- Synthesis and Antiviral/Fungicidal/Insecticidal Activities Study of Novel Chiral Indole Diketopiperazine Derivatives Containing Acylhydrazone Moiety
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On the basis of the mechanism of acylhydrazone compounds inhibiting the assembly of TMV CP and the unique structural characteristics of diketopiperazine ring, a series of optically pure indole diketopiperazine acylhydrazone were designed and synthesized. In order to systematically study the effect of the spatial configuration of the compounds on the antiviral activity, four compounds with different spatial configurations at C6 and C12a were also prepared. The bioassay results indicated that most of these new compounds displayed moderate to good antiviral activity, among which compounds 23, 25, 27, 28, 31, and 5d showed a significantly higher activity than that of commercial ribavirin. An in-depth structure-activity relationship investigation showed that the spatial conformation was one of the most important factors in adjusting antiviral activity; the research results provided information about the possible optimum configuration for interaction of this molecular with its target protein. At the same time, these new compounds also exhibited broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi. What's more, some of these compounds exhibited good insecticidal activity to Plutella xylostella and Culex pipiens pallens.
- Liu, Yuxiu,Song, Hongjian,Wang, Qingmin,Xie, Jialin,Xu, Wentao,Zhang, Jingjing
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- Structural Basis for β-Carboline Alkaloid Production by the Microbial Homodimeric Enzyme McbB
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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.
- Mori, Takahiro,Hoshino, Shotaro,Sahashi, Shusaku,Wakimoto, Toshiyuki,Matsui, Takashi,Morita, Hiroyuki,Abe, Ikuro
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- Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor
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In GPIIb/IIIa mediated arterial thrombosis platelet activation plays a central role. To discover platelet activation inhibitor the pharmacophores of GPIIb/IIIa receptor inhibitors and anti-thrombotic agents were analyzed. This led to the design of (1R,3S)- and (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acids as GPIIb/IIIa inhibitors. Comparing to (1S,3S)-isomer (1R,3S)-isomer had lower cdocker interaction energy. AFM image showed that the minimal effective concentration of (1S,3S)-isomer and (1R,3S)-isomer inhibiting platelet activation were 10?5 M and 10?6 M, respectively. In vivo 1 μmol/kg of oral (1S,3S)-isomer effectively inhibited the rats to form arterial thrombus and down regulated GPIIb/IIIa expression, but the activities were significantly lower than those of 1 μmol/kg of oral (1R,3S)-isomer. Both (1S,3S)-isomer and (1R,3S)-isomer can be safely used for structural modifications, but (1R,3S)-isomer should be superior to (1S,3S)-isomer.
- Wang, Xiaozhen,Wang, Yuji,Wu, Jianhui,Gui, Lin,Zhang, Xiaoyi,Zheng, Meiqing,Wang, Yaonan,Zhao, Shurui,Li, Ze,Zhao, Ming,Peng, Shiqi
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Read Online
- Synthesis method of chloroindole hydrazide
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The invention relates to a synthesis method of chloroindole hydrazide, and belongs to the technical field of pesticides. The specific preparation method comprises the following steps: (1) uniformly mixing a compound shown as a formula (I), a solvent I, acetonitrile and a catalyst I, and then adding a hydrogen source for reaction; after the reaction is finished, treating to obtain a compound shown as a formula (II); (2) mixing the compound shown in the formula (II), (4-chlorphenyl) methylene hydrazine, a solvent II and a catalyst II for reaction, and after the reaction is completed, performing post-treatment to obtain chloroindole hydrazide; a novel synthetic route is provided, catalytic hydrogenation cyclization is performed on tryptophan or ester thereof and acetonitrile, and then reacts with (4-chlorphenyl) methylene hydrazine to obtain the chloroindole hydrazide through two steps. Compared with the prior art, the preparation method has the advantages of short synthesis steps, high reaction yield, no use of high-toxicity, strong-corrosivity and strong-irritation reagents, and convenience in realization of industrial production.
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Paragraph 0065-0068
(2022/03/18)
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- Discovery of pyridoindole derivatives as potential inhibitors for phosphodiesterase 5A: in silico and in?vivo studies
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The aim of this work was to synthesise derivatives from identified plant based pyridoindole lead scaffold, and to assess phosphodiesterase 5A inhibitory potential by in silico and in?vivo. Pyridoindole derivatives were synthesised by using six-stage reactor. In silico screening was carried out by grip-based docking methodology. In step-I, tryptophan as a starting material was reacted with different aldehydes and ketones to obtain 11 molecules. In step-II, obtained molecules were reacted with ethanol and benzyl alcohols to obtain D1 to D22 derivatives. In silico investigation resulted in best three molecules D12, D4 and D8 with promising BE score. Oral acute toxicity study of selected molecules resulted in LD50 value 500 mg/kg in rats. The result of in?vivo antihypertensive study shown that molecule D12 was found to be the best antihypertensive lead molecule. This study could be a best platform to tailor novel biomolecules for inhibiting phosphodiesterase 5A enzyme in hypertension management.
