8-methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]-chromene-5,6-dione | 305836-33-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并吡喃类
• 英文名称: 8-methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]-chromene-5,6-dione
• 英文别名: 3,4-dihydro-8-methoxy-2,2-dimethyl-2H-benzo[h]chromene-5,6-dione；8-methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione；8-methoxy-β-lapachone；8-Methoxy-beta-lapachone；8-methoxy-2,2-dimethyl-3,4-dihydrobenzo[h]chromene-5,6-dione
• CAS: 305836-33-3
• 化学式: C₁₆H₁₆O₄
• 分子量: 272.301
• InChiKey: OFUVMXZHDYXMJK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]-chromene-5,6-dione 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以53%的产率得到3,4-dihydro-8-hydroxy-2,2-dimethyl-2H-benzo[h]chromene-5,6-dione
  参考文献：
  名称：

  β-Lapachone analogs with enhanced antiproliferative activity

  摘要：

  In this study, we describe the synthesis of a series of alpha- and beta-lapachone containing hydroxyl or methoxyl groups on the benzene ring, by means of the selective acid promoted cyclization of the appropriate lapachol analog. The evaluation of the antiproliferative activity in human solid tumor cell lines provided 7-hydroxy-beta-lapachone as lead with enhanced activity over the parent drug beta-lapachone. Cell cycle studies, protein expression experiments, and reactive oxygen species analysis revealed that, similarly to beta-lapachone, ROS formation and DNA damage are critical factors in the cellular toxicity of 7-hydroxy-beta-lapachone. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.04.008
• 作为产物：
  描述：

  7-甲氧基-1-萘满酮 在 iron(III) chloride 、 potassium tert-butylate 、 氧气 、 lithium hydride 作用下， 以 二氯甲烷 、 二甲基亚砜 、 叔丁醇 为溶剂， 反应 17.5h， 生成 8-methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]-chromene-5,6-dione
  参考文献：
  名称：

  Identification of β-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma

  摘要：

  The treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the urgent unmet medical needs because it is the most resistant DLBCL subtype to current therapies eagerly awaiting effective therapeutic strategies. Recently, the paracaspase MALT1 has emerged as a promising therapeutic target for the treatment of ABC-DLBCL. Herein, we report a new class of MALT1 inhibitors developed by high-throughput screening and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone series inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search led to the discovery of structurally similar beta-lapachone that is a direct inhibitor of MALT1 and possesses favorable physicochemical properties. Molecular simulation studies suggested the possibility of the formation of a covalent bond between MALT1 and, beta-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure activity relationships by incorporating electron-withdrawing substituents at C8 position of beta-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1.

  DOI：

  10.1021/acs.jmedchem.5b01415
• 作为试剂：
  描述：

  硫酸 、 7-methoxylapachol 在 8-methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]-chromene-5,6-dione 、 水 作用下， 以 ice water 为溶剂， 反应 0.33h， 以It was obtained as a red powder (2.36 g, 96%)的产率得到8-methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]-chromene-5,6-dione
  参考文献：
  名称：

  Quinones as disease therapies

  摘要：

  本发明提供了新型的醌类物质，以及包含这些新型醌类物质的组合物。还提供了使用这些新型醌类物质治疗各种疾病，包括癌症的方法。

  公开号：

  US06482943B1

文献信息

• Synthesis, Characterization, and Antileukemic Properties of Naphthoquinone Derivatives of Lawsone
  作者：Ryuta Inagaki、Masayuki Ninomiya、Kaori Tanaka、Mamoru Koketsu

  DOI：10.1002/cmdc.201500189

  日期：2015.8

  Naphthoquinones are considered privileged structures for anticancer drug molecules. The Heck reaction of 2‐hydroxy‐1,4‐naphthoquinone (lawsone) with 1‐bromo‐3‐methyl‐2‐butene offered easy access to lapachol. Several naturally occurring linear and angular heterocyclic quinoids (α‐lapachone, β‐lapachone, dunnione, and related analogues) were prepared from lapachol. Furthermore, we demonstrated that the

