6502-82-5Relevant articles and documents
Enantioselective Synthesis of (+)-Peganumine A
Piemontesi, Cyril,Wang, Qian,Zhu, Jieping
, p. 11148 - 11151 (2016)
A gram-scale enantioselective total synthesis of (+)-peganumine A was accomplished in 7 steps from commercially available 6-methoxytryptamine. Key steps included (a) a Liebeskind-Srogl cross-coupling; (b) a one-pot construction of the tetracyclic skeleton from an ω-isocyano-γ-oxo-aldehyde via a sequence of an unprecedented C-C bond forming lactamization and a transannular condensation; (c) a one-pot organocatalytic process merging two achiral building blocks into an octacyclic structure via a sequence of enantioselective Pictet-Spengler reaction followed by a transannular cyclization. This last reaction created two spirocycles and a 2,7-diazabicyclo[2.2.1]heptan-3-one unit with excellent control of both the absolute and relative stereochemistry of the two newly created quaternary stereocenters.
Structural simplification of evodiamine: Discovery of novel tetrahydro-β-carboline derivatives as potent antitumor agents
Ma, Zonglin,Huang, Yahui,Wan, Kun,Zhu, Fugui,Sheng, Chunquan,Chen, Shuqiang,Liu, Dan,Dong, Guoqiang
, (2021/04/02)
Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-β-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G2/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure–activity relationships of evodiamine.
Production process of evodiamine and method for recycling solvent in production
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Paragraph 0018; 0042-0044; 0052-0054, (2021/02/24)
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.
Design, synthesis, and biological evaluation of 3′,4′,5′-trimethoxy evodiamine derivatives as potential antitumor agents
Peng, Yijiao,Xiong, Runde,Li, Zhen,Peng, Junmei,Xie, Zhi-Zhong,Lei, Xiao-Yong,He, Dongxiu,Tang, Guotao
, p. 1021 - 1032 (2021/02/26)
A series of compounds bearing 3′,4′,5′-trimethoxy module into the core structure of evodiamine were designed and synthesized. The synthesized compounds were screened in vitro for their antitumor potential. MTT results showed that compounds 14a–14c and 14i–14j had significant effects, with compound 14h being the most prominent, with an IC50 value of 3.3 ± 1.5?μM, which was lower than evodiamine and 5-Fu. Subsequent experiments further confirmed that compound 14h could inhibit cell proliferation and migration, and induce G2/M phase arrest to inhibit the proliferation of HGC-27 cells, which is consistent with the results of the cytotoxicity experiment. Besides, 14h could inhibit microtubule assembly and might kill tumor cells by inhibiting VEGF and glycolysis. All experimental results indicate that compound 14h might be a potential drug candidate for the treatment of gastric cancer and was worthy of further study.
Continuous-flow synthesis of thioureas, enabled by aqueous polysulfide solution
ábrányi-Balogh, Péter,Keser?, Gy?rgy M.,Mándity, István M.,Németh, András Gy.,Orsy, Gy?rgy,Szabó, Renáta
supporting information, (2021/06/25)
We have developed the continuous-flow synthesis of thioureas in a multicomponent reaction starting from isocyanides, amidines, or amines and sulfur. The aqueous polysulfide solution enabled the application of sulfur under homogeneous and mild conditions. The crystallized products were isolated by simple filtration after the removal of the co-solvent, and the sulfur retained in the mother liquid. Presenting a wide range of thioureas synthesized by this procedure confirms the utility of the convenient continuous-flow application of sulfur.
Amino evodiamine derivative and preparation method and application thereof
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Paragraph 0013, (2020/09/16)
The invention discloses an amino evodiamine derivative and a preparation method and application thereof. A carboline compound and N-methyl-7-nitro isatoic anhydride are used for preparing a 2-nitro evodiamine derivative, and the 2-nitro evodiamine derivative is reduced to obtain the amino evodiamine derivative. A cytotoxicity experiment is performed by using a CCK-8 method, the anti-proliferationeffect of the compound on breast cancer MDA-MB-231 cells, colon cancer SW620 cells and normal liver LO2 cells is evaluated, and cell apoptosis detection is performed by using FITC/PI double staining;experiments show that compared with evodiamine, the compound 2-NH2-EVO has a very strong inhibition effect on breast cancer cells MDA-MB-231, the IC50 value is 0.79 uM, meanwhile, cell apoptosis can be remarkably induced, and the compound 2-NH2-EVO is expected to be developed into an anti-cancer drug with potential.