- Mali, Dipak P.,Gaikwad, Dinanath T.,Bhatia, Manish S.,Bhatia, Neela M.
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- 1-substituted beta-carboline derivative and application thereof
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The invention discloses 1-substituted beta-carboline derivatives and an application of the 1-substituted beta-carboline derivatives. According to the invention, beta-carboline is used as a parent nucleus; the 1-substituted beta-carboline derivatives are mainly synthesized by introducing alkyl and electron withdrawing groups at the No.1 position, agriculturally important plant pathogenic fungi andbacteria are selected, the inhibitory activity of the compound on fungi and bacteria is tested, and bacteriostatic activity test results show that the 1-substituted beta-carboline derivatives have inhibitory activity on various plant pathogenic bacteria.
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Paragraph 0037
(2020/07/13)
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- Preparation method and application of [beta]-carboline compound intermediate
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The invention provides a preparation method and application of a [beta]-carboline compound intermediate, and belongs to the technical field of chemical engineering, the preparation method comprises the following steps: mixing an aqueous solution of L-tryptophan, acetaldehyde and methanol, lewis acid, Bronsted acid and chiral amine, carrying out a synthetic reaction on the obtained mixture, and obtaining a [beta]-carboline compound intermediate (1S, 3S)-1-methyl-2, 3, 4, 9-tetrahydropyrido[3, 4-b]indole-3-formic acid. The (1S, 3S)-1-methyl-2, 3, 4, 9-tetrahydropyrido[3, 4-b]indole-3-formic acidprepared by adopting the method is high in product yield and high in ee value.
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Paragraph 0031; 0042-0043; 0048-0051
(2021/01/11)
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- Carboline derivative, production method of carboline derivative and application of carboline derivative on aspects of plant virus control, fungus killing and insect killing
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The invention relates to a tetrahydro-beta-carboline derivative containing a diketopiperazine acylhydrazone structure, a production method of the tetrahydro-beta-carboline derivative containing the diketopiperazine acylhydrazone structure and application
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Paragraph 0101-0102
(2020/02/17)
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- Novel β-carboline-based indole-4,7-quinone derivatives as NAD(P)H: Quinone-oxidoreductase-1 inhibitor with potent antitumor activities by inducing reactive oxygen species, apoptosis, and DNA damage
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Eighteen new β-carboline-based indole-4,7-quinone derivatives (12a–i and 13a–i) were designed and synthesized, and their in vitro and in vivo antiproliferative activities were studied. Most of target compounds showed strong inhibition on three human tumor cells' proliferation. In particular, the most active compound 13g not only displayed more prominent antiproliferative activities than β-lapachone, a clinical antitumor candidate, but also exerted significant NAD(P)H: quinone-oxidoreductase-1 (NQO1) inhibitory activity and NQO1-dependent cytotoxicity in HT29 cells. Furthermore, 13g dose-dependently induced high ROS levels in HT29 cells, and selectively inhibited cancer cell but not non-tumor colon cell proliferation in vitro. Importantly, 13g promoted HT29 cell apoptosis and DNA damage by regulating relative apoptotic proteins and H2AX expression. Finally, 13g displayed significant growth inhibition of HT29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.
- Guo, Yibing,Xu, Liancheng,Ling, Changchun,Yang, Tao,Zheng, Wenjie,Lv, Jin,Guo, Qingsong,Chen, Bohua
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p. 1433 - 1446
(2020/07/13)
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- β-Carboline and N-hydroxycinnamamide hybrids as anticancer agents for drug-resistant hepatocellular carcinoma
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In an effort to develop anticancer agents that may overcome drug resistance, the number one reason in caner death, we have developed a series of novel hybrids of β-carboline and N-hydroxycinnamamide as histone deacetylase (HDAC) inhibitors. Most of the hybrids 13a-p showed strong antiproliferative effects with low-micromolar IC50 values against four human cancer cells. The most potent compound of series 13p exhibited high HDAC1/6 inhibitory effects, and also increased the acetylation levels of histone H3, H4 and α-tubulin. Importantly, 13p demonstrated high anticancer potency against drug-sensitive HepG2 and Bel7402 cells and drug-resistant Bel7402/5FU cells. Hybrid 13p triggered significant apoptosis by regulating apoptotic relative proteins expression in these Bel7402/5FU cells. Finally, 13p induced a substantial amount of autophagic flux activity by the accretion of the expression of LC3-II and the degeneration of expression of p62 and LC3-I in Bel7402/5FU cells. Overall, 13p is a novel β-carboline/N-hydroxycinnamamide hybrid with significant anticancer potency that warrants further evaluation for the treatment of drug-resistant hepatocellular carcinoma.