  萘醌被认为是抗癌药物分子的特殊结构。2-羟基-1,4-萘醌（劳松）与 1-溴-3-甲基-2-丁烯的赫克反应提供了容易获得拉帕酚的途径。几种天然存在的线性和角杂环醌类化合物（α-lapachone、β-lapachone、dunnione 和相关类似物）由拉帕酚制备。此外，我们证明合成萘醌可抑制人白血病 HL-60 细胞的细胞增殖。特别是，角型衍生物被发现具有中等的细胞毒性并提高细胞内谷胱甘肽二硫化物（GSSG）的水平。我们的工作突出了天然存在的角系列萘醌作为抗白血病药物的巨大潜力。
• Synthetic methods for the preparation of ARQ 501 (β-Lapachone) human blood metabolites
  作者：Rui-Yang Yang、Darin Kizer、Hui Wu、Erika Volckova、Xiu-Sheng Miao、Syed M. Ali、Manish Tandon、Ronald E. Savage、Thomas C.K. Chan、Mark A. Ashwell

  DOI：10.1016/j.bmc.2008.03.073

  日期：2008.5

  ARQ 501 (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione), a synthetic version of beta-Lapachone, is a promising anti-cancer agent currently in multiple Phase II clinical trials. Promising anti-cancer activity was observed in Phase I and Phase II trials. Metabolism by red blood cells of drugs is an understudied area of research and the metabolites arising from oxidative ring opening (M2 and M3), decarbonylation/ ring contraction (M5), and decarbonylation/ oxidation (M4 and M6) of ARQ 501 offer a unique opportunity to provide insight into these metabolic processes. Since these metabolites were not detected in in vitro incubations of ARQ 501 with liver microsomes and were structurally diverse, confirmation by chemical synthesis was considered essential. In this report, we disclose the synthetic routes employed and the characterization of the reference standards for these blood metabolites as well as additional postulated structures, which were not confirmed as metabolites. (C) 2008 Elsevier Ltd. All rights reserved.
• US7253207B2
  申请人：——

  公开号：US7253207B2

  公开（公告）日：2007-08-07
• β-Lapachone analogs with enhanced antiproliferative activity
  作者：Carla Ríos-Luci、Evelyn L. Bonifazi、Leticia G. León、Juan C. Montero、Gerardo Burton、Atanasio Pandiella、Rosana I. Misico、José M. Padrón

  DOI：10.1016/j.ejmech.2012.04.008

  日期：2012.7

  In this study, we describe the synthesis of a series of alpha- and beta-lapachone containing hydroxyl or methoxyl groups on the benzene ring, by means of the selective acid promoted cyclization of the appropriate lapachol analog. The evaluation of the antiproliferative activity in human solid tumor cell lines provided 7-hydroxy-beta-lapachone as lead with enhanced activity over the parent drug beta-lapachone. Cell cycle studies, protein expression experiments, and reactive oxygen species analysis revealed that, similarly to beta-lapachone, ROS formation and DNA damage are critical factors in the cellular toxicity of 7-hydroxy-beta-lapachone. (C) 2012 Elsevier Masson SAS. All rights reserved.
• Identification of β-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma
  作者：Sang Min Lim、Yujeong Jeong、Suhyun Lee、Honggu Im、Hyun Seop Tae、Byung Gyu Kim、Hee Dong Park、Jonghoon Park、Sungwoo Hong

  DOI：10.1021/acs.jmedchem.5b01415

  日期：2015.11.12

  The treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the urgent unmet medical needs because it is the most resistant DLBCL subtype to current therapies eagerly awaiting effective therapeutic strategies. Recently, the paracaspase MALT1 has emerged as a promising therapeutic target for the treatment of ABC-DLBCL. Herein, we report a new class of MALT1 inhibitors developed by high-throughput screening and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone series inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search led to the discovery of structurally similar beta-lapachone that is a direct inhibitor of MALT1 and possesses favorable physicochemical properties. Molecular simulation studies suggested the possibility of the formation of a covalent bond between MALT1 and, beta-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure activity relationships by incorporating electron-withdrawing substituents at C8 position of beta-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1.