罗米鲁曲 | 192441-08-0

• 物质功能分类: 生物化工 - 抑制剂 - 表观遗传学(Epigenetics)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 罗米鲁曲
• 中文别名: 2-氨基-6-[(4-溴-2-噻吩基)甲氧基]-9H-嘌呤；洛美呱曲
• 英文名称: 6-((4-bromothiophen-2-yl)methoxy)-9H-purin-2-amine
• 英文别名: 2-amino-6-[(4-bromo-2-thienyl)methoxy]-9H-purine；O⁶-(4-bromothenyl)guanine；lomeguatrib；PaTrin-2；4-bromothenylguanine；6-[(4-bromothiophen-2-yl)methoxy]-7H-purin-2-amine
• CAS: 192441-08-0
• 化学式: C₁₀H₈BrN₅OS
• 分子量: 326.176
• InChiKey: JUJPKFNFCWJBCX-UHFFFAOYSA-N

物化性质

• 沸点：
  683.8±65.0 °C(Predicted)
• 密度：
  2.07
• 溶解度：
  DMSO：可溶10mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  6

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R22
• WGK Germany：
  3
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  室温

制备方法与用途

生物活性

Lomeguatrib (PaTrin-2) 是一种有效的O6-alkylguanine-DNA-alkyltransferase抑制剂，其IC50值为5 nM。

靶点

Target	Value
O6-alkylguanine-DNA-alkyltransferase	5 nM

体外研究

Lomeguatrib能够抑制OLomeguatrib作用于MCF-7细胞，有效抑制MGMT，其IC50值为6 nM。在使用10 μM Lomeguatrib作用于MCF-7细胞时，显著增加了Temozolomide的抑制生长效果（与Lomeguatrib联用时D60为10 μM，单独使用时为400 μM）。

体内研究

在A375M人类黑色素瘤移植瘤模型中，通过每天20 mg/kg剂量处理5天后，再与Temozolomide (每天100 mg/kg，处理5天) 联用时，可显著延迟肿瘤生长。使用Lomeguatrib处理的肿瘤平均尺寸变五倍的时间增加了22天，并且未观察到细胞毒性的增加。

Lomeguatrib单独处理A375M移植瘤模型后，在2小时内使ATase完全消耗。当Temozolomide每天按100 mg/kg剂量处理时，可以显著延迟肿瘤生长（使肿瘤尺寸变五倍的时间延长为9.6天）。同时将Lomeguatrib加入到Temozolomide中使用，则可以使肿瘤尺寸变五倍的时间缩短至8.7天。此外，在与Temozolomide联用的情况下，产生的毒性较少（0/9 vs. 2/9死亡；6.84%体重丢失 vs. 9.48%）。

Lomeguatrib单独处理A375M移植瘤时，并未观察到显著的肿瘤生长抑制效果。

反应信息

• 作为反应物：
  描述：

  罗米鲁曲 在 sodium methylate 、 lithium hydride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 4-[O⁶-(4-bromothenyl)-guan-9-yl]-butyl-β-D-glucoside
  参考文献：
  名称：

  Monosaccharide-Linked Inhibitors of O⁶-Methylguanine-DNA Methyltransferase (MGMT):  Synthesis, Molecular Modeling, and Structure−Activity Relationships

  摘要：

  A series of potential inhibitors of the human DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) were synthesized, characterized in detail by NMR, and tested for their ability to deplete MGMT activity in vitro. The new compounds, omega-[O-6-R-guan-9-yl]-(CH2)(n)-beta -d-glucosides with R = benzyl or 4-bromothenyl and omega = n = 2, 4, ... 12, were compared with the established inhibitors O-6 -benzylguanine (O-6-BG), 8-aza-O-6-benzylguanine (8-aza-BG), and O-6-(4-bromothenyl)guanine (4-BTG), which exhibit in an in vitro assay IC50 values of 0.62, 0.038, and 0.009 muM, respectively. Potential advantages of the glucosides are improved water solubility and selective uptake in tumor cells. The 4-BTG glucosides with n = 2, 4, 6 show moderate inhibition with an IC50 of ca. 0.5 muM, while glucosides derived from BG and 8-aza-BG showed significantly poorer inhibition compared to the parent compounds. The 4-BTG glucosides with n = 8, 10, 12 were effective inhibitors with IC50 values of ca. 0.03 muM. To understand this behavior, extensive molecular modeling studies were performed using the published crystal structure of MGMT (PDB entry: 1QNT). The inhibitor molecules were docked into the BG binding pocket, and molecular dynamics simulations with explicit water molecules were carried out. Stabilization energies for the interactions of specific regions of the inhibitor and individual amino acid residues were calculated. The alkyl spacer is located in a cleft along helix 6 of MGMT. With increasing spacer length there is increasing interaction with several amino acid residues which play an important role in the proposed nucleotide flipping mechanism required for DNA repair.

