- Design, synthesis and evaluation of a novel π-π Stacking nano-intercalator as an anti-tumor agent
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Based on the knowledge that cyclohexane-1,4-dione, piperazine and β-carboline are the essential building blocks of DNA intercalators, β-carboline-3-carboxylic acid is a π-π stack-like DNA intercalator, and β-carboline derivatives can form nanoparticles, this paper hypothesized that (2′S,5′S)-tetrahydropyrazino[1′,2′:1,6]- di{2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole}-1′,4′-dione (THPDTPI) would be a π-π stacking lead nano-intercalator. The docking investigation found that THPDTPI can intercalate into DNA in a π-π stacking manner. The simple condensation of 3S-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid provided THPDTPI in good yield and high purity. The TEM, SEM and AFM imaging visualized that THPDTPI formed nanoparticles in ultrapure water, in the solid state and in rat plasma. The Faraday-Tyndall effect proved that THPDTPI exhibited nano-properties in pH 2.0 and pH 7.0 water. Spectrophotometric assays suggested that the interaction model of THPDTPI and CT DNA was π-π stacking intercalation. In vivo THPDTPI dose-dependently slowed the tumor growth of S180 mice with a minimal effective dose of 0.01 μmol kg-1 per day. In vitro THPDTPI exhibited anti-proliferation activities on S180 and HeLa cells with IC50 values of 0.39 and 3.5 μM, respectively. Even when the single dose was raised up to 10 000 fold of the minimal effective dose, i.e. 100 μmol kg-1, THPDTPI still did not show liver, kidney and systemic toxicity in mice. These findings provide a strategy for designing THPDTPI-like π-π stacking nano-intercalators.
- Zhu, Haimei,Song, Yuanbo,Wang, Yuji,Zhao, Ming,Ren, Yi,Wang, Yaonan,Zhao, Shurui,Wu, Jianhui,Peng, Shiqi
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- Fluorescence of a rotationally constrained tryptophan derivative, 3-carboxy-1,2,3,4-tetrahydro-2-carboline
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Despite a plethora of work on tryptophan photophysics, the origin of the complex fluorescence decay kinetics is still unknown. A question remains whether the two fluorescence lifetimes of the tryptophan zwitterion are due to ground-state and therefore excited-state heterogeneity resulting from rotameric forms. To test the conformer model, we synthesized a tryptophan derivative, 3-carboxy-1,2,3,4-tetrahydro-2-carboline, which restricts rotation of the alanyl side chain. The constraint limits the number of conformations available to the molecule without greatly affecting the electronic properties. The absorption and emission spectra and the pK of the amino group are similar to those of tryptophan. The fluorescence decay of the constrained derivative is an apparent monoexponential. The zwitterion has a lifetime of 6.2 ± 0.2 ns and the anion has a lifetime of 4.7 ± 0.2 ns at 25°C. Global analysis of time-resolved emission spectral data for the zwitterion reveals a double-exponential decay, which may reflect two stable conformations of the partially unsaturated six-membered ring. This is discussed in detail in the following paper.
- Tilstra, Luanne,Sattler, Melissa C.,Cherry, William R.,Barkley, Mary D.
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- Synthesis and crystal structure analysis of 9-phenyl-β-carboline
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An efficient method is described for the synthesis of 9-phenyl-9H-pyrido[3,4-b]indole and 9-(4-chlorophenyl)-9H-pyrido[3,4-b]indole by employing a catalytic amount of CuI (10 mole%) without any ligand. The single crystal of 9-phenyl-9H-pyrido[3,4-b]indole
- Meesala, Ramu,Mordi, Mohd Nizam,Mansor, Sharif Mahsufi,Rosli, Mohd Mustaqim
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- Histone demethylating agents as potential S-adenosyl-l-methionine-competitors
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Histone H3 methylation on K9 and/or K27 depends on histone lysine methyltransferases (KMTs). EZH2, one of the components of the PRC2 complex, catalyzes the trimethylation of histone H3K27, which is associated with transcriptional repression and tumor development. H3K9me3 mediated gene silencing may result from other KDMs such as G9a/GLP, SUV39H1-2, SETDB1, CCLD8 and RIZ1. Their disturbance leads to defective cell mitosis. It is therefore desirable to find small molecules that are able to decrease H3K9 and K27 tagging to reinitiate gene transcription. Most KDM inhibitors are still based on SAM co-factor competition/modulation. Herein, functional screening of a diversity library proved to be a useful tool for finding new specific KDM inhibitors; the use of SAM-based pharmacophoric models facilitated the understanding of their possible mechanism of action.
