1-benzoyl-9H-β-carboline-3-carboxylic acid

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 1-benzoyl-9H-β-carboline-3-carboxylic acid
• 英文别名: 1-benzoyl-3-carboxy-β-carboline；1-benzoyl-9H-pyrido[3,4-b]indole-3-carboxylic acid
• 化学式: C₁₉H₁₂N₂O₃
• 分子量: 316.316
• InChiKey: NAILBXPDNRIENT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  83
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-benzoyl-9H-β-carboline-3-carboxylic acid 、 1-甲基-3-苯基丙胺 在 inorganic phosphatase 、 amide bond synthetase from Streptoalloteichus hindustanus 、 5’-三磷酸腺苷 作用下， 以 aq. buffer 为溶剂， 以18%的产率得到
  参考文献：
  名称：

  来自 Streptoalloteichus hindustanus 的广谱对映选择性酰胺键合成酶

  摘要：

  酰胺键的合成是药物合成中最常进行的反应之一，但在既定方法中对偶联剂和活化底物的化学计量量的要求引发了对生物催化替代品的兴趣。酰胺键合成酶 （ABS） 在酶的活性位点内主动催化羧酸底物的 ATP 依赖性腺苷酸化及其随后使用胺亲核试剂的酰胺化，从而能够仅使用少量过量的胺伴侣。我们已经评估了来自 Streptoalloteichus hindustanus （ShABS） 的 ABS 偶联一系列羧酸底物和胺以形成胺类产品的能力。ShABS 显示出优于先前研究的 ABS 、 McbA 的活性，以及显着的互补底物特异性，包括从外消旋酸和胺偶联伴侣形成酰胺库的对映选择性形成。ShABS 的 X 射线晶体结构允许羧酸和胺结合位点的突变映射，揭示了 L207 和 F246 在确定酶相对于手性酸和胺底物的对映选择性中的关键作用。ShABS 应用于药物酰胺的合成，包括伊利吡酰亚胺、拉扎贝胺、甲氧苯甲酰胺和桂哌齐特，后者转化率为

  DOI：

  10.1021/acscatal.3c05656
• 作为产物：
  描述：

  甲基色氨酸 在 碘 、 sodium hydroxide 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 反应 1.0h， 生成 1-benzoyl-9H-β-carboline-3-carboxylic acid
  参考文献：
  名称：

  酰胺键合成酶McbA的宽芳酸特异性表明酰胺的生物催化合成潜力

  摘要：

  酰胺键的形成是药物合成化学中最重要的反应之一。因此，引起酰胺键形成的可持续方法的发展，包括被酶催化的那些方法，引起了人们的极大兴趣。ATP依赖的酰胺键合成酶（ABS）酶McbA，来自Marinoctinospora thermotolerans，催化酰胺的形成，这是通向玛丽娜咔啉次生代谢物的生物合成途径的一部分。反应通过腺苷酸中间体进行，在一个活性位点内催化了腺苷酸化和酰胺化步骤。在这项研究中，McbA被用于由一系列芳基羧酸与伴侣胺以1-5摩尔当量提供的合成药物型酰胺。McbA的结构揭示了芳酸底物耐受性的结构决定因素以及与催化的两个半反应相关的构象差异。McbA的催化性能以及其结构表明，该酶和其他ABS酶可能经过工程改造，可用于药物相关（手性）酰胺的可持续合成。

  DOI：

  10.1002/anie.201804592

文献信息

• Design, Synthesis, and Biological Activity of Marinacarboline Analogues as STAT3 Pathway Inhibitors for Docetaxel-Resistant Triple-Negative Breast Cancer
  作者：Woong Sub Byun、Hyewon Lim、Junhwa Hong、Eun Seo Bae、Seok Beom Lee、Younggwan Kim、Jeeyeon Lee、Sang Kook Lee、Suckchang Hong

  DOI：10.1021/acs.jmedchem.2c01115

  日期：2023.2.23

  triple-negative breast cancer (mTNBC) is a fatal type of breast cancer (BC), and signal transducer and activator of transcription 3 (STAT3) has emerged as an effective target for mTNBC. In the present study, compound MC0704 was found to be a novel synthetic STAT3 pathway inhibitor, and its potential antitumor activity was demonstrated using in vitro and in vivo models in docetaxel-resistant TNBC cells. Based

  转移性三阴性乳腺癌 (mTNBC) 是一种致命类型的乳腺癌 (BC)，信号转导和转录激活因子 3 (STAT3) 已成为 mTNBC 的有效靶点。在本研究中，化合物MC0704被发现是一种新型合成 STAT3 通路抑制剂，其潜在的抗肿瘤活性在多西紫杉醇耐药的 TNBC 细胞中使用体外和体内模型得到证实。基于 marinacarboline (MC)，合成了一系列 β-咔啉衍生物，并研究了它们对多西紫杉醇耐药 MDA-MB-231 (MDA-MB-231-DTR) 细胞的抗肿瘤活性。结合抗增殖和 STAT3 抑制活性，MC0704被选为最有前途的 β-咔啉化合物。MC0704在体外有效地阻止了 MDA-MB-231-DTR 细胞的转移潜能，并且MC0704和多西他赛的组合在异种移植小鼠模型中表现出有效的抗肿瘤活性。这些发现表明，MC0704可以作为具有多西紫杉醇耐药性的 TNBC 患者的靶向治疗药物的主要候选药物。
• A versatile route to the synthesis of 1-substituted β-carbolines by a single step Pictet–Spengler cyclization
  作者：Mei-Lin Yang、Ping-Chung Kuo、Amooru G. Damu、Ren-Jie Chang、Wen-Fei Chiou、Tian-Shung Wu

