73818-29-8Relevant academic research and scientific papers
Discovery and preliminary mechanism of 1-carbamoyl β-carbolines as new antifungal candidates
Sheng, Tao,Kong, Mengmeng,Wang, Yujie,Wu, HuiJun,Gu, Qin,Chuang, Anita Shyying,Li, Shengkun,Gao, Xuewen
, (2021/06/21)
Natural β-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted β-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant in vitro antifungal activity against G. graminis. Significantly, compound 4m (EC50 = 0.45 μM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement in antifungal potential compared to Silthiopham (EC50 = 8.95 μM). Moreover, compounds 6, 7, and 4i exhibited excellent in vitro antifungal activities and in vivo protective and curative activities against B. cinerea and F. graminearum. Preliminary mechanism studies revealed that compound 4m caused reactive oxygen species accumulation, cell membrane destruction, and deregulation of histone acetylation. These findings indicated that 1-carbamoyl β-carboline can be selected as a promising model for the discovery of novel and broad-spectrum fungicide candidates.
The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides
Petchey, Mark,Cuetos, Anibal,Rowlinson, Benjamin,Dannevald, Stephanie,Frese, Amina,Sutton, Peter W.,Lovelock, Sarah,Lloyd, Richard C.,Fairlamb, Ian J. S.,Grogan, Gideon
supporting information, p. 11584 - 11588 (2018/09/10)
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 pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical-type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.
Direct Synthesis of Structurally Divergent Indole Alkaloids from Simple Chemicals
Shen, Tao,Zhu, Bencong,Lin, Fengguirong,Pan, Jun,Wei, Jialiang,Luo, Xiao,Liu, Jianzhong,Jiao, Ning
, p. 815 - 818 (2018/07/31)
A direct and structurally divergent synthesis of indole alkaloids from very simple 2-vinylanilines, alkynes and TBN via a novel substrate fragmentation/cycloaddition strategy has been developed, which provides an efficient noble-metal-free approach to access a library of highly valuable indole derivatives of tryptamines and tryptamine-related oximes, lactams, and lactones, as well as β-carbolines, spiroindolines, and hexa-hydropyrrolo[2,3-b]indoles.
Structural Basis for β-Carboline Alkaloid Production by the Microbial Homodimeric Enzyme McbB
Mori, Takahiro,Hoshino, Shotaro,Sahashi, Shusaku,Wakimoto, Toshiyuki,Matsui, Takashi,Morita, Hiroyuki,Abe, Ikuro
, p. 898 - 906 (2015/08/03)
Summary The β-carboline (βC) alkaloids occur throughout nature and exhibit diverse biological activities. In contrast to βC 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 βC scaffold of marinacarbolines. In this study, we solved the crystal structure of McbB complexed with L-tryptophan at 2.48 ? 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-β-carboline.
An efficient synthesis method targeted to marine alkaloids marinacarbolines A-D and their antitumor activities
Li, Jun,Tang, Yang,Jin, Hui-Juan,Cui, Yi-Di,Zhang, Li-Juan,Jiang, Tao
, p. 299 - 305 (2015/09/02)
Marinacarbolines A-D are a series of marine β-carboline alkaloids isolated from actinomycete Marinactinospora thermotolerans of the deep South China Sea with antiplasmodial activities. In inhibition assays of in vitro growth of Plasmodium falciparum, marinacarbolines exhibited antiplasmodial activity against drug-sensitive line 3D7 and drug-resistant line Dd2 of P. falciparum. However, approaches for the synthesis of such useful compounds are very limited. In this work, we reported a simple, efficient, and versatile process to synthesize marinacarbolines A-D (1-4). On the basis of that, the antitumor activities of marinacarbolines in a structure-dependent manner were allowed to be unveiled.
