- Production process of evodiamine and method for recycling solvent in production
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The invention relates to the field of organic synthesis, in particular to a production process of evodiamine and a method for recycling a solvent in production. According to the method, tryptamine isadopted as a raw material, evodiamine is obtained through formylation, cyclization and condensation ring closing, phosgene and ethyl chloroformate are prevented from being used in the whole process, the safety risk in the production process is reduced, and the reaction steps are greatly simplified. Meanwhile, a solvent application process in production is realized, so that the production cost is greatly reduced, and the method has an industrial popularization value.
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- Design, synthesis and bioactivity study of evodiamine derivatives as multifunctional agents for the treatment of hepatocellular carcinoma
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Topoisomerase has been found extremely high level of expression in hepatocellular carcinoma (HCC) and proven to promote the proliferation and survival of HCC. Cancer-associated fibroblasts (CAFs) as a kind of key reactive stromal cell that abundantly present in the microenvironment of HCC, could enhance the metastatic ability and drug resistance of HCC. Therefore, developing new drugs that address the above conundrums would be of the upmost significant in the fight against HCC. Evodiamine, as a multi-target natural product, has been found to exert various biological activities such as anti-cancer and anti-hepatic fibrosis via blocking topoisomerase, NF-κB, TGF-β/HGF, and Smad2/3. Inspired by these facts, 15 evodiamine derivatives were designed and synthesized for HCC treatment by simultaneously targeting Topo I and CAFs. Most of them displayed preferable anti-HCC activities on three HCC cell lines and low cytotoxicity on one normal hepatic cell. In particular, compound 8 showed the best inhibitory effect on HCC cell lines and a good inhibition on Topo I in vitro. Meanwhile, it also induced obvious G2/M arrest and apoptosis, and significantly decreased the migration and invasion capacity of HCC cells. In addition, compound 8 down-regulated the expression of type I collagen in the activated HSC-T6 cells, and induced the apoptosis of activated HSC-T6 cells. In vivo studies demonstrated that compound 8 markedly decreased the volume and weight of tumor (TGI = 40.53%). In vitro and in vivo studies showed that its effects were superior to those of evodiamine. This preliminary attempt may provide a promising strategy for developing anti-HCC lead compounds taking effect through simultaneous inhibition on Topo I and CAFs.
- Fan, Xiaohong,Deng, Jiedan,Shi, Tao,Wen, Huaixiu,Li, Junfang,Liang, Ziyi,Lei, Fang,Liu, Dan,Zhang, Honghua,Liang, Yan,Hao, Xiangyong,Wang, Zhen
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- Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket
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Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 ? movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.
- Zhang, Tianhua,Lai, Zengwei,Yuan, Suying,Huang, Yi-You,Dong, Guoqiang,Sheng, Chunquan,Ke, Hengming,Luo, Hai-Bin
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p. 9828 - 9837
(2020/10/19)
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- Palladium-Catalyzed Carbonylative Difunctionalization of C=N Bond of Azaarenes or Imines to Quinazolinones
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Supporting information for this article is given via a link at the end of the document. By intercepting the acylpalladium species with C=N bond of azaarenes or imines other than free amines or alcohols, the difunctionalization of C=N bond was established via palladium-catalyzed carbonylation/nucleophilic addition sequence. This method is compatible with a diverse range of azaarenes and imines and allows for the efficient synthesis of a wide range of quinazolinones and derivatives. The synthetic utility has been demonstrated by one-step synthesis of evodiamine and its analogue with inexpensive starting materials.
- Zhou, Xibing,Ding, Yongzheng,Huang, Hanmin
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p. 1678 - 1682
(2020/05/05)
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- Palladium-Catalyzed Multistep Tandem Carbonylation/N-Dealkylation/Carbonylation Reaction: Access to Isatoic Anhydrides
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A novel and efficient synthesis of isatoic anhydride derivatives was developed via palladium-catalyzed multistep tandem carbonylation/N-dealkylation/carbonylation reaction with alkyl as the leaving group and tertiary anilines as nitrogen nucleophiles. This approach features good functional group compatibility and readily available starting materials. Furthermore, it provided a convenient approach for the synthesis of biologically and medicinally useful evodiamine.
- Wang, Shoucai,Li, Xuan,Zang, Jiawang,Liu, Meichen,Zhang, Siyu,Jiang, Guangbin,Ji, Fanghua
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p. 2672 - 2679
(2020/02/04)
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- A concise synthesis and biological study of evodiamine and its analogues
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Efficient access to evodiamine and its analogues is presented via Lewis acid catalysis. In this reaction, three chemical bonds and two heterocyclic-fused rings are constructed in one step. The reaction shows good functional group tolerance and atom economy, and various heteroatom-containing evodiamine analogues are obtained in moderate to excellent yields even on a gram scale. An anti-tumor study in vitro demonstrates compound 2b possesses potent efficacy against hepatoma cell line (IC50 = 5.7 μM).
