Ethyl 1-methyl-4-[(1-methylpyrrole-2-carbonyl)amino]imidazole-2-carboxylate | 1086330-67-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: Ethyl 1-methyl-4-[(1-methylpyrrole-2-carbonyl)amino]imidazole-2-carboxylate
• CAS: 1086330-67-7
• 化学式: C₁₃H₁₆N₄O₃
• 分子量: 276.295
• InChiKey: WFBXLNLLLDUMKY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  78.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Ethyl 1-methyl-4-[(1-methylpyrrole-2-carbonyl)amino]imidazole-2-carboxylate 在 sodium hydroxide 、 水 、 盐酸 作用下， 以 甲醇 为溶剂， 反应 24.0h， 以88%的产率得到DNA荧光探针前驱体,DNA小沟配体
  参考文献：
  名称：

  Sequence specific and high affinity recognition of 5′-ACGCGT-3′ by rationally designed pyrrole-imidazole H-pin polyamides: Thermodynamic and structural studies

  摘要：

  Imidazole (Im) and Pyrrole (Py)-containing polyamides that can form stacked dimers can be programmed to target specific sequences in the minor groove of DNA and control gene expression. Even though various designs of polyamides have been thoroughly investigated for DNA sequence recognition, the use of H-pin polyamides (covalently cross-linked polyamides) has not received as much attention. Therefore, experiments were designed to systematically investigate the DNA recognition properties of two symmetrical H-pin polyamides composed of PyImPyIm (5) or f-ImPyIm (3e, f = formamido) tethered with an ethylene glycol linker. These compounds were created to recognize the cognate 5 '-ACGCGT-3 ' through an overlapped and staggered binding motif, respectively. Results from DNaseI footprinting, thermal denaturation, circular dichroism, surface plasmon resonance and isothermal titration microcalorimetry studies demonstrated that both H-pin polyamides bound with higher afinity than their respective monomers. The binding afinity of formamido-containing H-pin 3e was more than a hundred times greater than that for the tetraamide H-pin 5, demonstrating the importance of having a formamido group and the staggered motif in enhancing affinity. However, compared to H-pin 3e, tetraamide H-pin 5 demonstrated superior binding preference for the cognate sequence over its non-cognates, ACCGGT and AAATTT. Data from SPR experiments yielded binding constants of 1.6 x 10(8) M (1) and 2.0 x 10(10) M (1) for PyImPyIm H-pin 5 and f-ImPyIm H-pin 3e, respectively. Both H-pins bound with significantly higher affinity (ca. 100-fold) than their corresponding unlinked PyImPyIm 4 and f-ImPyIm 2 counterparts. ITC analyses revealed modest enthalpies of reactions at 298 K (Delta H of -3.3 and -1.0 kcal mol (1) for 5 and 3e, respectively), indicating these were entropic-driven interactions. The heat capacities (Delta C(p)) were determined to be -116 and -499 cal mol (1) K (1), respectively. These results are in general agreement with Delta C(p) values determined from changes in the solvent accessible surface areas using complexes of the H-pins bound to (5 ' CCACGCGTGG)(2) . According to the models, the H-pins fit snugly in the minor groove and the linker comfortably holds both polyamide portions in place, with the oxygen atoms pointing into the solvent. In summary, the H-pin polyamide provides an important molecular design motif for the discovery of future generations of programmable small molecules capable of binding to target DNA sequences with high affinity and selectivity. 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.09.034
• 作为产物：
  描述：

  4-氨基-1-甲基-1H-咪唑-2-羧酸乙酯 、 1-甲基吡咯-2-羰酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以24%的产率得到Ethyl 1-methyl-4-[(1-methylpyrrole-2-carbonyl)amino]imidazole-2-carboxylate
  参考文献：
  名称：

  Sequence specific and high affinity recognition of 5′-ACGCGT-3′ by rationally designed pyrrole-imidazole H-pin polyamides: Thermodynamic and structural studies

