N,N,O-trimethylagelastatin A | 159622-52-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N,N,O-trimethylagelastatin A
• 英文别名: (1R,9R,10S,14S)-3-bromo-14-methoxy-8,11,13-trimethyl-2,8,11,13-tetrazatetracyclo[7.6.0.02,6.010,14]pentadeca-3,5-diene-7,12-dione
• CAS: 159622-52-3
• 化学式: C₁₅H₁₉BrN₄O₃
• 分子量: 383.245
• InChiKey: JZSDFNCRGYQMEZ-NYMYIZQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  58
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N,N,O-trimethylagelastatin A 在 吡啶 、 Amberlyst 15 作用下， 以 吡啶 、 水 、 丙酮 为溶剂， 反应 24.0h， 生成 (1R,9R)-3-bromo-8,11,13-trimethyl-2,8,11,13-tetrazatetracyclo[7.6.0.02,6.010,14]pentadeca-3,5,10(14)-triene-7,12-dione
  参考文献：
  名称：

  Agelastatin A的活性中心，这是珊瑚海海绵体Agelas dendromorpha的一种强细胞毒性生物碱，由半合成衍生物的比较生物测定法确定† ‡

  摘要：

  Agelastatin A（1），一种来自珊瑚海的无心轴海绵海绵Agelas dendromorpha的不常见生物碱，可以在OHC（8a）上选择性乙酰化（7）或甲基化（4），在OHC（8a）上过乙酰化（8）或全甲基化， NH（5）和NH（6）（5），或者最后经过C（9）C（8a）（14）或C（5b）C（8a）β消除（11-13），视反应条件而定是否为区域特异性方式。在酸性条件下，化合物12区域选择性地（虽然不是内/外立体选择性地）添加H 2 O或MeOH ，从而产生了类固醇/类固醇混合物1/18或4/19。类似地，11或13添加MeOH，分别得到混合物（-）- 2/20或15/16。化合物13还加入AcOH，得到混合物8/17。中间cisoid治疗的形式得到21用H 3 ö +经受N（5）N（6），得到桥接五环22，其构成用于一个证明cisoid配置。从构象研究中，设计了规则，以允许从NM

  DOI：

  10.1002/hlca.19960790315
• 作为产物：
  描述：

  agelastatin A 在 N,N-二异丙基乙胺 、 potassium hydroxide 作用下， 以 二甲基亚砜 、 异丙醇 、 乙腈 为溶剂， 反应 0.67h， 生成 N,N,O-trimethylagelastatin A
  参考文献：
  名称：

  Potent Fluorinated Agelastatin Analogues for Chronic Lymphocytic Leukemia: Design, Synthesis, and Pharmacokinetic Studies

  摘要：

  Chronic lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in Western societies and is currently incurable. Multiple treatment options are practiced, but the available small molecule drugs suffer from dose-limiting toxicity and undesirable side effects. The need for new, less toxic treatments is a pressing concern. Here, we demonstrate that (-)-agelastatin A (1a), a pyrrole-imidazole alkaloid obtained from a marine sponge, exhibits potent in vitro activity against primary cell lines of CLL and disclose the synthesis of several analogues that are equipotent or exceed the potency of the natural product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl agelastatin A (1j), showed higher activity than the natural product when tested against the same cell lines and is the most potent agelastatin derivative reported to date. A detailed in vitro structure-activity relationship of 1a in CLL compared to that of 22 synthetic analogues is described along with preliminary in vivo pharmacokinetic and metabolism studies on the most potent compounds.

  DOI：

  10.1021/jm4016922

文献信息

• Conformational Preferences and Absolute Configuration of Agelastatin A, a Cytotoxic Alkaloid of the Axinellid SpongeAgelas dendromorpha from the Coral Sea,via combined molecular modelling, NMR, and exciton splitting for diamide and hydroxyamide derivatives
  作者：Antonio Guerriero、Michele D'Ambrosio、Giuseppe Chiasera、Francesco Pietra

  DOI：10.1002/hlca.19940770720

  日期：1994.11.2

  The absolute configuration of agelastatin A (1), the major, strongly cytotoxic alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, is proposed here to be (5aS,5bS,8aS,9aR), as deduced from combined molecular-mechanics calculations and a novel application of exciton splitting to the bis[4-(dimethylamino)benzoyl] compounds (–)-9 and (–)-13, derivatives of a diamide and a hydroxyamide