- Deng, Jie-Dan,Lei, Shuai,Jiang, Yi,Zhang, Hong-Hua,Hu, Xiao-Ling,Wen, Huai-Xiu,Tan, Wen,Wang, Zhen
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p. 3089 - 3092
(2019/03/29)
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- One-Pot Total Synthesis of Evodiamine and Its Analogues through a Continuous Biscyclization Reaction
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The one-pot total synthesis of evodiamine and its analogues is achieved using a three-component reaction. Through continuous biscyclization, various readily available substrates with good functional group tolerance were easily incorporated into biologically active quinazolinocarboline backbones. The use of triethoxymethane as a cosolvent was crucial for this quick and straightforward transformation.
- Wang, Zi-Xuan,Xiang, Jia-Chen,Wang, Miao,Ma, Jin-Tian,Wu, Yan-Dong,Wu, An-Xin
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p. 6380 - 6383
(2018/10/20)
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- A method for utilizing the carbonylation reaction three-step synthetic evodiamine method (by machine translation)
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The invention discloses a three-step synthesis of carbonylation reaction evodiamine method. First of all in order to N, N - dimethyl aniline as the raw materials of reaction by oxidative carbonylation reaction to obtain N - methyl isatin anhydride, by ammonolysis reaction to obtain N - (2 - indole ethyl) - 2 - (methylamino) benzamide, finally through the cyclization reaction of the three-step synthesis tetradium alkalizing compound. The method of the invention the synthesis of novel means, reaction and is simple, the synthesis step is succinct, mild reaction conditions, the process is simple, consistent with the requirements of the development of green chemistry, and utilize the carbonylation reaction has succeeded in synthesizing evodiamine. (by machine translation)
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- Silver Nitrate-Catalyzed Isocyanide Insertion/Lactamization Sequence to Imidazolones and Quinazolin-4-ones: Development and Application in Natural Product Synthesis
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Silver nitrate-catalyzed reaction of methyl α,α-disubstituted α-isocyanoacetates with primary amines afforded 3,5,5-trisubstituted imidazolones in good to excellent yields. A silver salt-catalyzed insertion of the isocyano group into the N-H bond of the amine followed by in situ lactamization accounted for the reaction outcome. The same transformation between methyl 2-isocyanobenzoate and amines afforded quinazolin-4-ones in excellent yields. The utility of this chemistry was illustrated by the development of concise syntheses of (±)-evodiamine and rutaecarpine.
- Clemenceau, Antonin,Wang, Qian,Zhu, Jieping
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supporting information
p. 4872 - 4875
(2017/09/23)
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- Investigation into the stability and reactivity of the pentacyclic alkaloid dehydroevodiamine and the benz-analog thereof
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Limited synthetic approaches to obtain the biologically active alkaloid dehydroevodiamine (DHED) are known to date. Undesired demethylation in the most widely applied route was found to be a hampering side reaction for the benz-DHED derivative leading to a quinazolinone, which represents a benz-rutaecarpine derivative. For rutaecarpine, a related plant alkaloid, many different synthetic approaches have been described. Alternative reaction procedures to obtain DHED such as methylation of rutaecarpine and oxidation of evodiamine were investigated to make DHED more easily accessible and the latter method proved to be the most successful one. Furthermore, the remarkable equilibrium between the ring closed quinazolinium and the ring open form of the compounds was systematically investigated by UV-vis measurements. The ring open form and the quinazolinium salt, form the same species when incubated in buffer solution for 24 h. A better soluble form, i.e., 'hydroxyevodiamine', seems to represent the biologically active form that has not yet been described.
- Wehle, Sarah,Espargaró, Alba,Sabaté, Raimon,Decker, Michael
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p. 2535 - 2543
(2016/04/26)
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- Condensation of anthranilic acids with pyridines to furnish pyridoquinazolones via pyridine dearomatization
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The unprecedented carbodiimide-mediated condensation between pyridines and anthranilic acids via pyridine dearomatization at room temperature has been developed to provide a straightforward approach to pyridoquinazolones. The value of this approach has further been demonstrated by its application to one-step, gram-scale syntheses of a series of pyridoquinazolone-based natural products and their analogues from readily available starting materials.
- Yang, Yajun,Zhu, Cuiju,Zhang, Min,Huang, Shijun,Lin, Jingjing,Pan, Xiandao,Su, Weiping
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supporting information
p. 12869 - 12872
(2016/11/06)
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- Glyoxylic acid in the reaction of isatoic anhydride with amines: A rapid synthesis of 3-(un)substituted quinazolin-4(3H)-ones leading to rutaecarpine and evodiamine
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A dual reactant/catalyst role of glyoxylic acid in the reaction of isatoic anhydride with various amines afforded a novel, robust and rapid synthesis of 3-(un)substituted quinazolin-4(3H)-ones. This metal catalyst-free reaction proceeds via an unusual and unexpected cleavage of C-C bond. A shorter and common route to two alkaloids, that is, rutaecarpine and evodiamine is also accomplished.
- Rao, K. Raghavendra,Raghunadh, Akula,Mekala, Ramamohan,Meruva, Suresh Babu,Pratap,Krishna,Kalita, Dipak,Laxminarayana, Eppakayala,Prasad, Bagineni,Pal, Manojit
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supporting information
p. 6004 - 6006
(2014/12/12)
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- Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine
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Two sets of carbamates based on the natural alkaloid evodiamine were desined, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Althouh a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very ood selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and stron neuroprotection even from 1 μM onwards. These combined activities miht enable compound 11c to be a potential candidate for treatment of Alzheimer's disease.
