N-[9-chloro-6-(3-pyrrolidin-1-yl-propionylamino)-acridin-3-yl]-3-pyrrolidin-1-yl-propionoamide | 351351-79-6

• 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: N-[9-chloro-6-(3-pyrrolidin-1-yl-propionylamino)-acridin-3-yl]-3-pyrrolidin-1-yl-propionoamide
• 英文别名: 9-chloro-3,6-bis(3-pyrrolidin-1-yl-propionamido)acridine；3,6-bis(3-pyrrolidin-1-ylpropionamido)-9-chloroacridine；BRACO-19；2,7-bis[3-(pyrrolidino)propionamido]-9-chloroacridine；N-[9-chloro-6-(3-pyrrolidin-1-ylpropanoylamino)acridin-3-yl]-3-pyrrolidin-1-ylpropanamide
• CAS: 351351-79-6
• 化学式: C₂₇H₃₂ClN₅O₂
• 分子量: 494.036
• InChiKey: AURVVALVMSUKNI-UHFFFAOYSA-N

物化性质

• 沸点：
  795.0±60.0 °C(Predicted)
• 密度：
  1.322±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  77.6
• 氢给体数：
  2
• 氢受体数：
  5

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	3,6-bis-[3-pyrrolidinopropionamide]-9-acridone	351351-78-5	C27H33N5O3	475.591
  ——	3-chloro-N-[6-(3-chloro-propionylamino)-9-oxo-4a,9,9a,10-tetrahydro-acridin-3-yl]-propionamide	351351-77-4	C19H17Cl2N3O3	406.268

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	N-{9-[3-(N,N-dimethyl)aminopropylamino]}-3,6-bis(3-pyrrolidinopropionamido)acridine	393570-20-2	C32H45N7O2	559.755
  ——	N-[9-(cyclopropylamino)]-3,6-bis(3-pyrrolidinopropionamido)acridine	393570-33-7	C30H38N6O2	514.671
  ——	N-[9-(N,N-dimethylethylenediamino)]-3,6-bis(3-pyrrolidinopropionamido)acridine	393570-29-1	C31H43N7O2	545.728
  ——	N-[9-(2-methoxy-ethylamino)]-3,6-bis(3-pyrrolidinopropionamido)acridine	393570-26-8	C30H40N6O3	532.686
  ——	N-[9-(2-piperidin-1-yl-ethylamino)]-3,6-bis(3-pyrrolidinopropionamido)acridine	393570-21-3	C34H47N7O2	585.793
  ——	3,6-bis(3-pyrrolidin-1-ylpropionamido)-9-(cycloheptylamino)acridine	393570-27-9	C34H46N6O2	570.778
  ——	3,6-bis(3-pyrrolidin-1-ylpropionamido)-9-[2-(1-methylpyrrolidin-2-yl)ethylamino]acridine	393570-30-4	C34H47N7O2	585.793
  ——	N-[9-(4'-aminophenylamino)]-3,6-bis(3-pyrrolidinopropionamido)acridine	351351-76-3	C33H39N7O2	565.718
  ——	N-{9-[4'-(3-pyrrolidin-1-yl-propionylamino)-phenylamino]}-3,6-bis(3-pyrrolidinopropionamido)acridine	393570-34-8	C40H50N8O3	690.889
  ——	N-{9-[3'-(amino)phenylamino]}-3,6-bis(3-pyrrolidinopropionamido)acridine	393570-22-4	C33H39N7O2	565.718

反应信息

• 作为反应物：
  描述：

  N,N-二甲基-对苯二胺 、 N-[9-chloro-6-(3-pyrrolidin-1-yl-propionylamino)-acridin-3-yl]-3-pyrrolidin-1-yl-propionoamide 以 氯仿 为溶剂， 反应 2.0h， 以88%的产率得到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：

  Therapeutic acridone and acridine compounds

  摘要：

  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。

  公开号：

  US20030207909A1
• 作为产物：
  描述：

  2,2’,4,4’-四硝基二苯基甲烷 在 chromium(VI) oxide 、 盐酸 、 sodium carbonate 、 溶剂黄146 、 tin(ll) chloride 、 三氯氧磷 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 生成 N-[9-chloro-6-(3-pyrrolidin-1-yl-propionylamino)-acridin-3-yl]-3-pyrrolidin-1-yl-propionoamide
  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

