3-chloro-N-[6-(3-chloro-propionylamino)-9-oxo-4a,9,9a,10-tetrahydro-acridin-3-yl]-propionamide | 351351-77-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 3-chloro-N-[6-(3-chloro-propionylamino)-9-oxo-4a,9,9a,10-tetrahydro-acridin-3-yl]-propionamide
• 英文别名: 3,6-bis(3-chloropropionamido)-9(10H)-acridone；3-chloro-N-[6-(3-chloropropanoylamino)-9-oxo-10H-acridin-3-yl]propanamide
• CAS: 351351-77-4
• 化学式: C₁₉H₁₇Cl₂N₃O₃
• 分子量: 406.268
• InChiKey: DZVYMUMKTCQHQT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  87.3
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-chloro-N-[6-(3-chloro-propionylamino)-9-oxo-4a,9,9a,10-tetrahydro-acridin-3-yl]-propionamide 在 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 乙腈 为溶剂， 反应 28.0h， 生成 N-[9-(4-dimethylamino-phenylamino)-6-(3-pyrrolidin-1-yl-propionylamino)-acridin-3-yl]-3-pyrrolidin-1-yl-propionamide
  参考文献：
  名称：

  Structure-based design of benzylamino-acridine compounds as G-quadruplex DNA telomere targeting agents

  摘要：

  The design, synthesis, biophysical and biochemical evaluation is presented of a new series of benzylamino-substituted acridines as G-quadruplex binding telomerase inhibitors. Replacement of the previously reported anilino substituents by benzylamino groups results in enhanced quadruplex interaction, and for one compound, superior telomerase inhibitory activity. (c) 2007 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2007.01.056
• 作为产物：
  描述：

  2,2’,4,4’-四硝基二苯甲酮 在 盐酸 、 sodium carbonate 、 tin(ll) chloride 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 生成 3-chloro-N-[6-(3-chloro-propionylamino)-9-oxo-4a,9,9a,10-tetrahydro-acridin-3-yl]-propionamide
  参考文献：
  名称：

  Structure-based design of benzylamino-acridine compounds as G-quadruplex DNA telomere targeting agents

  摘要：

  The design, synthesis, biophysical and biochemical evaluation is presented of a new series of benzylamino-substituted acridines as G-quadruplex binding telomerase inhibitors. Replacement of the previously reported anilino substituents by benzylamino groups results in enhanced quadruplex interaction, and for one compound, superior telomerase inhibitory activity. (c) 2007 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2007.01.056

文献信息

• Therapeutic acridone and acridine compounds
  申请人：——

  公开号：US20030207909A1

  公开（公告）日：2003-11-06

  The present invention pertains to acridone and acridine compounds of formula (I), wherein either: (a) K is ═O, L is —H, alpha is a single bond, beta is a double bond, gamma is a single bond (acridones); or, (b) K is a 9-substituent, L is absent, alpha is a double bond, beta is a single bond, gamma is a double bond (acridines); and wherein: J 1 is a 2- or 3-substituent; J 2 is a 6- or 7-substituent; J 1 and J 2 are each independently a group of the formula —NHCO(CH 2 ) n NR 1 R 2 , wherein: n is an integer from 1 to 5; and, R 1 and R 2 are independently hydrogen, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl, or R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 3 to 8 ring atoms; and wherein, when K is a 9-substituent. K is a group of the formula —N(R N )Q, wherein: R N is an amino substituent and is hydrogen, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl; and, Q is C 1-7 alkyl, C 3-20 heterocyclyl, or (C 5-20 aryl, and is optionally substituted; and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit telomerase, to regulate cell prol iferation, and in the treatment of proliferative conditions, such as cancer.

  本发明涉及式(I)的吖啶和吖啶类化合物，其中：(a) K为═O，L为—H，α为单键，β为双键，γ为单键（吖啶类）；或者，(b) K为9-取代基，L不存在，α为双键，β为单键，γ为双键（吖啶类）；其中：J1为2-或3-取代基；J2为6-或7-取代基；J1和J2各自独立为式—NHCO(CH2)nNR1R2的基团，其中：n为1到5的整数；R1和R2独立地为氢、C1-7烷基、C3-20杂环烷基或C5-20芳基，或者R1和R2与它们连接的氮原子一起形成具有3到8个环原子的杂环环；当K为9-取代基时，K为式—N(RN)Q的基团，其中：RN为氨基取代基，为氢、C1-7烷基、C3-20杂环烷基或C5-20芳基；Q为C1-7烷基、C3-20杂环烷基或(C5-20芳基，且可选择性取代；以及药学上可接受的盐、酯、酰胺、溶剂化合物、水合物和其保护形式。本发明还涉及包含此类化合物的药物组合物，以及在体内外使用此类化合物和组合物来抑制端粒酶、调节细胞增殖，以及治疗增殖性疾病，如癌症。
• Recognition and discrimination of DNA quadruplexes by acridine-peptide conjugates
  作者：James E. Redman、J. M. Granadino-Roldán、James A. Schouten、Sylvain Ladame、Anthony P. Reszka、Stephen Neidle、Shankar Balasubramanian