- Navakauskiene,Mori,Christodoulou,Zentelyte,Botta,Via, L. Dalla,Ricci,Damia,Passarella,Zilio,Martinet
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- Highly diastereoselective synthesis of 1-carbamoyl-4-aminoindoloazepinone derivatives via the Ugi reaction
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A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component
- Jida, Mouhamad,Betti, Cecilia,Urbanczyk-Lipkowska, Zofia,Tourwe, Dirk,Ballet, Steven
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- Discovery of furyl/thienyl β-carboline derivatives as potent and selective PDE5 inhibitors with excellent vasorelaxant effect
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Based on our previous studies and predictive docking results, furans and thiophenes were introduced to the privileged tetrahydro-β-carboline scaffold to generate more potent and selective PDE5 inhibitors. A total of 66 novel furyl/thienyl tetrahydro-β-carboline derivatives were designed, synthesized and evaluated for PDE5 inhibition. Tetrahydro-β-carboline-piperazinedione 19f and tetrahydro-β-carboline-hydantoin 26b with optimized pendant 5-ethylfuran/5-ethylthiophene were identified as the most potent PDE5 inhibitors, and showed high selectivity towards PDE5 versus other PDE isozymes, especially PDE6 and PDE11. Further vasorelaxant activity assessments revealed that these PDE5 inhibitors also exhibited significant angiectasis on the norepinephrine-precontracted 3rd-order mesenteric arteries (110–150 μm) via NO–sGC–cGMP pathway, implying their further application for the treatment of vascular diseases.
- Zheng, Hongbo,Wu, Yifeng,Sun, Bin,Cheng, Chuanle,Qiao, Yanan,Jiang, Yuehua,Zhao, Shengtian,Xie, Zhiyu,Tan, Jing,Lou, Hongxiang
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- Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor
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Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, syn
- Roy, Ashis,Sarkar, Tonmoy,Datta, Sebak,Maiti, Arup,Chakrabarti, Monali,Mondal, Trisha,Mondal, Chaitali,Banerjee, Apurba,Roy, Subhasis,Mukherjee, Soumen,Muley, Pragati,Chakraborty, Sabyasachi,Banerjee, Manish,Kundu, Mrinalkanti,Roy, Kuldeep K.
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p. 496 - 503
(2022/01/08)
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- Discovery and preliminary mechanism of 1-carbamoyl β-carbolines as new antifungal candidates
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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.
- Sheng, Tao,Kong, Mengmeng,Wang, Yujie,Wu, HuiJun,Gu, Qin,Chuang, Anita Shyying,Li, Shengkun,Gao, Xuewen
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- Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile
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Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.
- Tran, Kien,Van Den Hauwe, Robin,Sainsily, Xavier,Couvineau, Pierre,C?té, Jér?me,Simard, Louise,Echevarria, Marco,Murza, Alexandre,Serre, Alexandra,Théroux, Léa,Saibi, Sabrina,Haroune, Lounès,Longpré, Jean-Michel,Lesur, Olivier,Auger-Messier, Mannix,Spino, Claude,Bouvier, Michel,Sarret, Philippe,Ballet, Steven,Marsault, éric
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supporting information
p. 5345 - 5364
(2021/02/16)
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- Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids
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We report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L-tryptophan as the starting material. Two key bridged skeleton-forming reactions, namely tandem sequential oxidative cyclopropanol ring-opening cyclization and ketone α-allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, Na-methyl-16-epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N-demethylkoumine) with more complex cage scaffolds has been accomplished.