  DOI：

  10.1021/jm010006e
• 作为产物：
  描述：

  4-溴-2-噻吩甲醛 在 sodium tetrahydroborate 、 sodium hydride 、 二甲基亚砜 作用下， 以 异丙醇 为溶剂， 反应 3.0h， 生成 罗米鲁曲
  参考文献：
  名称：

  Monosaccharide-Linked Inhibitors of O⁶-Methylguanine-DNA Methyltransferase (MGMT):  Synthesis, Molecular Modeling, and Structure−Activity Relationships

  摘要：

  A series of potential inhibitors of the human DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) were synthesized, characterized in detail by NMR, and tested for their ability to deplete MGMT activity in vitro. The new compounds, omega-[O-6-R-guan-9-yl]-(CH2)(n)-beta -d-glucosides with R = benzyl or 4-bromothenyl and omega = n = 2, 4, ... 12, were compared with the established inhibitors O-6 -benzylguanine (O-6-BG), 8-aza-O-6-benzylguanine (8-aza-BG), and O-6-(4-bromothenyl)guanine (4-BTG), which exhibit in an in vitro assay IC50 values of 0.62, 0.038, and 0.009 muM, respectively. Potential advantages of the glucosides are improved water solubility and selective uptake in tumor cells. The 4-BTG glucosides with n = 2, 4, 6 show moderate inhibition with an IC50 of ca. 0.5 muM, while glucosides derived from BG and 8-aza-BG showed significantly poorer inhibition compared to the parent compounds. The 4-BTG glucosides with n = 8, 10, 12 were effective inhibitors with IC50 values of ca. 0.03 muM. To understand this behavior, extensive molecular modeling studies were performed using the published crystal structure of MGMT (PDB entry: 1QNT). The inhibitor molecules were docked into the BG binding pocket, and molecular dynamics simulations with explicit water molecules were carried out. Stabilization energies for the interactions of specific regions of the inhibitor and individual amino acid residues were calculated. The alkyl spacer is located in a cleft along helix 6 of MGMT. With increasing spacer length there is increasing interaction with several amino acid residues which play an important role in the proposed nucleotide flipping mechanism required for DNA repair.

  DOI：

  10.1021/jm010006e

文献信息

• 一种低氧激活AGT蛋白抑制剂及其制备方法 与应用
  申请人：北京工业大学

  公开号：CN106083854B

  公开（公告）日：2017-10-27

  本发明提供了一种如通式(I)所示的具有低氧激活特性的AGT蛋白抑制剂及其制备方法与应用：R1＝R2＝H，或R1＝H，R2＝CH3，或R1＝R2＝CH3；R3＝H，NO2，NH2，OCH3，CH2OH或CO2CH3。该化合物具有良好的低氧激活特性和肿瘤细胞靶向性，能够在低氧环境下靶向性地抑制实体瘤中AGT的活性，提高肿瘤细胞对化疗药物的敏感性；本发明化合物与ACNU联合用药对多种实体瘤细胞系均有明显的抑制作用；与烷化剂类抗癌药物联合使用时，可明显提高肿瘤细胞对抗癌药物的敏感性，可用于恶性肿瘤的靶向联合化疗。
• [EN] 2-AMINO-O4-SUBSTITUTED PTERIDINES AND THEIR USE AS INACTIVATORS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE<br/>[FR] PTERIDINES A SUBSTITUTION 2-AMINO-O4-ET LEUR UTILISATION COMME INACTIVEURS DE LA O6-ALKYLGUANINE-ADN ALKYLTRANSFERASE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2005068465A1

  公开（公告）日：2005-07-28

  Disclosed are pteridine derivatives of formula (I): (I), wherein, for example, R1 and R2 are hydrogen, C1-C6 alkyl, carboxyl, formyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, C1-C6 formyl alkyl, C1-C6 alkoxy, acyloxy, acyloxyalkyl wherein the alkyl is C1-C6, halogen, or hydroxy, or a group of formula II: (II); and R3 is (a) phenyl or (b) a cyclic group having at least one 5 or 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, wherein each heterocyclic ring has at least one hetero atom chosen from O, N, or S; or (c) a phenyl group or a cyclic group, the cyclic group optionally with a carbocyclic or heterocyclic ring fused thereto, which is substituted with 1 to 5 substituents. Disclosed also are pharmaceutical compositions, a method of enhancing the chemotherapeutic effectiveness of cancer treatment agents, a method of deactivating the O6-alkylguanine-DNA alkyltransferase enzyme, and a method of inhibiting the reaction of O6-alkylguanine-DNA alkyltransferase enzyme with an alkylated DNA.