  DOI：10.1039/b814682a

  日期：——

  We have explored a series of trisubstituted acridine-peptide conjugates for their ability to recognize and discriminate between DNA quadruplexes derived from the human telomere, and the c-kit and N-ras proto-oncogenes. Quadruplex affinity was measured as the peptide sequences were varied, together with their substitution position on the acridine, and the identity of the C-terminus (acid or amide). Surface plasmon resonance measurements revealed that all compounds bound to the human telomeric quadruplex with sub-micromolar affinity. Docking calculations from molecular modelling studies were used to model the effects of substituent orientation and peptide sequence. Modelling and experiment were in agreement that placement of the peptide over the face of the acridine is detrimental to binding affinity. The highest degrees of selectivity were observed towards the N-ras quadruplex by compounds capable of forming simultaneous contacts with their acridine and peptide moieties. The ligands that bound best displayed quadruplex affinities in the 1–5 nM range and at least 10-fold discrimination between the quadruplexes studied.

  我们研究了一系列三取代吖啶肽共轭物，以了解它们识别和区分来自人类端粒、c-kit 和 N-ras 原癌基因的 DNA 四联体的能力。随着肽序列的变化、吖啶上的替代位置以及 C 端（酸或酰胺）的特性的变化，四链亲和力也随之变化。表面等离子共振测量显示，所有化合物与人类端粒四联体的结合亲和力都在亚微摩级以下。分子建模研究中的对接计算用于模拟取代基方向和肽序列的影响。建模和实验结果一致表明，将肽置于吖啶面上不利于结合亲和力。能够与吖啶和肽分子同时形成接触的化合物对 N-ras 四联体的选择性最高。结合效果最好的配体显示出 1-5 nM 范围内的四重亲和力，而且所研究的四重之间至少有 10 倍的区分度。
• Solid-Phase Synthesis of Symmetrical 3,6-Bispeptide−Acridone Conjugates
  作者：Sylvain Ladame、R. John Harrison、Stephen Neidle、Shankar Balasubramanian

  DOI：10.1021/ol026130p

  日期：2002.7.1

  [GRAPHIC]A novel high-yielding method for the solid-phase synthesis of 3,6-bispdptide-acridone conjugates is reported. It involves initial coupling of bifunctionalized acridone to a resin-bound peptide followed by an on-bead site-site reaction to couple the second peptide. This method leads to clean symmetrical bispeptide derivatives and appears to be general. This strategy will enable the generation of a library of 3,6-bispeptide-acridones to be screened for selective binding to telomeric G-quadruplex DNA.
• WO2006/95139
  申请人：——

  公开号：——

  公开（公告）日：——
• Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding
  作者：R. John Harrison、Anthony P. Reszka、Shozeb M. Haider、Barbara Romagnoli、James Morrell、Martin A. Read、Sharon M. Gowan、Christopher M. Incles、Lloyd R. Kelland、Stephen Neidle

  DOI：10.1016/j.bmcl.2004.09.037

  日期：2004.12

  The synthesis and evaluation of a group of 2,6-, 2,7- and 3,6-bis-aminoalkylamido acridones are reported, which show a similar level of activity against telomerase in vitro compared to their acridine counterparts. Computer modelling and calculations of relative binding energies suggest an equivalent binding mode to human intramolecular G-quadruplex DNA, but with significantly reduced affinity; as a result of the limited delocalisation of the acridone chromophore compared to the acridine system. Thermal melting studies on acridone and acridine quadruplex complexes using a FRET approach support these predictions. Long-term cell proliferation studies at sub-cytotoxic doses with two representative acridones using the SKOV3 cell line, show that neither compound produces growth arrest, in contrast with the effects produced by the tri-substituted acridine compound BRACO-19. It is concluded that telomerase inhibitory activity is a necessary though by itself insufficient property in order for cellular growth arrest to occur at sub-toxic concentrations, and that tight quadruplex binding is also required. (C) 2004 Elsevier Ltd. All rights reserved.