- Huan, Uozhen,Klin, Beata,Darras, Fouad H.,Heilmann, J?r,Decker, Michael
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- Substrate scope in the direct imine acylation of ortho-substituted benzoic acid derivatives: The total synthesis (±)-cavidine Dedicated to the memory of Sandy McKillop - Colleague, mentor, collaborator and friend
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The direct imine acylation (DIA) and subsequent cyclisation of a range of imines with ortho-substituted benzoic acid derivatives is described. Variation in the coupling reagents, imine and benzoic acid were all examined. The DIA procedure was also applied in the total synthesis of (±)-cavidine.
- Kitsiou, Christiana,Unsworth, William P.,Coulthard, Graeme,Taylor, Richard J.K.
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p. 7172 - 7180
(2015/06/23)
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- Intramolecular N-aza-amidoalkylation in association with Witkop-Winterfeldt oxidation as the key step to synthesize Luotonin-A analogues
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An expedient four-step approach for the synthesis of a short library of original analogues of the Topo-I Luotonin-A inhibitor, substituted at their C8- and N15-positions, was investigated. This consists of Rutaecarpines formation, their Witkop-Winterfeldt oxidation followed ultimately with functional adjustment of the pyrroloquinolone intermediates. In the first step of these investigations, Rutaecarpines including the Topo-I poison Evodiamine were obtained via the new tandem N-acylation/aza-amidoalkylation using a nitrogen atom as an internal nucleophile with or without association with a decarboxylation.
- Pin, Frédéric,Comesse, Sébastien,Da?ch, Adam
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experimental part
p. 5564 - 5571
(2011/08/09)
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- Selection of evodiamine as a novel topoisomerase i inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as antitumor agents
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Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to the discovery of structurally diverse TopoI inhibitors. From 23 compounds selected by virtual screening, a total of 14 compounds were found to be TopoI inhibitors. Five hits (compounds 1, 14, 20, 21, and 23) also showed moderate to good in vitro antitumor activity. These novel structures can be considered as good starting points for the development of new antitumor lead compounds. Hit 20 (evodiamine) was chosen for preliminary structure-activity relationship studies. Various groups, including alkyl, benzoyl, benzyl and ester, were introduced to the indole nitrogen atom of evodiamine. The substituted benzoyl groups were found to be favorable for the antitumor activity and spectrum. The 4-Cl benzoyl derivative, compound 29u, was the most active one with IC50 values in the range 0.049-2.6 μM.
- Dong, Guoqiang,Sheng, Chunquan,Wang, Shengzheng,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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scheme or table
p. 7521 - 7531
(2011/02/21)
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- Compounds and compositions for treating infection
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Compounds from 14 Kenyan plants, including from the root of Dovyalis abyssinica and Clutia robusta have been characterized and isolated, and their uses are disclosed.
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- Synthesis and cytotoxic activity of novel quinazolino-β-carboline-5- one derivatives
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A novel series of quinazolino-β-carbolinone derivatives was synthesized and evaluated for their in vitro and in vivo anticancer activity. Many compounds have shown good in vitro activity in the range 1-8μM concentration. Three of the compounds were further tested in nude mice bearing HT-29 colon cancer xenografts.
- Baruah, Bipul,Dasu, Kavitha,Vaitilingam, Balasubramanian,Mamnoor, Premkumar,Venkata, Prasanthi Penubaka,Rajagopal, Sriram,Yeleswarapu, Koteswar Rao
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p. 1991 - 1994
(2007/10/03)
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- Studies of Rutaecarpine and Related Quinazolinocarboline Alkaloids
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Quinazolinocarboline alkaloids, e.g., rutaecarpine (1), can readily be synthesized by treating tryptamine with 2-(trifluoromethyl)-4H-3,1-benzoxazin-4-one (quickly generated in situ from trifluoroacetic anhydride (TFAA) and 2H-3,1-benzoxazine-2,4(1H)-dione.The product formed, 3--2-(trifluoromethyl)-4-(3H)-quinazolinone (5), is then cyclized (HCl/HOAc) to 13b-(trifluoromethyl)-13b,14-dihydrorutaecarpine (6), whereupon CF3H is eliminated by treatment with base.The sequence can conveniently be performed as a three-reaction one-pot procedure giving rutaecarpine (1) in 99percent yield within 3h.The approach can readily be extended to the synthesis of evodiamine (2), 13,13b-dehydroevodiamine (38a), and 13b,14-dihydrorutaecarpine (21).Thus treatment of 3--4(3H)-quinazolinone (19) with TFAA affected cyclization to 13b-(trifluoroacetyl)-13b,14-dihydrorutaecarpine (20), which can be readily hydrolyzed to 13b,14-dihydrorutaecarpine (21).
- Bergman, Jan,Bergman, Solveig
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p. 1246 - 1255
(2007/10/02)
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