  根据合成的推论，这里提出了来自珊瑚海的海绵状海绵体Agelas dendromorpha的主要的，具有强烈细胞毒性的生物碱生物碱Agelastatin A（1）的绝对构型为（5a S，5b S，8a S，9a R）。分子力学计算和激子分裂在双[4-（二甲基氨基）苯甲酰基]化合物（–）- 9和（–）- 13中分别是二酰胺和羟酰胺衍生物的激子分裂的新应用。A 1的构象平衡的位置可以通过轻微的分子变化进行微调。次要类似物agelastatin B（3），被分离为三甲基衍生物（–）- 4。
• Agelastatins C and D, New Pentacyclic Bromopyrroles from the Sponge <i>Cymbastela</i> sp., and Potent Arthropod Toxicity of (−)-Agelastatin A
  作者：Tamilyn W. Hong、Desmond R. Jímenez、Tadeusz F. Molinski

  DOI：10.1021/np9703813

  日期：1998.1.1

  Two new agelastatins, C (3) and D (4), along with the known compound (-)-agelastatin A ii), were isolated from the Indian Ocean sponge Cymbastela sp. The structures were determined by analysis of spectroscopic data and chemical correlation of 4 with a common derivative 5, also prepared from 1. Agelastatin A (1) exhibited potent activity against brine shrimp (LC50 1.7 ppm) in addition to insecticidal activity against larvae of beet army worm, Spodoptera exigua, and corn rootworm, Diabrotica undecimpunctata.
• The Active Centres of Agelastatin A, a Strongly Cytotoxic Alkaloid of the Coral Sea Axinellid SpongeAgelas dendromorpha, as Determined by Comparative Bioassays with Semisynthetic Derivatives
  作者：Michele D'Ambrosio、Antonio Guerriero、Francesco Pietra、Marina Ripamonti、C�cile Debitus、Jean Waikedre

  DOI：10.1002/hlca.19960790315

  日期：1996.5.8

  Agelastatin A (1), an unusual alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, can be selectively acetylated (7) or methylated at OHC(8a) (4), peracetylated (8) or permethylated at OHC(8a), NH(5), and NH(6) (5), or, finally, subjected to C(9)C(8a) (14) or C(5b)C(8a) β-elimination (11–13), in a regiospecific manner or not, depending on the reaction conditions. Under acidic conditions

  Agelastatin A（1），一种来自珊瑚海的无心轴海绵海绵Agelas dendromorpha的不常见生物碱，可以在OHC（8a）上选择性乙酰化（7）或甲基化（4），在OHC（8a）上过乙酰化（8）或全甲基化， NH（5）和NH（6）（5），或者最后经过C（9）C（8a）（14）或C（5b）C（8a）β消除（11-13），视反应条件而定是否为区域特异性方式。在酸性条件下，化合物12区域选择性地（虽然不是内/外立体选择性地）添加H 2 O或MeOH ，从而产生了类固醇/类固醇混合物1/18或4/19。类似地，11或13添加MeOH，分别得到混合物（-）- 2/20或15/16。化合物13还加入AcOH，得到混合物8/17。中间cisoid治疗的形式得到21用H 3 ö +经受N（5）N（6），得到桥接五环22，其构成用于一个证明cisoid配置。从构象研究中，设计了规则，以允许从NM
• Potent Fluorinated Agelastatin Analogues for Chronic Lymphocytic Leukemia: Design, Synthesis, and Pharmacokinetic Studies
  作者：E. Paige Stout、Michael Y. Choi、Januario E. Castro、Tadeusz F. Molinski

  DOI：10.1021/jm4016922

  日期：2014.6.26

  Chronic lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in Western societies and is currently incurable. Multiple treatment options are practiced, but the available small molecule drugs suffer from dose-limiting toxicity and undesirable side effects. The need for new, less toxic treatments is a pressing concern. Here, we demonstrate that (-)-agelastatin A (1a), a pyrrole-imidazole alkaloid obtained from a marine sponge, exhibits potent in vitro activity against primary cell lines of CLL and disclose the synthesis of several analogues that are equipotent or exceed the potency of the natural product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl agelastatin A (1j), showed higher activity than the natural product when tested against the same cell lines and is the most potent agelastatin derivative reported to date. A detailed in vitro structure-activity relationship of 1a in CLL compared to that of 22 synthetic analogues is described along with preliminary in vivo pharmacokinetic and metabolism studies on the most potent compounds.