- Ling, Yong,Gao, Wei-Jie,Ling, Changchun,Liu, Ji,Meng, Chi,Qian, Jianqiang,Liu, Siqun,Gan, Huiling,Wu, Hongmei,Tao, Jinhua,Dai, Hong,Zhang, Yanan
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p. 515 - 526
(2019/03/08)
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- Synthesis and biological evaluation of novel N9-heterobivalent β-carbolines as angiogenesis inhibitors
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A series of novel N9-heterobivalent β-carbolines has been synthesized. All the novel compounds were tested for their anticancer activity against six tumour cell lines in vitro. Among these molecules, compounds 5b, and 5w exhibited strong cytotoxic activities with IC50 value of lower than 20 μM. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 5b and 5w exhibited that tumour inhibition rate of over 40% in the Sarcoma 180 and Lewis lung cancer animal models. Preliminary structure–activity relationships (SARs) analysis indicated that: (1) C1-methylation and C7-methoxylation were favorable for increased activities; (2) 3-Pyridyl or 2-thienyl group substituent into position-1 of the β-carboline core, and the aryl substituent into another β-carboline ring might be detrimental to cytotoxic effects of this class compounds. Investigation of the preliminary mechanism of action demonstrated that compound 5b had obvious angiogenesis inhibitory effects in the chicken chorioallantoic membrane (CAM) assay.
- Guo, Liang,Ma, Qin,Chen, Wei,Fan, Wenxi,Zhang, Jie,Dai, Bin
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p. 375 - 387
(2019/01/10)
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- Dipeptide modified 1-methyl-3-hydroxymethyl-tetrahydro-beta-carboline, synthesis and applications thereof
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The invention relates to dipeptide modified 1-methyl-3-hydroxymethyl-tetrahydro-beta-carboline, synthesis and applications thereof, and discloses (1S,3S)-1-methyl-3-(AA-Val-methoxy)-2,3,4,9-tetrahydro-beta-carboline represented by the following formula (AA is Gly residue, L-Ala residue, L-Leu residue, L-Ile residue, L-Pro residue, L-Phe residue, L-Val residue and L-Lys residue), a preparation method, antitumor activity and P-selectin expression inhibition activity thereof, such that the invention discloses applications of the (1S,3S)-1-methyl-3-(AA-Val-methoxy)-2,3,4,9-tetrahydro-beta-carboline in preparation of antitumor drugs and in P-selectin expression inhibitors. The formula is defined in the specification.
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Paragraph 0018; 0019
(2019/01/08)
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- Novel heptacyclic compound as well as synthesis, activity rating and application thereof
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The invention discloses a novel heptacyclic compound (2'S,5'S)-tetrahydropyrazine[1',2':1,6]bis{(1S)-1-methyl-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]diindole}-1',4'-diketone (ZMC for short), discloses apreparation method thereof, discloses an anti- thrombosis function thereof, discloses an anti-inflammation effect thereof, disclosed an anti-tumor effect thereof, and further discloses a free radicalscavenging effect and a P-selectin expression inhibiting effect thereof. Thus, the invention discloses application of the ZMC to preparation of a P-selectin-targeted medicament capable of inhibitingthrombosis, inflammation and tumors. Since the thrombosis and the inflammation are most common complications of tumor patients, the ZMC disclosed by the invention can be used for not only treating thetumors, but also preventing the complications of the thrombosis and the inflammation in the tumor patients. The ZMC disclosed by the invention has a good clinical application prospect.
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Paragraph 0020-0021
(2018/04/03)
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- Design, Synthesis, and Biological Activity of β-Carboline Analogues Containing Hydantoin, Thiohydantoin, and Urea Moieties
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A series of novel β-carboline derivatives was designed by combining the anti-tobacco mosaic virus (TMV) lead compound tetrahydro-β-carboline ester with the hydantoin, thiohydantoin, and urea motifs. These derivatives were synthesized from tetrahydro-β-carboline ester via a structural diversity-oriented synthesis in one step, and their biological activities were evaluated. Most of the derivatives exhibited anti-TMV activity higher than that of commercial plant virucide ribavirin, such as compounds 2, 4, 5, 7, 9, 15, 16, 19, and 21. Compared with the lead compounds, some of these derivatives showed good insecticidal activity against Plutella xylostella and Culex pipiens pallens. At the same time, these derivatives also showed broad-spectrum fungicidal activity. The systematic study provides strong evidence that the hydantoin, thiohydantoin, and urea motifs of these molecules can improve and modulate the activities of the analogues of natural products.
- Huang, Yuanqiong,Guo, Zhonglin,Song, Hongjian,Liu, Yuxiu,Wang, Lizhong,Wang, Qingmin
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p. 8253 - 8261
(2018/08/16)
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- Synthesis and structure-activity relationships of asymmetric dimeric β-carboline derivatives as potential antitumor agents
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A series of newly asymmetric dimeric β-carbolines with a spacer of 4–6 methylene units between the indole nitrogen and the harmine oxygen were synthesized. Structures of all the novel synthesized compounds were confirmed by their spectral and analytical studies. All of the synthesized compounds were screened for their in vitro cytotoxic activity against nine cancer cell lines. The results revealed that compounds 7c, 7o and 7s exhibited the highest cytotoxic activities with IC50 values of less than 20 μM against the tumor cell lines tested. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, and compound 7o exhibited potent antitumor activities with the tumor inhibition rate of over 40%. The wound healing assay displayed a specific impairment in the motility of the HT-29 cells, which suggested the anti-metastatic potential of compound 7o. Moreover, compound 7o had obvious angiogenesis inhibitory effects in the chicken chorioallantoic membrane (CAM) assay. Preliminary structure-activity relationship (SAR) analysis indicated that: (1) 3-phenylpropyl substituent at the N9-position of the indole ring was the most suitable group giving rise to potent cytotoxic agents; (2) the spacer length affected the antitumor potencies, and four methylene units were more favorable.
