4-[(4-Amino-1-methyl-1H-pyrrole-2-carbonyl)-amino]-1-methyl-1H-imidazole-2-carboxylic acid (2-dimethylamino-ethyl)-amide | 868744-75-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-[(4-Amino-1-methyl-1H-pyrrole-2-carbonyl)-amino]-1-methyl-1H-imidazole-2-carboxylic acid (2-dimethylamino-ethyl)-amide
• CAS: 868744-75-6
• 化学式: C₁₅H₂₃N₇O₂
• 分子量: 333.393
• InChiKey: UWDCVSAEUVSKAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.12
• 重原子数：
  24.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  110.21
• 氢给体数：
  3.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  4-[(4-Amino-1-methyl-1H-pyrrole-2-carbonyl)-amino]-1-methyl-1H-imidazole-2-carboxylic acid (2-dimethylamino-ethyl)-amide 在 palladium on activated charcoal benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 240.0h， 生成
  参考文献：
  名称：

  SOLUTION PHASE SYNTHESIS OF IMIDAZOLE- AND PYRROLE-CONTAINING HAIRPIN POLYAMIDES

  摘要：

  DOI：

  10.1515/hc.2007.13.1.17
• 作为产物：
  描述：

  1-Methyl-4-[(1-methyl-4-nitro-1H-pyrrole-2-carbonyl)-amino]-1H-imidazole-2-carboxylic acid (2-dimethylamino-ethyl)-amide 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 生成 4-[(4-Amino-1-methyl-1H-pyrrole-2-carbonyl)-amino]-1-methyl-1H-imidazole-2-carboxylic acid (2-dimethylamino-ethyl)-amide
  参考文献：
  名称：

  NOVEL PICOLINIC ACID-CONTAINING PYRROLE-IMIDAZOLE POLYAMIDES: SYNTHESIS AND T-G MISMATCHED BASE PAIR RECOGNITION

  摘要：

  DOI：

  10.1515/hc.2005.11.2.163

文献信息

• Modifying the N-terminus of polyamides: PyImPyIm has improved sequence specificity over f-ImPyIm
  作者：Toni Brown、Hilary Mackay、Mark Turlington、Arden Sutterfield、Traci Smith、Alan Sielaff、Laura Westrate、Chrystal Bruce、Jerome Kluza、Caroline O’Hare、Binh Nguyen、W. David Wilson、John A. Hartley、Moses Lee

  DOI：10.1016/j.bmc.2008.03.008

  日期：2008.5

  Seven N-terminus modified derivatives of a previously published minor-groove binding polyamide (f-ImPyIm, 1) were synthesized and the biochemical and biophysical chemistry evaluated. These compounds were synthesized with the aim of attaining a higher level of sequence selectivity over f-ImPyIm (1), a previously published strong minor-groove binder. Two compounds possessing a furan or a benzofuran moiety at the N-terminus showed a footprint of 0.5 mu M at the cognate ACGCGT site (determined by DNase I footprinting); however, the specificity of these compounds was not improved. In contrast, PyImPyIm (4) produced a footprint of 0.5 mu M but showed a superior specificity using the same technique. When evaluated by thermal melting experiments and circular dichroism using ACGCGT and the non-cognate AAATTT sequence, all compounds were shown to bind in the minor-groove of DNA and stabilize the cognate sequence much better than the non-cognate (except for the non-amido-compound that did not bind either sequence, as expected). PyImPyIm (4) was interesting as the Delta T(m) for this compound was only 4 degrees C but the footprint was very selective. No binding was observed for this compound with a third DNA (non-cognate, ACCGGT). ITC studies on compound 4 showed exothermic binding with ACGCGT and no heat change was observed for titrating the compound to the other two DNA sequences. The heat capacity (Delta C(p)) of the PIPI/ACGCGT complex calculated from the hydrophobic interactions and SASA calculations was comparable to the experimental value obtained from ITC (-146 cal mol(-1) K(-1)). SPR results provided con. firmation of the sequence specificity of PyImPyIm (4), with a K(eq) value determined to be 7.1 x 10(6) M(-1) for the cognate sequence and no observable binding to AAATTT and ACCGGT. Molecular dynamic simulations affirmed that PyImPyIm (4) binds as a dimer in an overlapped conformation, and it fits snugly in the minor-groove of the ACGCGT oligonucleotide. PyImPyIm (4) is an especially interesting molecule, because although the binding affinity is slightly reduced, the specificity with respect to f-ImPyIm (1) is significantly improved. (C) 2008 Elsevier Ltd. All rights reserved.
• Hx, a Novel Fluorescent, Minor Groove and Sequence Specific Recognition Element: Design, Synthesis, and DNA Binding Properties of <i>p</i>-Anisylbenzimidazole-imidazole/pyrrole-Containing Polyamides
  作者：Sameer Chavda、Yang Liu、Balaji Babu、Ryan Davis、Alan Sielaff、Jennifer Ruprich、Laura Westrate、Christopher Tronrud、Amanda Ferguson、Andrew Franks、Samuel Tzou、Chandler Adkins、Toni Rice、Hilary Mackay、Jerome Kluza、Sharjeel A Tahir、Shicai Lin、Konstantinos Kiakos、Chrystal D. Bruce、W. David Wilson、John A. Hartley、Moses Lee