  本发明涉及式(I)的黄嘌呤衍生物：(I)，其中，例如，R1和R2是氢、C1-C6烷基、羧基、甲酰基、C1-C6羟基烷基、C1-C6羧基烷基、C1-C6甲酰基烷基、C1-C6烷氧基、酰氧基、酰氧基烷基，其中烷基为C1-C6，卤素或羟基，或式II的基团：(II)；以及R3是(a)苯基或(b)至少具有一个5或6元杂环环的环状基团，可选地与碳环或杂环环融合在一起，其中每个杂环环至少有一个从O、N或S中选择的杂原子；或(c)苯基或环状基团，环状基团可选地与碳环或杂环环融合在一起，其被1到5个取代基取代。本发明还涉及制药组合物、增强癌症治疗药物的化疗效果的方法、失活O6-烷基鸟嘌呤-DNA烷基转移酶酶的方法以及抑制O6-烷基鸟嘌呤-DNA烷基转移酶与烷基化DNA反应的方法。
• [EN] O<6>-SUBSTITUTED GUANINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND THEIR USE IN TREATING TUMOUR CELLS<br/>[FR] DERIVES DE GUANINE SUBSTITUEE EN POSITION O<6>, LEUR PROCEDE DE PREPARATION ET LEUR APPLICATION AU TRAITEMENT DES CELLULES TUMORALES
  申请人：CANCER RESEARCH CAMPAIGN TECHNOLOGY LIMITED

  公开号：WO1994029312A1

  公开（公告）日：1994-12-22

  (EN) O^_6-hetarylalkyl- or naphthylalkylguanine derivatives of formula (I) wherein Y is H, ribosyl, deoxyribosyl, or R'XCHR'', wherein X is O or S, R'' and R''' are alkyl, or substituted derivatives thereof; R' is H, or alkyl or hydroxyalkyl; R is (i) a cyclic group having at least one 5- or 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, the or each heterocyclic ring having at least one hereto atom chosen from O, N or S, or a substituted derivative thereof; or (ii) naphthyl or a substituted derivative thereof; and pharmaceutically acceptable salts thereof, exhibit the ability to deplete O^_6-alkylguanine-DNA alkyltransferase (ATase) activity. A process for preparation of the compounds is described. The compounds have utility in combination with alkylating agents in the chemotherapeutic treatment of tumour cells.(FR) Dérivés de naphtylalkylguanine ou hétarylalkylguanine substituée en position O^_6, répondant à la formule (I), dans laquelle Y représente H, ribosyle, désoxyribosyle ou R'XCHR'', où X représente O ou S, R' et R'' représentent alkyle, ou leurs dérivés substitués; R' représente H, alkyle ou hydroxyalkyle; R représente (i) un groupe cyclique possédant au moins un hétérocycle pentagonal ou hexagonal éventuellement condensé avec un carbocycle ou hétérocycle, le ou chaque hétérocycle possédant au moins un hétéroatome choisi parmi O, N et S, ou son dérivé substitué; ou (ii) naphtyle ou son dérivé substitué; et leurs sels pharmaceutiquement acceptables; pouvant diminuer l'activité de l'O^_6-alkylguanine-ADN alkyltransférase (Atase). On décrit un procédé de préparation de ces composés. Lesdits composés sont utilisables en association avec des agents d'alkylation dans le traitement chimiothérapeutique des cellules tumorales.

  化合物公式（I）中，O^_6-萜基烷基或萘基烷基鸟嘌呤衍生物，其中Y为H，核糖基，脱氧核糖基或R'XCHR''，其中X为O或S，R''和R'''为烷基或其取代衍生物；R'为H，烷基或羟基烷基；R为（i）至少具有一个5-或6-成员杂环环的环状基团，可选地与碳环或杂环融合，或其取代衍生物，其中每个杂环环至少具有一个来自O，N或S的杂原子；或（ii）萘基或其取代衍生物；及其药学上可接受的盐，具有降低O^_6-烷基鸟嘌呤-DNA烷基转移酶（ATase）活性的能力。描述了制备该化合物的过程。该化合物在联合烷基化剂治疗肿瘤细胞方面具有实用价值。
• [EN] PYRIMIDINE DERIVATIVES AND GUANINE DERIVATIVES, AND THEIR USE IN TREATING TUMOUR CELLS<br/>[FR] DERIVES DE LA PYRIMIDINE ET DERIVES DE LA GUANINE, ET LEUR UTILISATION POUR TRAITER DES CELLULES TUMORALES
  申请人：CANCER RESEARCH CAMPAIGN TECHNOLOGY LIMITED