Amino evodiamine polymer micelle as well as preparation method and application thereof
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Paragraph 0017, (2020/10/04)
The invention discloses an amino evodiamine polymer micelle as well as a preparation method and application thereof. The preparation method comprises the following steps: preparing a 2-nitro evodiamine derivative from a carboline compound and N-methyl-7-nitro isatoic anhydride, reducing the 2-nitro evodiamine derivative to obtain an amino evodiamine derivative, and reacting a polymer with amino evodiamine to prepare an amino evodiamine polymer conjugate; and then carrying out self-assembly on the amino evodiamine polymer conjugate to obtain the amino evodiamine polymer micelle. The water solubility and bioavailability of a drug are improved, the drug is combined with a nanotechnology, a nano drug loading system is developed for drug delivery, and the nano drug can be passively enriched intumor tissues in a targeting manner through an EPR effect.
Doxorubicin-loaded polymeric micelle as well as preparation method and application thereof
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Paragraph 0014, (2020/10/04)
The present invention discloses a doxorubicin-loaded polymeric micelle as well as a preparation method and application thereof. Novel amino evodiamine is adopted to react with polyethylene glycol, a micelle obtained by self-assembly is used as a carrier to load doxorubicin, a prepared mPEG-CO-NH-EVO micelle and a mPEG-CO-NH-EVO-OCH3 micelle have low toxicity to normal hepatocytes so that the two amphipathic polymeric micelles are used as carriers to load DOX to prepare DOX-loaded polymeric micelles, namely a mPEG-CO-NH-EVO/DOX micelle and a mPEG-CO-NH-EVO-OCH3/DOX micelle, and DOX enters hydrophobic shells of the micelles due to the dialysis effect; shapes of the micelles are represented by using a transmission electron microscope and a scanning electron microscope, and the drug loading efficiency and encapsulation efficiency of DOX are tested and calculated by using an ultraviolet spectrophotometer; and finally, evaluating the cytotoxicity by using a CCK-8 method. Shown by cytotoxicity tests, a DOX-loaded polymer has an effect on inhibiting breast cancer cells and particularly has greatly reduced toxicity to the normal hepatocytes.
Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket
Zhang, Tianhua,Lai, Zengwei,Yuan, Suying,Huang, Yi-You,Dong, Guoqiang,Sheng, Chunquan,Ke, Hengming,Luo, Hai-Bin
, p. 9828 - 9837 (2020/10/19)
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.
Hydrogen-Bonding-Promoted Cascade Rearrangement Involving the Enlargement of Two Rings: Efficient Access to Polycyclic Quinoline Derivatives
Cao, Wen-Bin,Ji, Shun-Jun,Lan, Yu,Li, Haiyan,Li, Shijun,Xu, Meng-Meng,Xu, Xiao-Ping
supporting information, p. 21425 - 21430 (2020/09/23)
An efficient cascade reaction of tryptamine-derived isocyanides with C,N-cyclic azomethine imines is described. The polycyclic pyrrolo[2,3-c]quinoline derivatives, which benefited from rearrangement process driven by hydrogen bonding, could be directly assembled in moderate to good yields (40–87 %) under metal-free and mild conditions. This transformation involved four new heterocyclic rings formations and uniquely, ring opening of indole as well as ring expansion of C,N-cyclic azomethine imine. Both experimental and DFT studies provided guidance on the in-depth insight into the reaction pathways and hydrogen bonding was identified to lower the free energy barrier in transition states. This work constitutes a rare example of tryptamine-derived isocyanide-based cascade reactions, and potentially could be a powerful synthetic strategy for accessing polycyclic analogues involved in natural products.