First total syntheses of 1,3-disubstituted β-carboline alkaloids, dichotomide I and marinacarbolines A-D
Tagawa, Shinji,Choshi, Tominari,Okamoto, Asuka,Nishiyama, Takashi,Watanabe, Shiroh,Hatae, Noriyuki,Hibino, Satoshi
, p. 357 - 367 (2013/03/14)
The first total syntheses of dichotomide I (1), and marinacarbolines A-D (3-6) were achieved in four steps from methyl 1-chloro-β-carboline-3- carboxlyate (9), which was previously used as a synthetic intermediate of dichotomine C. The required compound 9 was prepared in a six-step sequence including a microwave-assisted thermal electrocyclic reaction of a 1-azahexatriene system.
Discovery of McbB, an enzyme catalyzing the β-carboline skeleton construction in the marinacarboline biosynthetic pathway
Chen, Qi,Ji, Changtao,Song, Yongxiang,Huang, Hongbo,Ma, Junying,Tian, Xinpeng,Ju, Jianhua
, p. 9980 - 9984 (2013/10/01)
Three genes, mcbABC, that drive the biosynthesis of marinacarbolines, have been elucidated through genome mining, gene inactivation, heterologous expression, feeding, and site-directed mutagenesis experiments. McbB is highlighted as a novel enzyme for the β-carboline core construction, which involves a Pictet-Spengler cyclization process and requiring E97 for biochemical activity.
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
Yang, Mei-Lin,Kuo, Ping-Chung,Hwang, Tsong-Long,Chiou, Wen-Fei,Qian, Keduo,Lai, Chin-Yu,Lee, Kuo-Hsiung,Wu, Tian-Shung
experimental part, p. 1674 - 1682 (2011/04/16)
In the present study, various 1-substituted and 1,3-disubstituted β-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
The role of methylglyoxal in the non-enzymatic conversion of tryptophan, its methyl ester and tryptamine to 1-acetyl-β-carbolines
Nemet, Ina,Varga-Defterdarovic, Lidija
, p. 4551 - 4562 (2008/12/20)
Non-enzymatic modification of l-tryptophan (1) and its metabolites and derivatives with aldehydes, via the Pictet-Spengler reaction, affords β-carbolines. Here we demonstrate that methylglyoxal (2) generates 1-acetyl-β-carbolines from tryptophan (1), from its methyl ester (6) and from tryptamine (4); however, 2 did not generate 1-(1-hydroxyethyl)-β-carboline derivates. HPLC analysis of model reaction systems showed formation of 1-acetyl-β-carboline (3) and 1-acetyl-β-carboline-3-carboxylic acid (5) during incubation of 1 and 2, at pH 5.7 and 7.4, at 100 °C, and only 5 at 37 °C, at the same pH values, with limited access of oxygen. Aerobic conditions caused higher formation of 3 at 37 °C at both pH values, while, at higher temperature, the same effect was only observed at pH 5.7. Lack of oxygen did not much influence the formation of 3 or 5 at both pH and temperature values, in comparison with the formation at limited access of oxygen. Incubation of 2 and 6 generated methyl-1-acetyl-β-carboline-3-carboxylate (7) together with 3 and 5 as a result of hydrolysis of 6 into 1 and, partially, 7 into 5, while in incubation mixtures of 2 and 4 only unstable 1-acetyl-3,4-dihydro-β-carboline (8) was observed. Incubation of 1 with d-glucose as well as incubation of tryptophan with Amadori product 18 under similar conditions did not generate carbolines 3 or 5. For the first time, we were able to demonstrate the presence of 1-acetyl-β-carboline-3-carboxylic acid (5) in some commercially available ketchups and in previously heated tomato concentrate.
A versatile route to the synthesis of 1-substituted β-carbolines by a single step Pictet-Spengler cyclization
Yang, Mei-Lin,Kuo, Ping-Chung,Damu, Amooru G.,Chang, Ren-Jie,Chiou, Wen-Fei,Wu, Tian-Shung
, p. 10900 - 10906 (2007/10/03)
A one-step conversion of l-tryptophan and activated aldehydes (1,2-dicarbonyl compounds) directly to 1-substituted β-carbolines without formation of the tetrahydro derivatives under modified Pictet-Spengler conditions was described. Moreover, a practical
