of D-1 and 2a-(ClO4)(2) are described; an X-ray structure reveals two pentacoordinate Cu(I) ions (Cu ... Cu = 11.70 Angstrom), each bound by the N-4-tetradentate and an EtCN molecule. Cyclic voltammetric data for 1a' and 2a are reported. At 193 K in EtCN, 2a reacts with O-2 (Cu/O-2 = 2:1, manometry) to produce an intensely purple colored solution of adduct [(D-1)Cu-2(O-2)](2+) (2c), lambda(max) = 540 nm (epsilon 11 100 M(-1) cm(-1)). This peroxo-dicopper(II) species reacts with PPh(3), liberating O-2 and producing the isolatable bis-phosphine adduct [(D')Cu-2(PPh(3))(2)](2+). The kinetic investigation provides spectral characterization of transient Cu/O-2 1:1 adducts generated upon oxygenation of cold solutions of 1a' or 2a. [(TMPAE)Cu(O-2)](+) (1b') forms reversibly (lambda(max) = 415 nm) with k(1) (8.2 +/- 0.4) x 10(3) M(-1) s(-1) and K-1 = k(1)/k(-1) = (284 +/- 9) M(-1) at 183 K, with Delta H-1 degrees (-32 +/- 1) kJ mol(-1), Delta S-1 degrees = (-127 +/- 3) J K-1 mol(-1). Two types of Cu(II)-O-2(-) complexes form in the reaction of 2a: a 2:1 open form (i.e., [(D-1)Cu-2(O-2)(EtCN)](2+), 2b) and a bis-O-2 2:2 open adduct (i.e., [(D-1)Cu-2(O-2)(2)](2+), 2b'). For the formation of 2b, k(1) (1.63 +/- 0.01) x 10(4) M(-1) s(-1) and K-1 = (2.03 +/- 0.04) x 10(3) M(-1) at 183 K. Complexes 2b and 2b' have identical spectroscopic properties (lambda(max) = 416 nm, epsilon = 4500 M(-1) cm(-1)) per Cu-O-2 unit, and their rate constants are statistically related. Intermediates 1b' and 2b further convert into (mu-peroxo)dicopper(II) [(2 Cu):(1 O-2)] complexes. [((TMPAE)Cu)(2)(O-2)](2+) (1c') (lambda(max) = 532 nm, epsilon = 9380 M(-1) cm(-1)) forms in a second-order reaction of 1b' with 1a' with K1K2 = (2.1 +/- 0.4) X 10(11) M(-2) at 183 K (Delta H(12)degrees = -77 +/- 1 kJ mol(-1) and Delta S(12)degrees = -203 +/- 5 J K-1 mol(-1)), while [D-1)Cu-2(O-2)](2+) (2c) (lambda(max) 540 nn, epsilon = 11 100 M(-1) cm(-1)) is generated from 2b in an intramolecular reaction, with k(2) = (3.51 +/- 0.05) x 10(1) s(-1) and k(on), = k(1)k(2)/k(-1) (7.1 +/- 0.2) x 10(4) M-l s(-1) (183 K). The overall formation of 2c is faster than for 1c' or [((TMPA)Cu)(2)(O-2)](2+) (1c) because of a more positive entropy of activation (Delta S-on(double dagger), = (-139 +/- 3) J K-1 mol(-1) for 2c vs Delta S-on(double dagger) = (-201 +/- 5) J K-1 mol(-1) for 1c). However, this significantly enhanced kinetic reactivity (for 2a --> 2c) is not reflected by an analogous increase in thermodynamic stability. [(D-1)Cu-2(O-2)](2+) (2c) is enthalpically less stable (Delta H(12)degrees = (-34.8 +/- 0.4) kJ mol(-1)) than Cu2O2 species 1c and 1c' (Delta H(12)degrees = -81 to -77 kJ mol(-1), respectively), which are formed from mononuclearprecursors. There is a substantially larger overall formation entropy for 2c [Delta S(12)degrees = (-89.3 +/- 1.5) J K-1 mol(-1) compared to -220 and -203 J K-1 mol(-1) for 1c and 1c', respectively] since Cu2O2 formation is an intramolecular, rather than intermolecular, process. Examination of other kinetic parameters and spectral differences provides complementary information that 2c has a strained structure. In fact, 2c is not the ultimate oxidation product: relief of steric constraints occurs at higher temperatures by a slow rearrangement (lambda(max) = 540 nm --> lambda(max) = 529 nm) producing (Cu2O2)(n) oligomers containing intermolecular Cu-O-2-Cu bonds. A particularly stable trimer species [((D-1)Cu-2(O-2))(3)](6+) (2d) was characterized, with Delta H-3 degrees (-153 kJ mol(-1))/3 = -51 KJ mol(-1) per Cu2O2 unit, intermediate between that seen for 2c, 1c, and 1c'. Thus, (peroxo)dicopper(II) complexes formed from mononuclear precursors are the most stable, while secondary rearrangements within intramolecularly formed Cu-2-O-2 complexes with dinucleating ligands can and do occur. Comparisons are made with relevant copper-dioxygen complexes, and the chemical and biological relevance of this chemistry is discussed.