  公开号：WO1997020843A1

  公开（公告）日：1997-06-12

  (EN) The invention provides compounds exhibiting the ability to deplete O6-alkylguanine-DNA alkyltransferase (ATase) activity in tumour cells. The compounds include certain pyrimidine derivatives of formula (II), wherein R is (i) a cyclic group having at least one 5- or 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, the or each heterocyclic ring having at least one hetero atom chosen from O, N, or S, or a substituted derivative thereof; or (ii) phenyl or a substituted derivative thereof, R2 is selected from H, C1-C5 alkyl, halogen or NH2, R4 and R5 which are the same or different are selected from H, NH-Y' or NOn wherein Y' is H, ribosyl, deoxyribosyl, arabinosyl, (a) wherein X is O or S, R' is alkyl and R''' is H or alkyl, or substituted derivatives thereof, n = 1 or 2 or R4 and R5 together with the pyrimidine ring form a 5-or 6-membered ring structure containing one or more hetero atoms, and pharmaceutically acceptable salts thereof. They include certain guanine derivatives of formula (XIII), wherein R6 is as defined at (i) for R above and Y' is as defined above.(FR) L'invention concerne des composés capables de neutraliser l'activité de la O6-alkylguanine-ADN transférase (ATase) dans les cellules tumorales. Parmi ces composés, il y a certains dérivés de la pyrimidine ayant la formule (II). Dans cette formule, R est (i) un groupe cyclique ayant au moins un noyau hétérocyclique à 5 ou 6 éléments, éventuellement fusioné avec un cycle carboxylique ou hétérocyclique, le ou chaque noyau hétérocyclique ayant au moins un hétéroatome choisi parmi O, N ou S ou un dérivé substitué; ou (ii) phényle ou un dérivé substitué de celui-ci, R2 est choisi parmi H, C1-C5 alkyle, halogène ou NH2, R4 et R5 qui sont les mêmes ou différents sont choisis parmi H, NH-Y' ou NOn, où Y' est H, ribosyle, désoxyribosyle, arabinosyle, un radical de la formule (a), dans laquelle X est O ou S, R'' est un alkyle et R''' est H ou alkyle ou un alkyle substitué, n = 1 ou 2 ou R4 et R5 forment avec le cycle de la pyridine une structure à 5 ou 6 éléments contenant un ou plusieurs hétéroatomes. L'invention concerne également les sels de ces composés acceptables sur le plan pharmaceutique. L'invention concerne en outre les dérivés de la guanadine de la formule XIII, où R6 est défini comme R en (i) et Y' est comme défini ci-dessus.

  本发明提供了一种能够降低肿瘤细胞中O6-烷基鸟嘌呤-DNA烷基转移酶(ATase)活性的化合物。这些化合物包括以下公式(II)中的某些嘧啶衍生物，其中R是(i)至少具有一个5-或6-成员杂环环的环状基团，可选地与碳环或杂环融合，或其取代衍生物，该杂环中的每个杂环至少有一个从O、N或S中选择的杂原子；或(ii)苯基或其取代衍生物，R2选择自H、C1-C5烷基、卤素或NH2，R4和R5相同或不同，选择自H、NH-Y'或NOn，其中Y'是H、核糖基、去氧核糖基、阿拉伯糖基、(a)式中的基团，其中X是O或S，R'是烷基，R'''是H或烷基，或其取代衍生物，n=1或2，或R4和R5与嘧啶环一起形成一个含有一个或多个杂原子的5-或6-成员环结构，以及其在药学上可接受的盐。它们包括以下公式(XIII)中的某些鸟嘌呤衍生物，其中R6如上所述的R(i)，Y'如上所述。
• PHARMACEUTICAL COMPOSITION COMPRISING AZATHIOPRINE AS ACTIVE INGREDIENT FOR PREVENTING OR TREATING BRAIN TUMORS OR TEMODAL-RESISTANT GLIOBLASTOMAS
  申请人：Korea Research Institute of Chemical Technology

  公开号：EP2873419A1

  公开（公告）日：2015-05-20

  The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer or Temodal resistant glioblastoma multiform comprising azathioprine as an active ingredient. The azathioprine of the present invention is not only effective in inhibiting the growth of glioblastoma multiform, a kind of brain tumor, but also excellent in treating glioblastoma multiform that displays resistance against Temodal (temozolomide), the conventional therapeutic agent for glioblastoma multiform, so that it can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of such cancer as brain tumor (particularly, glioblastoma multiform) and particularly Temodal resistant glioblastoma multiform.

  本发明涉及一种用于预防或治疗癌症或 Temodal 抗药性多形性胶质母细胞瘤的药物组合物，其活性成分包括硫唑嘌呤。本发明的硫唑嘌呤不仅能有效抑制多形性胶质母细胞瘤（一种脑肿瘤）的生长，还能很好地治疗对多形胶质母细胞瘤的传统治疗药物替莫唑胺（Temozolomide）产生耐药性的多形胶质母细胞瘤，因此可以有效地用作预防或治疗脑肿瘤（特别是多形胶质母细胞瘤）等癌症，尤其是对替莫唑胺产生耐药性的多形胶质母细胞瘤的药物组合物的活性成分。