- He, Ling,Jiang, Yan,Qiao, Zhen,Qiu, Hanyue,Su, Xiaojiao,Tan, Qiuyuan,Yang, Jiaojiao,Yang, Zhao,Zhang, Min,Zhou, Wenqiang
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supporting information
p. 13105 - 13111
(2021/05/10)
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- NITROGEN-CONTAINING COMPOUND, METHOD FOR MANUFACTURING THE SAME, AND OPTICAL FUNCTIONAL MATERIAL INCLUDING THE SAME
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PROBLEM TO BE SOLVED: To provide a novel nitrogen-containing compound having luminescence property. SOLUTION: A nitrogen-containing compound represented by the following formula (I) in which RA, RB, R1, R2, R3, R4, and X are either one of the following (1) and (2). SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0144-0145
(2021/08/21)
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- Nanoparticles of a new small-molecule P-selectin inhibitor attenuate thrombosis, inflammation, and tumor growth in two animal models
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Purpose: To assess whether the newly designed small-molecule oral P-selectin inhibitor 3S-1,2,3,4-tetrahydro-β-carboline-3-methyl aspartyl ester (THCMA) as a nanomedicine enhances antithrombosis, anti-inflammation, and antitumor activity more than the clinical trial drug PSI-697. Methods: THCMA was designed as an amphiphile containing pharmacophores of PSI-697. Its nanofeatures were explored with TEM, SEM, Tyndall effect, ζ-potential, FT-ICR-MS, and NOESY 2D1H NMR. The P-selectin inhibitory effect of THCMA was demonstrated with molecular docking, ultraviolet (UV) spectra, and competitive ELISA. In vivo and in vitro assays — anti-arterial thrombosis, anti–venous thrombosis, anti-inflammation, antitumor growth, anti–platelet aggregation, rat-tail bleeding time, anticoagulation index, soluble P-selectin (sP-selectin) expression, and serum TNFα expression — were performed to explore bioactivity and potential mechanisms. Water solubility of THCMA was measured using UV-absorption spectra. Results: THCMA self-assembled into nanorings of approximately 100 nm in diameter. Its water solubility was about 1,030-fold that of PSI-697. THCMA exhibited more potent P-selectin inhibitory effect than PSI-697. The oral efficacy of THCMA was 100-fold that of PSI-697 in inhibiting arterial and venous thrombosis and tenfold in inhibiting inflamma-tion. THCMA inhibited thrombosis at a dose that produces no coagulation disorders and no bleeding risk. THCMA exhibited enhanced antitumor activity over PSI-697 without systemic chemotherapy toxicity. THCMA significantly inhibited platelet aggregation in vitro and downregulated the expression levels of serum sP-selectin and TNFα in vivo. Conclusion: A new small-molecule P-selectin inhibitor, THCMA, has been successfully designed as a nanomedicine with largely enhanced oral efficacy compared to the clinical trial drug PSI-697, and thus might be developed for the oral treatment of arterial thrombosis, venous thrombosis, inflammation, and cancer-associated thrombosis.
- Feng, Qiqi,Wang, Mengyang,Muhtar, Eldar,Wang, Yaonan,Zhu, Haimei
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p. 5777 - 5795
(2021/09/03)
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- Discovery of β-carboline-(phenylsulfonyl)furoxan hybrids as potential anti-breast cancer agents
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The cytotoxicity properties of the β-carboline alkaloids have been broadly investigated. However, the potential application of β-carbolines was hindered due to the moderate activity in cancer. In the present study, thirty β-carboline-(phenylsulfonyl)furoxan hybrids (11a–j, 12a–j and 13a–j) were designed and synthesized through esterification and amidation reaction strategy, and their inhibitory activities against the human breast cancer cell lines MCF-7 and MDA-MB-231 were evaluated by CCK-8 assay. Biological evaluation presented that the most promising amide derivative 13h, substituted with p-methoxyphenyl group at position 1, generated high concentration of NO and evidently depressed the MCF-7 (IC50 = 0.89 μM) and MDA-MB-231 (IC50 = 0.62 μM) cells proliferation. Particularly, the wound healing and transwell assays demonstrated that 13h significantly inhibited the migration and invasion of MDA-MB-231cells. Furthermore, the preliminary mechanisms studies indicated that 13h induced G2/M phase arrest and apoptosis possibly causing by ROS accumulation and ROS-mediated DNA damage. Based on these considerations, 13h may be a promising antimetastatic agent for breast cancer, which is noteworthy for further exploration.