- Guo, Liang,Chen, Wei,Cao, Rihui,Fan, Wenxi,Ma, Qin,Zhang, Jie,Dai, Bin
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p. 253 - 265
(2018/02/15)
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- Synthesis route of 1R,3S-1-methyltetrahydro-beta-carboline-3-carboxylic acid, antithrombotic activity and application
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The invention discloses a synthetic route for preparing 1R,3S-1-methyltetrahydro-beta-carboline-3-carboxylic acid with a formula shown in the description, discloses antithrombotic activity of the compound, and discloses application of the compound in preparation of antithrombotic drugs.
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Paragraph 0010; 0018-0019; 0020-0021
(2019/01/08)
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- Design, synthesis, and antifungal activity of novel aryl-1,2,3-triazole-β-carboline hybrids
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The copper catalytic azide and terminal alkyne cycloaddition reaction, namely “click chemistry”, gives a new and convenient way to create l,4-disubstitutd-l,2,3-triazoles. In this work, 2-pyrrolecarbaldiminato–Cu(II) complexes were established as efficient catalysts for the three-component 1,3-dipolar cycloaddition reaction of arylboronic acid and sodium azide (NaN3) with terminal alkynes in ethanol at room temperature to 50 ?C, 1,4-disubstituted 1,2,3-triazoles were synthesized. Following the optimized protocol, two series of new aryl-1,2,3-triazole-β-carboline hybrids have been designed and synthesized, and the chemical structures were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). All of the target compounds were evaluated in vitro for their antifungal activity against Rhizoctorzia solani, Fusarium oxysporum, Botrytis cinerea Pers., sunflower sclerotinia rot, and rape sclerotinia rot by mycelia growth inhibition assay at 50 μg/mL. The antifungal evaluation of the novel hybrids showed that, among the tested compounds, 5a, 5b, 5c, and 9b showed good antifungal activity against sunflower sclerotinia rot. Specifically, compound 9b also exhibited high broad-spectrum fungicidal against all the tested fungi with inhibition rates of 58.3%, 18.52%, 63.07%, 84.47%, and 81.23%. However, for F. oxysporum, all the target compounds showed no in vitro antifungal activities with an inhibition rate lower than 20%. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents.
- Huo, Xin-Yu,Guo, Liang,Chen, Xiao-Fei,Zhou, Yue-Ting,Zhang, Jie,Han, Xiao-Qiang,Dai, Bin
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- ?-CARBOLINE, DIHYDRO-?-CARBOLINE AND TETRAHYDRO-?-CARBOLINE ALKALOID DERIVATIVES AND PREPARATION METHODS SAME AND USE IN ASPECTS OF PREVENTING AND TREATING PLANT VIRUSES, FUNGICIDES AND INSECTICIDES
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The present invention relates to β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives (I) and a method for preparing same and the use in the aspects of preventing and treating plant viruses, fungicides and insecticides. For the meaning of each group in formula (I) see the description. The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives of the present invention show a particularly ourstanding anti-plant virus activity, and also have fungicidal and insecticidal activities.
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Paragraph 0140-0142
(2016/11/28)
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- Tetrahydro-β-carboline-3-carboxyl-thymopentin: A nano-conjugate for releasing pharmacophores to treat tumor and complications
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To improve the therapeutic efficacy of cancer patients a novel conjugate of thymopentin (TP5) and (1S,3S)-1-methyl-tetrahydro-β-carboline-3-carboxylic acid (MTC) was presented. In water and mouse plasma MTCTP5 forms the nanoparticles of 14-139 nm in diameter, the suitable size for delivery in blood circulation. In mouse plasma MTCTP5 releases MTC, while in the presence of trypsin MTCTP5 releases MTC and TP5. On mouse and rat models the MTCTP5 dose dependently slows down the tumor growth, inhibits inflammatory response and blocks thrombosis. The anti-tumor activity as well as the anti-inflammation activity and anti-thrombotic activity of MTCTP5 are 100 fold and 10 fold higher than those of MTC, respectively, which are attributed to the fact that it down-regulates the plasma levels of TNF-α and IL-8 of the treated animals. The immunology enhancing activities in vitro and in vivo of MTCTP5 are similar to those of TP5, which is attributed to the fact that MTCTP5 up-regulates the plasma levels of IL-2 and CD4 as well as down-regulates the plasma level of CD8 of the treated animals. The plasma alanine transaminase, aspartate transaminase and creatinine assays indicate that MTCTP5 therapy does not injure the liver and the kidney of the animals. The survival time of MTCTP5 treated mice is significantly longer than that of TP5 treated mice.