• Synthesis and biological evaluation of hybrid acridine-HSP90 ligand conjugates as telomerase inhibitors
  作者：S. Roe、M. Gunaratnam、C. Spiteri、P. Sharma、R. D. Alharthy、S. Neidle、J. E. Moses

  DOI：10.1039/c5ob01177a

  日期：——

  The synthesis and biological evaluation of a series of bifunctional acridine-HSP90 inhibitor ligands as telomerase inhibitors is herein described.

  本文介绍了一系列双功能的吖啶-HSP90抑制剂配体的合成和生物评价，作为端粒酶抑制剂。
• Toward the Design of a Catalytic Metallodrug: Selective Cleavage of G-Quadruplex Telomeric DNA by an Anticancer Copper-Acridine-ATCUN Complex
  作者：Zhen Yu、Menglu Han、James A. Cowan

  DOI：10.1002/anie.201410434

  日期：2015.2.2

  Telomeric DNA represents a novel target for the development of anticancer drugs. By application of a catalytic metallodrug strategy, a copper–acridine–ATCUN complex (CuGGHK‐Acr) has been designed that targets G‐quadruplex telomeric DNA. Both fluorescence solution assays and gel sequencing demonstrate the CuGGHK‐Acr catalyst to selectively bind and cleave the G‐quadruplex telomere sequence. The cleavage

  端粒DNA代表了开发抗癌药物的新靶标。通过应用催化金属药物策略，设计了靶向G-四链体端粒DNA的铜-ac啶-ATCUN复合物（CuGGHK-Acr）。荧光溶液测定和凝胶测序均证明CuGGHK-Acr催化剂可选择性结合并切割G-四链体端粒序列。裂解途径已通过基质辅助激光解吸电离飞行时间质谱（MALDI-TOF MS）实验绘制。CuGGHK-Acr可显着抑制癌细胞增殖并缩短端粒长度。在乳腺癌细胞系MCF7中诱导衰老和凋亡。
• Two-in-one: a pH-sensitive, acridine-based, fluorescent probe binds G-quadruplexes in oncogene promoters
  作者：Claudia Percivalle、Tariq Mahmood、Sylvain Ladame

  DOI：10.1039/c2md20173a

  日期：——

  We report the synthesis of an acridine-containing cyanine dye and demonstrate its potential as a pH-responsive colorimetric indicator and fluorescent probe.

  我们报告了一种含有吖啶基的青烷染料的合成，并展示了它作为pH响应性比色指示剂和荧光探针的潜力。
• 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。
• Trisubstituted Acridines as G-quadruplex Telomere Targeting Agents. Effects of Extensions of the 3,6- and 9-Side Chains on Quadruplex Binding, Telomerase Activity, and Cell Proliferation
  作者：Michael J. B. Moore、Christoph M. Schultes、Javier Cuesta、Francisco Cuenca、Mekala Gunaratnam、Farial A. Tanious、W. David Wilson、Stephen Neidle

  DOI：10.1021/jm050555a

  日期：2006.1.1

  The synthesis is reported of a group of 3,6,9-trisubstituted acridine compounds as telomeric quadruplex-stabilizing ligands with systematic variations at the 3-, 6-, and 9-positions. A new microwave-assisted methodology has been developed for trisubstituted acridine synthesis. Structure-activity relationships are reported using surface plasmon resonance and a fluorescence melting assay to examine quadruplex binding, together with a telomerase inhibition assay. These reveal relationships between G-quadruplex stabilization and telomerase inhibition and optimal 3,6- and 9-substituent side-chain lengths for maximal activity. Qualitative molecular modeling using molecular dynamics simulations has been undertaken on four quadruplex-DNA complexes. Long-term exposure of MCF7 cancer cells to a subset of the most active compounds, at doses lower than the IC50 values, showed that one compound produced a marked decrease in population growth, accompanied by senescence, which is consistent with telomere targeting by this agent.