N-{9-[4'-fluorophenylamino]}-3,6-bis(3-pyrrolidinopropionamido)acridine | 393570-35-9

• 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-[4'-fluorophenylamino]}-3,6-bis(3-pyrrolidinopropionamido)acridine
• 英文别名: N-[9-(4-Fluoro-phenylamino)-6-(3-pyrrolidin-1-yl-propionylamino)-acridin-3-yl]-3-pyrrolidin-1-yl-propionamide；N-[9-(4-fluoroanilino)-6-(3-pyrrolidin-1-ylpropanoylamino)acridin-3-yl]-3-pyrrolidin-1-ylpropanamide
• CAS: 393570-35-9
• 化学式: C₃₃H₃₇FN₆O₂
• 分子量: 568.694
• InChiKey: LQGJGUQFBRHVRA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  89.6
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-{9-[4'-fluorophenylamino]}-3,6-bis(3-pyrrolidinopropionamido)acridine 在 盐酸 作用下， 生成 3,6-bis(3-pyrrolidin-1-ylpropionamido)-9-(4-fluorophenylamino)acridine trihydrochloride
  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：

  3,6-bis-[3-pyrrolidinopropionamide]-9-acridone 在 三氯氧磷 作用下， 以 氯仿 为溶剂， 反应 5.0h， 生成 N-{9-[4'-fluorophenylamino]}-3,6-bis(3-pyrrolidinopropionamido)acridine
  参考文献：
  名称：

  Trisubstituted Acridine Derivatives as Potent and Selective Telomerase Inhibitors

  摘要：

  The synthesis and evaluation for telomerase-inhibitory and quadruplex DNA binding properties of three related series of rationally designed trisubstituted acridine derivatives are described. These are substituted on the acridine ring at the 2,6,9; 2,7,9; and 3,6,9 positions. The ability of several of the most potent compounds to interact with and stabilize an intramolecular G-quadruplex DNA was evaluated by surface plasmon resonance methods, and affinities were found to correlate with potency in a telomerase assay. The interactions of a number of compounds with a parallel quadruplex DNA structure were simulated by molecular modeling methods. The calculated interaction energies were compared with telomerase activity and showed generally consistent correlations between quadruplex affinity and telomerase inhibition. These data support a model for the action of these compounds that involves the stabilization of intermediate quadruplex structures that inhibit the elongation of telomeric DNA by telomerase in tumor cells.

  DOI：

  10.1021/jm0308693

文献信息

• 9-Amino Acridines Undergo Reversible Amine Exchange Reactions in Water: Implications on Their Mechanism of Action in Vivo
  作者：Alexis Paul、Sylvain Ladame

  DOI：10.1021/ol9019925

  日期：2009.11.5

  9-Amino substituted acridines undergo a reversible amine exchange reaction in water under near-physiological conditions via an unstable hemiaminal intermediate. This thermodynamically controlled reaction may have implications in understanding the mode of action of 9-aminoacridines in vivo and in the future design of drugs based on this scaffold.

  9-氨基取代的cr啶在近乎生理条件下通过不稳定的半胱氨酸中间体在水中进行可逆的胺交换反应。这种热力学控制的反应可能对理解9-氨基ac啶在体内的作用方式以及未来基于该支架的药物设计有影响。
• US7160896B2
  申请人：——

  公开号：US7160896B2

  公开（公告）日：2007-01-09
• US7300930B2
  申请人：——

  公开号：US7300930B2

  公开（公告）日：2007-11-27
• 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。
• Trisubstituted Acridine Derivatives as Potent and Selective Telomerase Inhibitors
  作者：R. John Harrison、Javier Cuesta、Gianni Chessari、Martin A. Read、Sanji K. Basra、Anthony P. Reszka、James Morrell、Sharon M. Gowan、Christopher M. Incles、Farial A. Tanious、W. David Wilson、Lloyd R. Kelland、Stephen Neidle

  DOI：10.1021/jm0308693

  日期：2003.10.1

  The synthesis and evaluation for telomerase-inhibitory and quadruplex DNA binding properties of three related series of rationally designed trisubstituted acridine derivatives are described. These are substituted on the acridine ring at the 2,6,9; 2,7,9; and 3,6,9 positions. The ability of several of the most potent compounds to interact with and stabilize an intramolecular G-quadruplex DNA was evaluated by surface plasmon resonance methods, and affinities were found to correlate with potency in a telomerase assay. The interactions of a number of compounds with a parallel quadruplex DNA structure were simulated by molecular modeling methods. The calculated interaction energies were compared with telomerase activity and showed generally consistent correlations between quadruplex affinity and telomerase inhibition. These data support a model for the action of these compounds that involves the stabilization of intermediate quadruplex structures that inhibit the elongation of telomeric DNA by telomerase in tumor cells.