- Hu, Xu,Gao, Xiang,Gao, Gang,Wang, Yanbing,Cao, Hao,Li, Dahong,Hua, Huiming
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supporting information
(2021/04/02)
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- Design and synthesis of β-carboline derivatives with nitrogen mustard moieties against breast cancer
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To discover the promising antitumor agents, a series of β-carboline derivatives with nitrogen mustard moieties were designed and synthesized. Most target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cells. Among them, (1-meth
- Bai, Jiao,Cao, Hao,Hu, Xu,Hua, Huiming,Li, Dahong,Sun, Jianan,Wang, Jiesen,Wang, Xinyan
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- A class β . Preparation method and anti-tumor application
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The invention discloses β -carbofuran mustard derivatives as well as a preparation method and application thereof, and belongs to the field of natural medicines and medicinal chemistry. The invention specifically relates to a preparation method of a serie
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Paragraph 0027-0030
(2021/09/22)
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- 3-di-amine β- carboline base compound, preparation method and pharmaceutical composition and application thereof
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The invention discloses a 3-position diamine connected beta-carboline alkali compound, and a preparation method, a medicinal composition and a use thereof. The above di-beta-carboline alkali compound and its medicinal salt are represented by general formu
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Paragraph 0145; 0147-0149
(2020/04/29)
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- Glucosamine modified pentacyclic piperazine diketone and preparation and application thereof (by machine translation)
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Aminoglucose-modified pentacyclic piperazinedione, and preparation and application thereofCH in the following formula is disclosed. 2 CO- Aminoglucose-modified pentacyclic piperazinedione The invention discloses a synthetic method thereof, disc
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Paragraph 0023; 0025-0026
(2020/12/14)
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- Hexacyclic piperazinedione compound and preparation, biological activity and application thereof
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The invention discloses a hexacyclic piperazinedione compound as shown in the following formula: tetrahydro-beta-carboline [3: 4] piperazine-2, 5-diketopiperidine [4: 5] imidazole. The invention discloses a preparation method and application thereof. The compound not only has an anti-tumor proliferation effect, but also can inhibit migration and invasion of tumor cells, and also has an in-vivo anti-metastasis effect.
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Paragraph 0017; 0019-0020
(2020/12/14)
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- Molecular hybrid design, synthesis, in vitro and in vivo anticancer evaluation, and mechanism of action of N-acylhydrazone linked, heterobivalent β-carbolines
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A series of N-acylhydrazone-linked, heterobivalent β-carboline derivatives was designed and synthesized from L-tryptophan in a nine-step reaction sequence. The effort resulted in the heterobivalent β-carbolines 10a–t in good yields. The target compounds were characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). The in vitro cytotoxic activity of the synthesized compounds was evaluated against normal EA.HY926 cells and five cancer cell lines: LLC (Lewis lung carcinoma), BGC-823 (gastric carcinoma), CT-26 (murine colon carcinoma), Bel-7402 (liver carcinoma), and MCF-7 (breast carcinoma). Compound 10e, with an IC50 value of 2.41 μM against EA.HY926 cells, was the most potent inhibitor. It showed cytotoxicity against all five cancer cell lines of different origin – murine and human, with IC50 values ranging from 4.2 ± 0.7 to 18.5 ± 3.1 μM. A study of structure-activity relationships indicated that the influence on cytotoxic activities of the substituent in the R9′-position followed the tendency, 2,3,4,5,6-perfluorophenylmethyl > 4-fluorobenzyl > 3-phenylpropyl group. The antitumor efficacies of the selected compounds were also evaluated in mice. Compound 10e exhibited potent antitumor activity, with tumor inhibition of more than 40% for Sarcoma 180 and 36.7% for Lewis lung cancer. Furthermore, the pharmacological mechanisms showed that compound 10e has a certain impairment in the motility of LLC cells, which suggests the anti-metastatic potential. And compound 10e inhibited angiogenesis in chicken chorioallantoic membrane assay, and the anti-angiogenetic potency was more potent than the reference drug combretastatin A4-phosphate (CA4P) at a concentration 50 μM.