  摘要：

  Imidazole (Im) and Pyrrole (Py)-containing polyamides that can form stacked dimers can be programmed to target specific sequences in the minor groove of DNA and control gene expression. Even though various designs of polyamides have been thoroughly investigated for DNA sequence recognition, the use of H-pin polyamides (covalently cross-linked polyamides) has not received as much attention. Therefore, experiments were designed to systematically investigate the DNA recognition properties of two symmetrical H-pin polyamides composed of PyImPyIm (5) or f-ImPyIm (3e, f = formamido) tethered with an ethylene glycol linker. These compounds were created to recognize the cognate 5 '-ACGCGT-3 ' through an overlapped and staggered binding motif, respectively. Results from DNaseI footprinting, thermal denaturation, circular dichroism, surface plasmon resonance and isothermal titration microcalorimetry studies demonstrated that both H-pin polyamides bound with higher afinity than their respective monomers. The binding afinity of formamido-containing H-pin 3e was more than a hundred times greater than that for the tetraamide H-pin 5, demonstrating the importance of having a formamido group and the staggered motif in enhancing affinity. However, compared to H-pin 3e, tetraamide H-pin 5 demonstrated superior binding preference for the cognate sequence over its non-cognates, ACCGGT and AAATTT. Data from SPR experiments yielded binding constants of 1.6 x 10(8) M (1) and 2.0 x 10(10) M (1) for PyImPyIm H-pin 5 and f-ImPyIm H-pin 3e, respectively. Both H-pins bound with significantly higher affinity (ca. 100-fold) than their corresponding unlinked PyImPyIm 4 and f-ImPyIm 2 counterparts. ITC analyses revealed modest enthalpies of reactions at 298 K (Delta H of -3.3 and -1.0 kcal mol (1) for 5 and 3e, respectively), indicating these were entropic-driven interactions. The heat capacities (Delta C(p)) were determined to be -116 and -499 cal mol (1) K (1), respectively. These results are in general agreement with Delta C(p) values determined from changes in the solvent accessible surface areas using complexes of the H-pins bound to (5 ' CCACGCGTGG)(2) . According to the models, the H-pins fit snugly in the minor groove and the linker comfortably holds both polyamide portions in place, with the oxygen atoms pointing into the solvent. In summary, the H-pin polyamide provides an important molecular design motif for the discovery of future generations of programmable small molecules capable of binding to target DNA sequences with high affinity and selectivity. 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.09.034

文献信息

• [EN] POLYAMIDES<br/>[FR] POLYAMIDES
  申请人：SPIROGEN LTD

  公开号：WO2009060215A1

  公开（公告）日：2009-05-14

  A polyamide moiety comprising at least one unit of formula I: -β1-X1-Y1-X3-X4-β3- (I) wherein: Y1 is either X2-β2 or β2-X2; β1 is -Rβ -CH2-NH- βa-, wherein βa is a β-alanine residue and Rβ is chosen from optionally substituted C1-7 alkylene, C1-7 alkenylene and C1-7 alkynylene groups; β2 and β3 are β-alanine residues; and X1, X2, X3 and X4 are independently fragments of formula (II): wherein E is an optionally substituted C5-6 heteroarylene group.

  一种聚酰胺基团，包括至少一个I式单位：-β1-X1-Y1-X3-X4-β3-（I），其中：Y1是X2-β2或β2-X2；β1是-Rβ-CH2-NH-βa-，其中βa是β-丙氨酸残基，Rβ选择自可选择取代的C1-7烷基，C1-7烯基和C1-7炔基；β2和β3是β-丙氨酸残基；X1、X2、X3和X4分别是式（II）的片段：其中E是可选择取代的C5-6杂芳烃基。
• Alkyl 4- [4- (5-Oxo-2,3,5, 11A-Tetrahydo-5H-Pyrrolo [2, 1-C] [1,4] Benzodiazepine-8-Yloxy) -Butyrylamino]-1H-Pyrrole-2-Carboxylate Derivatives and Related Compounds For the Treatment of a Proliferative Disease
  申请人：Howard Philip Wilson

  公开号：US20080214525A1

  公开（公告）日：2008-09-04

  A compound of formula (I); or a salt or solvate thereof, wherein: the dotted line indicates the optional presence of a double bond between C2 and C3; R 2 is selected from —H, —OH, =0, ═CH 2 , —CN, —R, OR, halo, ═CH—R, O—SO 2 —R, CO 2 R and COR; R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, where R and R′ are independently selected from optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; R 10 and R 11 either together form a double bond, or are selected from H and YR Y , where Y is selected from O, S and NH and R is H or C 1-7 alkyl or H and SO x M, where x is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; each X is independently a heteroarylene group; n is from 1 to 6; and R E is C 1-4 alkyl. The compound is useful for the treatment of proliferative diseases.