- Hu, Xi,Zhao, Ming,Wang, Yuji,Wang, Yaonan,Zhao, Shurui,Wu, Jianhui,Li, Xiangmin,Peng, Shiqi
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supporting information
p. 1384 - 1397
(2016/03/05)
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- Evaluation of canthinone alkaloids as cerebral protective agents
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Considerable attention has been paid to cerebral protective drugs as a potential therapy for dementia. Screening of a natural compound library here resulted in identification of five canthinone alkaloids, viz., picrasidine L (1), picrasidine O (2), eurycomine E (3), 3-ethyl-canthin-5,6-dione (4), and 3-ethyl-4-methoxy-canthin-5,6-dione (5), as novel cerebral protective agents. The structure–activity relationship indicated that C-4, C-9, and N-3 substitutions greatly affected their cerebral protective effect. Among these, compound 2 exhibited a cerebral protective effect through suppressing neuronal hyperexcitability due to an increase in the excitatory neurotransmitter glutamic acid. Furthermore, compound 2 did not affect heart rate and mean systolic blood pressure. This investigation suggests that compound 2 has potential for further development as a cerebral protective drug.
- Sasaki, Tatsunori,Li, Wei,Ohmoto, Taichi,Koike, Kazuo
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supporting information
p. 4992 - 4995
(2016/10/04)
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- A seed of common peganum alkali nenzoyl urea compound, and its preparation method and application
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The invention discloses banisterine benzoyl urea compounds and a preparation method and application thereof. The banisterine benzoyl urea compounds have a structural formula I shown in the specification; in the formula I, R1 can be methyl, phenyl, 3,4,5- triethoxy phenyl, p-methoxyphenyl or p-chlorphenyl, R2 can be H or Br, and X can be O or S. The banisterine benzoyl urea compounds have an outstanding insecticidal activity for Culex fatigans, prodenia litura and Chilo suppressalis; a part of the compounds are identical to a control insecticide Dibenzoyl-1-tert-butylhydrazine in term of activity; the banisterine benzoyl urea compounds have good inhibitory activity for rice sheath blight disease, alternaria solani, Collectotrichum musae, grey mould fruit rot of strawberry and sour rot pathogenic bacteria of citrus; a part of the compounds have better inhibitory activity for the above five phytopathogens than validamycin. The banisterine derivatives are simple in structure and easy to synthesize; the synthesis process is simple, the product purity is high; the banisterine benzoyl urea compounds and the preparation method thereof are suitable for large-scale industrial popularization and application.
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Paragraph 0050; 0051
(2016/10/09)
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- Synthesis and preliminary evaluation of novel alkyl diamine linked bivalent β-carbolines as angiogenesis inhibitors
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A series of novel bivalent β-carbolines linked with an alkyl diamine spacer at the C-3 position were synthesized and evaluated as potent angiogenesis inhibitors. The results demonstrated that most bivalent β-carbolines displayed significant anti-proliferative effects against EA.HY926 human umbilical vein cell lines. Compound 8z was found to be the most potent anti-proliferative agent with an IC50 value of 1.10 μM against EA.HY926 cell lines. Preliminary investigations on the mechanisms of action revealed that compound 8z could dramatically inhibit EA.HY926 cell migration and tube formation in a dose-dependent manner. Moreover, compound 8z exhibited significant angiogenesis inhibitory effects in CAM assay, and the anti-angiogenic potency was comparable with that of the reference drug Endostar. These molecules might serve as candidates for further development into vascular-targeting antitumor drugs.
- Guo, Liang,Chen, Wei,Fan, Wenxi,Ma, Qin,Sun, Rongqin,Shao, Guang,Cao, Rihui
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supporting information
p. 2177 - 2183
(2016/11/18)
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- Synthesis and biological evaluation of piperazine group-linked bivalent β-carbolines as potential antitumor agents
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A series of novel bivalent β-carbolines with a piperazine group spacer between 3-methylene units were synthesized and evaluated as antitumor agents. The results demonstrated that compounds 7e and 7g exhibited the most potent cytotoxic activities against ten tumor cell lines. Structure-activity relationships analysis indicated that (1) the substituents in positions 1 and 9 of the β-carboline ring played a significant role in modulating the antitumor activity; (2) the introduction of alkyl groups into position-9 of the β-carboline nucleus enhanced their cytotoxic potencies and the butyl substituent was the optimal group. Investigation of the preliminary mechanism of action demonstrated that compound 7g showed obvious anti-angiogenic activity in the in vivo CAM assay, and the potency was similar to that of CA4P (200 μM).