- Chen, Wei,Chen, Xiaofei,Dai, Bin,Fan, Wenxi,Guo, Liang,Ma, Qin,Zhang, Jie
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- Design, synthesis, characterization, and biological activities of novel spirooxindole analogues containing hydantoin, thiohydantoin, urea, and thiourea moieties
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On the basis of the scaffolds widely used in drug design, a series of novel spirooxindole derivatives containing hydantoin, thiohydantoin, urea, and thiourea moieties have been designed, synthesized, characterized, and first evaluated for their biological activities. The diastereoselectivity mechanism is proposed, and the systematic conformational analysis is performed. The bioassay results show that the target compounds possess moderate to good antiviral activities against tobacco mosaic virus (TMV), among which compound 22 shows the highest antiviral activity in vitro as well as inactivation, curative, and protection activities in vivo (45 ± 1, 47 ± 3, 50 ± 1, and 51 ± 1%, 500 mg/L, respectively), higher than ribavirin (38 ± 1, 36 ± 1, 38 ± 1, and 36 ± 1%, 500 mg/L, respectively). Thus, compound 22 is a promising candidate for anti-TMV development. Most of these compounds show broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi and selective fungicidal activities against Physalospora piricola, Sclerotinia sclerotiorum, and Rhizoctonia cerealis. Additionally, some of these compounds exhibit insecticidal activity against Culex pipiens pallens, Mythimna separata, Helicoverpa armigera, and Pyrausta nubilalis. Compound 17 exhibits the highest larvicidal activity (LC50 was 0.32 mg/L) against C. pipiens pallens.
- Chen, Linwei,Hao, Yanke,Li, Yongqiang,Liu, Yuxiu,Song, Hongjian,Wang, Qingmin,Zhang, Jingjing
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p. 10618 - 10625
(2020/11/26)
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- Carboline ruthenium complex as well as preparation method and application thereof
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The invention provides a carboline ruthenium complex as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The series of carboline ruthenium complexes provided by the invention not only can in
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Paragraph 0066-0068
(2020/10/14)
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- Design, synthesis, and biological evaluation of novel N-acylhydrazone bond linked heterobivalent β-carbolines as potential anticancer agents
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Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent β-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin—murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 μM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 μM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent β-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.
- Chen, Xiaofei,Guo, Liang,Ma, Qin,Chen, Wei,Fan, Wenxi,Zhang, Jie
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- AGENTS FOR DIFFERENTIATING STEM CELLS AND TREATING CANCER
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The present application discloses a method for identifying an agent for the treatment or prevention of cancer or metastatic cancer comprising the steps of contacting stem cell with a potential agent, and identifying an agent that induces differentiation, or inhibits stem cell pluripotency or growth of the stem cell, wherein such agent is determined to be an anti-cancer agent.
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Paragraph 00744-00745
(2018/10/25)
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- Spirooxoindole acylhydrazone derivative and preparation method thereof, and application of spirooxoindole acylhydrazone derivative in aspects of controlling plant viruses and killing bacteria and pests
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The invention relates to a spirooxoindole acylhydrazone derivative and a preparation method thereof, and an application of the spirooxoindole acylhydrazone derivative in the aspects of controlling plant viruses and killing bacteria and pests. The spirooxoindole acylhydrazone derivative has a formula with groups defined in the specification. The spirooxoindole acylhydrazone derivative provided by the invention shows excellent plant-virus resisting activity and has broad-spectrum bactericidal and pesticidal activities.
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Paragraph 0060; 0061; 0062
(2018/03/26)
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- Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells
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A series of novel β-carboline-based hydroxamate derivatives 12a-k were designed and synthesized, and their biological activities in a series of in vitro assays were evaluated. Several of these β-carboline derivatives not only showed excellent HDAC1/3/6 inhibitory effects, but also displayed significant antitumor activities against five human cancer cells. The most potent compound 12f demonstrated the highest anticancer potency against cancer cell lines with IC50 values of 0.53–1.56 μM, which was considerably more potent than harmine (IC50 = 46.7–55.3 μM) and also three-to ten-fold lower than that of SAHA (IC50 = 4.48–6.26 μM). Immunoblot analysis revealed that 12f dose-dependently inhibited histone H3 and α-tubulin acetylation, confirming its HDAC inhibitory effects. Moreover, 12f significantly arrested HepG2 cells at G2/M phase through inhibiting cell cycle related protein CDK1 and cyclin B in a concentration dependent manner. Interestingly, 12f also exerted strong anti-metastasis activity by simultaneously reducing the protein level of MMP2 and MMP9 and inhibiting MAPK signaling pathway.