  DOI：10.1016/j.tet.2006.08.081

  日期：2006.11

  A one-step conversion of L-tryptophan and activated aldehydes (1,2-dicarbonyl compounds) directly to 1-substituted beta-carbolines without formation of the tetrahydro derivatives under modified Pictet-Spengler conditions was described. Moreover, a practical application for the synthesis of a natural 1-substituted beta-carboline, luzongerine A, isolated from Illigera luzonensis was also successfully carried out utilizing this protocol. The effects of synthetic compounds 11 and 11a on nitric oxide (NO) production in LPS/IFN-gamma stimulated RAW 264.7 macrophage cells were evaluated in vitro. They displayed significant dose-dependent inhibition of inducible nitric oxide synthase (iNOS). (c) 2006 Elsevier Ltd. All rights reserved.
• Synthesis, in vitro anti-inflammatory and cytotoxic evaluation, and mechanism of action studies of 1-benzoyl-β-carboline and 1-benzoyl-3-carboxy-β-carboline derivatives
  作者：Mei-Lin Yang、Ping-Chung Kuo、Tsong-Long Hwang、Wen-Fei Chiou、Keduo Qian、Chin-Yu Lai、Kuo-Hsiung Lee、Tian-Shung Wu

  DOI：10.1016/j.bmc.2011.01.034

  日期：2011.3

  In the present study, various 1-substituted and 1,3-disubstituted beta-carboline derivatives were synthesized by a modified single-step Pictet-Spengler reaction. The compounds were examined for cytotoxicity and anti-inflammatory activity, as measured by the inhibition of prostaglandin E-2 (PGE(2)) production and nitric oxide (NO) production. While only two compounds (28 and 31) showed marginal cytotoxicity against four human cancer cell lines, most of the tested compounds exhibited potent inhibitory activity of both NO and PGE(2) production. Moreover, compounds 6 and 16 significantly reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2), suggesting that beta-carboline analogs can inhibit NO and PGE(2) production at the translational level. In addition, several of the beta-carboline derivatives (1, 2, 48, 11, 13, 22, 25, 27, 31, and 41-43) displayed significant inhibitory activity of superoxide anion (O-2(center dot-)) generation or elastase release compared to the reference compound, with 6 being the most potent. N-Formyl-L-methionyl-phenylalanine (FMLP)-induced phosphorylation of c-Jun N-terminal kinase (JNK) and protein kinase B (AKT) were also inhibited by 6, suggesting that it suppresses human neutrophil functions by inhibiting the activation of JNK and AKT signaling pathways. Therefore, the synthetic 1-benzoyl-3-carboxy beta-carboline analogs may have great potential to be developed as anti-inflammatory agents. (C) 2011 Elsevier Ltd. All rights reserved.
• Structural Basis for β-Carboline Alkaloid Production by the Microbial Homodimeric Enzyme McbB
  作者：Takahiro Mori、Shotaro Hoshino、Shusaku Sahashi、Toshiyuki Wakimoto、Takashi Matsui、Hiroyuki Morita、Ikuro Abe

  DOI：10.1016/j.chembiol.2015.06.006

  日期：2015.7

  The beta-carboline (beta C) alkaloids occur throughout nature and exhibit diverse biological activities. In contrast to beta C alkaloid synthesis in plants, the biosynthesis in microorganisms remains poorly understood. The recently reported McbB from Marinactinospora thermotolerans is a novel enzyme proposed to catalyze the Pictet-Spengler (PS) reaction of L-tryptophan and oxaloacetaldehyde to produce the beta C scaffold of marinacarbolines. In this study, we solved the crystal structure of McbB complexed with L-tryptophan at 2.48 angstrom resolution, which revealed the novel protein folding of McbB and the totally different structure from those of other PS condensation catalyzing enzymes, such as strictosidine synthase and norcoclaurine synthase from plants. Structural analysis and site-directed mutagenesis confirmed that the previously proposed catalytic Glu97 at the active-site center functions as an acid and base catalyst. Remarkably, the structure-based mutants R72A and H87A, with expanded active-site cavities, newly accepted bulky phenylglyoxal as the aldehyde substrate, to produce 1-benzoyl-3-carboxy-beta-carboline.
• The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides
  作者：Mark Petchey、Anibal Cuetos、Benjamin Rowlinson、Stephanie Dannevald、Amina Frese、Peter W. Sutton、Sarah Lovelock、Richard C. Lloyd、Ian J. S. Fairlamb、Gideon Grogan

  DOI：10.1002/anie.201804592

  日期：2018.9.3

  Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic

  酰胺键的形成是药物合成化学中最重要的反应之一。因此，引起酰胺键形成的可持续方法的发展，包括被酶催化的那些方法，引起了人们的极大兴趣。ATP依赖的酰胺键合成酶（ABS）酶McbA，来自Marinoctinospora thermotolerans，催化酰胺的形成，这是通向玛丽娜咔啉次生代谢物的生物合成途径的一部分。反应通过腺苷酸中间体进行，在一个活性位点内催化了腺苷酸化和酰胺化步骤。在这项研究中，McbA被用于由一系列芳基羧酸与伴侣胺以1-5摩尔当量提供的合成药物型酰胺。McbA的结构揭示了芳酸底物耐受性的结构决定因素以及与催化的两个半反应相关的构象差异。McbA的催化性能以及其结构表明，该酶和其他ABS酶可能经过工程改造，可用于药物相关（手性）酰胺的可持续合成。