- Sun, Rongqin,Liu, Rui,Zhou, Chi,Ren, Zhenghua,Guo, Liang,Ma, Qin,Fan, Wenxi,Qiu, Liqin,Yu, Huijuan,Shao, Guang,Cao, Rihui
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supporting information
p. 2170 - 2174
(2015/12/11)
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- Synthesis and antiviral and fungicidal activity evaluation of β-carboline, dihydro-β-carboline, tetrahydro-β-carboline alkaloids, and their derivatives
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Six known β-carboline, dihydro-β-carboline, and tetrahydro-β-carboline alkaloids and a series of their derivatives were designed, synthesized, and evaluated for their anti-tobacco mosaic virus (TMV) and fungicidal activities for the first time. All of the alkaloids and some of their derivatives (compounds 3, 4, 14, and 19) exhibited higher anti-TMV activity than the commercial antiviral agent Ribavirin both in vitro and in vivo. Especially, the inactivation, curative, and protection activities of alkaloids Harmalan (62.3, 55.1, and 60.3% at 500 μg/mL) and tetrahydroharmane (64.2, 57.2, and 59.5% at 500 μg/mL) in vivo were much higher than those of Ribavirin (37.4, 36.2, and 38.5% at 500 μg/mL). A new derivative, 14, with optimized physicochemical properties, obviously exhibited higher activities in vivo (50.4, 43.9, and 47.9% at 500 μg/mL) than Ribavirin and other derivatives; therefore, 14 can be used as a new lead structure for the development of anti-TMV drugs. Moreover, most of these compounds exhibited good fungicidal activity against 14 kinds of fungi, especially compounds 4, 7, and 11.
- Song, Hongjian,Liu, Yongxian,Liu, Yuxiu,Wang, Lizhong,Wang, Qingmin
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p. 1010 - 1018
(2014/03/21)
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- Synthesis and antiviral and fungicidal activity evaluation of β-carboline, dihydro-β-carboline, tetrahydro-β-carboline alkaloids, and their derivatives
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Six known β-carboline, dihydro-β-carboline, and tetrahydro-β-carboline alkaloids and a series of their derivatives were designed, synthesized, and evaluated for their anti-tobacco mosaic virus (TMV) and fungicidal activities for the first time. All of the alkaloids and some of their derivatives (compounds 3, 4, 14, and 19) exhibited higher anti-TMV activity than the commercial antiviral agent Ribavirin both in vitro and in vivo. Especially, the inactivation, curative, and protection activities of alkaloids Harmalan (62.3, 55.1, and 60.3% at 500 μg/mL) and tetrahydroharmane (64.2, 57.2, and 59.5% at 500 μg/mL) in vivo were much higher than those of Ribavirin (37.4, 36.2, and 38.5% at 500 μg/mL). A new derivative, 14, with optimized physicochemical properties, obviously exhibited higher activities in vivo (50.4, 43.9, and 47.9% at 500 μg/mL) than Ribavirin and other derivatives; therefore, 14 can be used as a new lead structure for the development of anti-TMV drugs. Moreover, most of these compounds exhibited good fungicidal activity against 14 kinds of fungi, especially compounds 4, 7, and 11.
- Song, Hongjian,Liu, Yongxian,Liu, Yuxiu,Wang, Lizhong,Wang, Qingmin
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p. 1010 - 1018
(2015/04/22)
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- Design, synthesis, anti-TMV, fungicidal, and insecticidal activity evaluation of 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid derivatives based on virus inhibitors of plant sources
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By drawing the creation ideas of botanical pesticides, a series of tetrahydro-β-carboline-3-carboxylic acid derivatives were designed and synthesized, and first evaluated for their anti-TMV, fungicidal and insecticidal activities. Most of these derivatives exhibited good antiviral activity against TMV both in vitro and in vivo. Especially, the activities of compounds 8 and 15 in vivo were higher than that of ribavirin. The compound 8 exhibited more than 70% fungicidal activities against Cercospora arachidicola Hori, Alternaria solani, Bipolaris maydis, and Rhizoctonia solani at 50 mg/kg, compounds 16 and 20 exhibited more than 60% insecticidal activities against Mythimna separate and Ostrinia nubilalis.
- Song, Hong-Jian,Liu, Yong-Xian,Liu, Yu-Xiu,Huang, Yuan-Qiong,Li, Yong-Qiang,Wang, Qing-Min
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supporting information
p. 5228 - 5233
(2015/01/08)
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- Synthesis and biological evaluation of novel tryptoline derivatives as indoleamine 2,3-dioxygenase (IDO) inhibitors
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Indoleamine 2,3-dioxygenase (IDO) plays a significant role in several disorders such as Alzheimer's disease, age-related cataracts and tumors. A series of novel tryptoline derivatives were synthesized and evaluated for their inhibitory activity against ID
- Tanaka, Minoru,Li, Xin,Hikawa, Hidemasa,Suzuki, Takafumi,Tsutsumi, Katsuhiko,Sato, Masashi,Takikawa, Osamu,Suzuki, Hideharu,Yokoyama, Yuusaku
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p. 1159 - 1165
(2013/03/14)
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- Cis-diastereoselectivity in pictet-spengler reactions of L-tryptophan and electronic circular dichroism studies
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The diastereoselective synthesis of optically active 1,3-disubstituted tetrahydro-β-carbolines using polar protic Pictet-Spengler cyclization of (S)-tryptophan methyl ester with five aldehydes RCHO (R=CH3, C 2H5, C3/
- Rashid, Naghmana,Alam, Samina,Hasan, Mashooda,Khan, Naeema,Khan, Khalid M.,Duddeck, Helmut,Pescitelli, Gennaro,Kenez, Agnes,Antus, Sandor,Kurtan, Tibor
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p. 789 - 795
(2012/11/07)
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- Synthesis and herbicidal activity evaluation of novel β-carboline derivatives
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Based on the original structure of harmine, several novel 1,2,3,4-tetrahydro-β- carboline, β-carboline and 1-substituted-β- carboline derivatives bearing a substituted carbohydrazide group at C-3 were designed and synthesized to investigate the structureactivity relationship of their analogues. All of the compounds were characterized by infrared (IR), proton and carbon nuclear magnetic resonance (1H-NMR, 13C-NMR), and mass spectroscopy (MS). The bioassay tests showed that N'-benzylidene-1-phenyl-β- carboline-3-carbohydrazide (C25H 18N4O, m.w. 390.4) (c2) and N'-(4- trifluoromethylbenzylidene)- 1-phenyl-β-carboline-3-carbohydrazide (C26H17N4OF3, m.w. 458) (d2) exhibited good inhibitory activity against dicotyledonous and monocotyledonous weeds, with EC50 values of 4.83 μM and 14.25 μM, respectively.