  化合物的公式（I）；或其盐或溶剂化物，其中：虚线表示C2和C3之间的双键是可选的；R2选择自-H，-OH，=0，═CH2，-CN，-R，OR，卤基，═CH-R，O-SO2-R，CO2R和COR；R7选择自H，R，OH，OR，SH，SR，NH2，NHR，NRR'，硝基，Me3Sn和卤基，其中R和R'独立选择自可选取代的C1-7烷基，C3-20杂环基和C5-20芳基基团；R10和R11要么一起形成双键，要么选择自H和YRY，其中Y选择自O，S和NH，R为H或C1-7烷基或H和SOxM，其中x为2或3，M为一价的药用可接受阳离子；每个X独立地是杂芳基基团；n为1至6；以及RE为C1-4烷基。该化合物可用于治疗增殖性疾病。
• US8637664B2
  申请人：——

  公开号：US8637664B2

  公开（公告）日：2014-01-28
• Sequence specific and high affinity recognition of 5′-ACGCGT-3′ by rationally designed pyrrole-imidazole H-pin polyamides: Thermodynamic and structural studies
  作者：Hilary Mackay、Toni Brown、Peter B. Uthe、Laura Westrate、Alan Sielaff、Justin Jones、James P. Lajiness、Jerome Kluza、Caroline O’Hare、Binh Nguyen、Zach Davis、Chrystal Bruce、W. David Wilson、John A. Hartley、Moses Lee

  DOI：10.1016/j.bmc.2008.09.034

  日期：2008.10

  Imidazole (Im) and Pyrrole (Py)-containing polyamides that can form stacked dimers can be programmed to target specific sequences in the minor groove of DNA and control gene expression. Even though various designs of polyamides have been thoroughly investigated for DNA sequence recognition, the use of H-pin polyamides (covalently cross-linked polyamides) has not received as much attention. Therefore, experiments were designed to systematically investigate the DNA recognition properties of two symmetrical H-pin polyamides composed of PyImPyIm (5) or f-ImPyIm (3e, f = formamido) tethered with an ethylene glycol linker. These compounds were created to recognize the cognate 5 '-ACGCGT-3 ' through an overlapped and staggered binding motif, respectively. Results from DNaseI footprinting, thermal denaturation, circular dichroism, surface plasmon resonance and isothermal titration microcalorimetry studies demonstrated that both H-pin polyamides bound with higher afinity than their respective monomers. The binding afinity of formamido-containing H-pin 3e was more than a hundred times greater than that for the tetraamide H-pin 5, demonstrating the importance of having a formamido group and the staggered motif in enhancing affinity. However, compared to H-pin 3e, tetraamide H-pin 5 demonstrated superior binding preference for the cognate sequence over its non-cognates, ACCGGT and AAATTT. Data from SPR experiments yielded binding constants of 1.6 x 10(8) M (1) and 2.0 x 10(10) M (1) for PyImPyIm H-pin 5 and f-ImPyIm H-pin 3e, respectively. Both H-pins bound with significantly higher affinity (ca. 100-fold) than their corresponding unlinked PyImPyIm 4 and f-ImPyIm 2 counterparts. ITC analyses revealed modest enthalpies of reactions at 298 K (Delta H of -3.3 and -1.0 kcal mol (1) for 5 and 3e, respectively), indicating these were entropic-driven interactions. The heat capacities (Delta C(p)) were determined to be -116 and -499 cal mol (1) K (1), respectively. These results are in general agreement with Delta C(p) values determined from changes in the solvent accessible surface areas using complexes of the H-pins bound to (5 ' CCACGCGTGG)(2) . According to the models, the H-pins fit snugly in the minor groove and the linker comfortably holds both polyamide portions in place, with the oxygen atoms pointing into the solvent. In summary, the H-pin polyamide provides an important molecular design motif for the discovery of future generations of programmable small molecules capable of binding to target DNA sequences with high affinity and selectivity. 2008 Elsevier Ltd. All rights reserved.