  DOI：10.1021/bi102028a

  日期：2011.4.19

  With the aim of incorporating a recognition element that acts as a fluorescent probe upon binding to DNA, three novel pyrrole (P) and imidazole (I)-containing polyamides were synthesized. The compounds contain a p-anisylbenzimidazolecarboxamido (Hx) moiety attached to a PP, IP, or PI unit, giving compounds HxPP (2), HxIP (3), and HxPI (4), respectively. These fluorescent hybrids were tested against their complementary nonfluorescent, non-formamido tetraamide counterparts, namely, PPPP (5), PPIP (6), and PPPI (7) (cognate sequences 5'-AAATTT-3', 5'-ATCGAT-3', and 5'-ACATGT-3', respectively). The binding affinities for both series of polyamides for their cognate and noncognate sequences were ascertained by surface plasmon resonance (SPR) studies, which revealed that the Fix-containing polyamides gave binding constants in the 10(6) M-1 range while little binding was observed for the noncognates. The binding data were further compared to the corresponding and previously reported formainido-triamides f-PPP (8), f-PIP (9), and f-PPI (10). DNase I footprinting studies provided additional evidence that the Fix moiety behaved similarly to two consecutive pyrroles (PP found in 5-7), which also behaved like a formamido-pyrrole (f-P) unit found in distamycin and many formamido-triamides, including 8-10. The biophysical characterization of polyamides 2-7 on their binding to the abovementioned DNA sequences was determined using thermal melts (Delta T-M), circular dichroism (CD), and isothermal titration calorimetry (ITC) studies. Density functional calculations (B3LYP) provided a theoretical framework that explains the similarity between PP and Hx on the basis of molecular electrostatic surfaces and dipole moments. Furthermore, emission studies on polyamides 2 and 3 showed that upon excitation at 322 nm binding to their respective cognate sequences resulted in an increase in fluorescence at 370 nm. These low molecular weight polyamides show promise for use as probes for monitoring DNA recognition processes in cells.
• Novel diamino imidazole and pyrrole-containing polyamides: Synthesis and DNA binding studies of mono- and diamino-phenyl-ImPy*Im polyamides designed to target 5′-ACGCGT-3′
  作者：Vijay Satam、Balaji Babu、Sameer Chavda、Mia Savagian、Robert Sjoholm、Samuel Tzou、Yang Liu、Konstantinos Kiakos、Shicai Lin、W. David Wilson、John A. Hartley、Moses Lee

  DOI：10.1016/j.bmc.2011.12.010

  日期：2012.1

  Pyrrole- and imidazole-containing polyamides are widely investigated as DNA sequence selective binding agents that have potential use as gene control agents. The key challenges that must be overcome to realize this goal is the development of polyamides with low molar mass so the molecules can readily diffuse into cells and concentrate in the nucleus. In addition, the molecules must have appreciable water solubility, bind DNA sequence specifically, and with high affinity. It is on this basis that the orthogonally positioned diamino/dicationic polyamide Ph-ImPy*Im 5 was designed to target the sequence 5'-ACGCGT-3'. Py* denotes the pyrrole unit that contains a N-substituted aminopropyl pendant group. The DNA binding properties of diamino polyamide 5 were determined using a number of techniques including CD, Delta T(M), DNase I footprinting, SPR and ITC studies. The effects of the second amino moiety in Py* on DNA binding affinity over its monoamino counterpart Ph-ImPylm 3 were assessed by conducting DNA binding studies of 3 in parallel with 5. The results confirmed the minor groove binding and selectivity of both polyamides for the cognate sequence 5'-ACGCGT-3'. The diamino/dicationic polyamide 5 showed enhanced binding affinity and higher solubility in aqueous media over its monoamino/monocationic counterpart Ph-ImPylm 3. The binding constant of 5, determined from SPR studies, was found to be 1.5 x 10(7) M(-1), which is similar to 3 times higher than that for its monoamino analog 3 (4.8 x 10(6) M(-1)). The affinity of 5 is now approaching that of the parent compound f-ImPyIm 1 and its diamino equivalent 4. The advantages of the design of diamino polyamide 5 over 1 and 4 are its sequence specificity and the ease of synthesis compared to the N-terminus pyrrole analog 2. (C) 2011 Elsevier Ltd. All rights reserved.
• Synthesis and DNA binding properties of 1-(3-aminopropyl)-imidazole-containing triamide f-Im∗PyIm: A novel diamino polyamide designed to target 5′-ACGCGT-3′
  作者：Vijay Satam、Balaji Babu、Alexander Porte、Mia Savagian、Megan Lee、Thomas Smeltzer、Yang Liu、Joseph Ramos、W. David Wilson、Shicai Lin、Kostantinos Kiakos、John A. Hartley、Moses Lee

  DOI：10.1016/j.bmcl.2012.07.071

  日期：2012.9

  A novel diamino/dicationic polyamide f-Im*PyIm (5) that contains an orthogonally positioned aminopropyl chain on an imidazole (Im*) moiety was designed to target 5'-ACGCGT-3'. The DNA binding properties of the diamino polyamide 5, determined by CD, Delta T-M, DNase I footprinting, SPR, and ITC studies, were compared with those of its monoamino/monocationic counterpart f-ImPyIm (1) and its diamino/dicationic isomer f-ImPy*Im (2), which has the aminopropyl group attached to the central pyrrole unit (Py*). The results gave evidence for the minor groove binding and selectivity of polyamide 5 for the cognate sequence 5'-ACGCGT-3', and with strong affinity (K-eq = 2.3 x 10(7) M-1). However, the binding affinities varied according to the order: f-ImPy*Im (2) > f-ImPyIm (1) >= f-Im*PyIm (5) confirming that the second amino group can improve affinity, but its position within the polyamide can affect affinity. (C) 2012 Elsevier Ltd. All rights reserved.