- Weng, Qunfang,Huang, Jingfei,Zeng, Yong,Deng, Yueye,Hu, Meiying
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experimental part
p. 3969 - 3980
(2012/09/10)
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- A class of novel N-(1-methyl-β-carboline-3-carbonyl)-N′- (aminoacid-acyl)-hydrazines: Aromatization leaded design, synthesis, in vitro anti-platelet aggregation/in vivo anti-thrombotic evaluation and 3D QSAR analysis
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High anti-thrombotic activity of aminoacid modified tetrahydro-β- carbolines was generally correlated with a small proximity of the side chain of the aminoacid residue to the carboline-cycle. This paper explored that the aromatization of the tetrahydro-β-
- Li, Chunyu,Zhang, Xiaoyi,Zhao, Ming,Wang, Yuji,Wu, Jianhui,Liu, Jiawang,Zheng, Meiqing,Peng, Shiqi
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experimental part
p. 5598 - 5608
(2011/12/21)
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- A class of oral N-[(1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3- carbonyl]- N′-(amino-acid-acyl)hydrazine: Discovery, synthesis, in vitro anti-platelet aggregation/in vivo anti-thrombotic evaluation and 3D QSAR analysis
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The in vivo anti-thrombotic activities of amino acid modified tetrahydro-β-carbolines depended upon the proximity of the side chain of the amino acid residue to the carboline-cycle. Based on this proximity the computerized screening of various tetrahydro-
- Yao, Kun,Zhao, Ming,Zhang, Xiaoyi,Wang, Yuji,Li, Li,Zheng, Meiqing,Peng, Shiqi
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experimental part
p. 3237 - 3249
(2011/08/03)
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- Cytotoxic and insecticidal activities of derivatives of harmine, a natural insecticidal component isolated from peganum harmala
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In a continuing effort to develop novel β-carbolines endowed with better insecticidal activity, a simple high-yielding method for the synthesis of harmine compounds starting from L-tryptophan has been developed and a series of 1,3-substituted β-carboline derivatives have been synthesized and evaluated for their cytotoxicity against insect cultured Sf9 cell line in vitro and insecticidal activities against 4th instar larvae of mosquitos, Culex pipiens quinquefasciatus and mustard aphid, Lipaphis erysimi. The results demonstrated that 1-phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (compound 2) and methyl 1-phenyl-β-carboline-3-carboxylate (compound 13) represented the best potential compounds, with Sf9 cells inhibition rates of 71.55% and 60.21% after 24 h treatment at concentrations of 50-200 mg/L, respectively. Both compounds 2 and 13 also showed strong insecticidal activity towards 4th instar larvae of mosquitos with LC50 values of 20.82 mg/L and 23.98 mg/L, and their LC90 values were 88.29 mg/L and 295.13 mg/L, respectively. Furthermore, the LC50 values of compounds 2 and 13 against mustard aphids were 53.16 mg/L and 68.05 mg/L, and their LC 90 values were 240.10 mg/L and 418.63 mg/L after 48 h treatment. The in vitro cytotoxicity of these compounds was consistent with the insecticidal activity in vivo. The results indicated that the 1- and 3-positions of the β-carboline ring deserve further investigation to develop biorational insecticides based on the natural compound harmine as a lead compound.
- Zeng, Yong,Zhang, Yaomou,Weng, Qunfang,Hu, Meiying,Zhong, Guohua
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experimental part
p. 7775 - 7791
(2011/03/19)
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- Synthesis and cytotoxic activities of β-carboline amino acid ester conjugates
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β-Carboline represents a class of compounds with potent anti-tumor activity by intercalating with DNA. To further enhance the cytotoxic potency and bioavailability of β-carboline, a series of novel β-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were tested using a panel of human tumor cell lines. In addition, the membrane permeability of these compounds was evaluated in vitro using a Caco-2 cell monolayer model. The β-carboline amino acid ester conjugates demonstrated improved cytotoxic activity compared to the parental β-carbolines. In particular, the Lys/Arg conjugates were the most potent analogs with an IC50 value of 4 and 1 μM against human cervical carcinoma cells. The low interaction energy of Arg conjugate based on molecular modeling may contribute to its enhanced cytotoxicity. Taken together, this study provided new insights into structure-activity relationships in the β-carboline amino acid ester conjugates and identified the β-carboline Lys/Arg conjugates as promising lead compounds for further in vivo biological and molecular evaluation.
- Zhao, Ming,Bi, Lanrong,Wang, Wei,Wang, Chao,Baudy-Floc'h, Michele,Ju, Jingfang,Peng, Shiqi
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p. 6998 - 7010
(2007/10/03)
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- HARMINE DERIVATIVES, INTERMEDIATES USED IN THEIR PREPARATION, PREPARATION PROCESSES AND USE THEREOF
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This invention relates to compounds of general formula (I), wherein R1, R2, R3, R4 and R5 are as defined specification; intermediates used in their preparation, preparation processes and use thereof. The present invention produce harmine derivatives with enhanced antihumour activity and lower nervous system toxicity by structurally modification parent structure of β-carboline of harmines at position 1, 2, 3, 7 and 9, The compounds of the present invention can be pre easily with high yield. They can be used in manufacture of a variety of antitumour medicines and medicines used in treatm tumour diseases in combination of light or radiation therapy.
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Page/Page column 14; 15; 95
(2008/06/13)
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- Isolation of mutagenic β-carboline derivatives after nitrite treatment of maillard reaction mixtures and analysis of these compounds from foodstuffs and human urine
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Mixtures of carbohydrate decomposition products and L-tryptophan were incubated at pH 7.0 and 37°C for 4 weeks. These mixtures exhibited mutagenic activity toward S. typhimurium TA 100 without metabolic activation after a nitrite treatment at pH 4.0. Four β-carboline derivatives were isolated as premutagens from mixtures of methylglyoxal and furfural. These premutagens were also found to be contained in daily foodstuffs and human urine samples.
- Masuda, Shuichi,Kanamori, Hisayuki,Kinae, Naohide
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p. 2232 - 2235
(2008/02/03)
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- Microwave accelerated Pictet-Spengler reactions of tryptophan with ketones directed toward the preparation of 1,1-disubstituted indole alkaloids
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Using the Pictet-Spengler reactions of tryptophan with aldehydes under acidic conditions at ambient temperature, diastereoisomers of 1,3-disubstituted-1,2,3,4-tetrahydro-β-carbolines could readily be furnished in short time (0.5-4 h) with good to excellent yields (50-98%). Though intrinsically slow in reaction rates, ketone reactions can be accelerated (from days to minutes) using microwaves in open vessels with high isolated yields (67-99%), making those carbolines feasible reaction intermediates for the synthesis of both natural and unnatural indole alkaloids. Preparation of two indole alkaloids, tetrahydro-β-carbolinediketopiperazines and tetrahydro-β-carbolinehydantoins, were briefly discussed. Graphical Abstract
- Kuo, Fu-Ming,Tseng, Ming-Chung,Yen, Ya-Hew,Chu, Yen-Ho
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p. 12075 - 12084
(2007/10/03)
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- Synthesis and biological evaluation of novel β-carboline derivatives as Tat-TAR interaction inhibitors
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Four new β-carboline derivatives were synthesized bearing guanidinium group or amino group-terminated side chain targeting the TAR element. Compounds 5 and 6 with terminal guanidinium group showed inhibitory activities on Tat-TAR interaction as well as to HIV-1 in MT4 cells. Furthermore, capillary electrophoresis assay implied that compound 6 could not only bind to TAR but also hinder the Tat-TAR interaction.
- Yu, Xiaolin,Lin, Wei,Li, Jingyun,Yang, Ming
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p. 3127 - 3130
(2007/10/03)
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- Kinetics of the formation and decomposition of 1,1′-ethylidenebis[L-tryptophan], an eosinophilia myalgia syndrome-associated compound
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1,1′-Ethylidenebis[L-tryptophan] (EBT), an impurity found in L-tryptophan associated with eosinophilia myalgia syndrome (EMS), has been suggested as one of the causative agents for EMS. High-performance liquid chromatography was used to study the kinetics of EBT formation and decomposition in buffer systems. Initial EBT decomposition was first-order with respect to EBT and strongly pH-dependent. The pH profile suggested that decomposition involved the addition of one proton. The value of the critical pH, above which the rate of EBT decomposition remained constant, was determined to be 4.8. The rate of EBT decomposition increased with increasing temperature, and the activation energy was calculated to be 12.5 kcal/mol. The rate of EBT formation decreased with increasing pH and decreasing temperature. The presence of excess acetaldehyde increased EBT formation to a lesser extent than did the presence of excess L-tryptophan. The results of this study are consistent with the hypothesis that EBT was formed during the absorption stage of the cation exchange operation in the commercial process that resulted in the formation of EMS-associated L-tryptophan.
- Fu, Tong-Jen
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p. 1224 - 1229
(2007/10/03)
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