- Ling, Yong,Guo, Jing,Yang, Qiuxing,Zhu, Peng,Miao, Jiefei,Gao, Weijie,Peng, Yanfu,Yang, Jiaying,Xu, Kun,Xiong, Biao,Liu, Gongqing,Tao, Jinhua,Luo, Lin,Zhu, Qing,Zhang, Yanan
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p. 398 - 409
(2018/01/01)
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- Design, synthesis and in vitro cytotoxicity studies of novel β-carbolinium bromides
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A series of novel β-carbolinium bromides has been synthesized from easily accessible β-carbolines and 1-aryl-2-bromoethanones. The newly synthesized compounds were evaluated for their in vitro anticancer activity. Among the synthesized derivatives, compounds 16l, 16o and 16s exhibited potent anticancer activity with IC50values of 50= 3.16–7.93 μM). In order to test the mechanism of cell death, we exposed castration resistant prostate cancer cell line (C4-2) to compounds 16l and 16s, which resulted in increased levels of cleaved PARP1 and AO/EB staining, indicating that β-carbolinium salts induce apoptosis in these cells. Additionally, the most potent β-carbolines 16l and 16s were found to inhibit tubulin polymerization.
- Venkataramana Reddy,Mishra, Shriprada,Tantak, Mukund P.,Nikhil, Kumar,Sadana, Rachna,Shah, Kavita,Kumar, Dalip
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supporting information
p. 1379 - 1384
(2017/03/08)
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- [...] - Orn (ClCH2NH) - AA - benzylamine, its synthesis, activity and application (by machine translation)
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The invention discloses the following formula of 13 for β - Carboline -3 - formyl - Orn (ClCH2 NH) - AA - NHCH2 C6 H5 (In the formula AA is selected from L - Arg, L - Asn, L - Asp, L - Glu, L - Gly, L - Ile, L - Leu, L - Met, L - Phe, L - Pro, L - Thr, L - Trp, L - Val residue), discloses a process for their preparation, discloses their inhibition of tumor cell growth, therefore this invention discloses their use as anti-tumor medicament. (by machine translation)
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Paragraph 0022; 0023
(2017/08/27)
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- Spirooxoindole (thio)hydantoin derivative as well as preparation method and application thereof to aspects of plant virus prevention and control, sterilization and insect killing
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The invention relates to a spirooxoindole (thio)hydantoin derivative as well as a preparation method and application thereof to aspects of plant virus prevention and control, sterilization and insect killing. A structural formula of the derivative is a structure shown as a general formula I. The spirooxoindole (thio)hydantoin derivative provided by the invention has excellent plant virus resisting activity and also has broad-spectrum sterilization activity and insect killing activity. (The formula I is shown in the description.).
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Paragraph 0018; 0039; 0041; 0042
(2017/12/04)
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- Indole-TEMPO conjugates alleviate ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function
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Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function.
- Bi, Wei,Bi, Yue,Gao, Xiang,Li, Pengfei,Hou, Shanshan,Zhang, Yanrong,Bammert, Cathy,Jockusch, Steffen,Legalley, Thomas D.,Michael Gibson,Bi, Lanrong
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p. 2545 - 2568
(2017/04/04)
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- Novel heptacyclic compound and synthesis, activity evaluation and application thereof
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The invention discloses a novel heptacyclic compound (2'S,5'S)-tetrahydropyrazine [1',2':1,6] and bis{2,3,4,9-tetrahydro-1H-pyridine [3,4-b] indole}-1',4'-diketone (THPDTPI for short), a preparation method thereof, and antithrombosis action, anti-inflammatory action, anti-tumor action, free radical scavenging action and P-selectin expression inhibition action thereof. Therefore, the invention discloses application of the THPDTPI in preparing a medicament which takes the P-selectin as a target and simultaneously inhibits thrombosis, inflammation and tumor. Because thrombosis and inflammation are the most popular complications in patients with tumor, the THPDTPI not only can treat tumor, but also can prevent patients with tumor from complicating thrombosis and inflammation. The THPDTPI disclosed by the invention has favorable clinical application prospects.
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Paragraph 0018; 0019
(2017/05/27)
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- Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with DNA damage and apoptosis inducing abilities
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A series of novel β-carboline-based hydroxamate derivatives (8a-n) as HDAC inhibitors have been designed and synthesized. Most of these compounds displayed potent histone deacetylase inhibitory effects and good antiproliferative activity with IC50/s
- Liu, Ji,Wang, Tingting,Wang, Xinyang,Luo, Lin,Guo, Jing,Peng, Yanfu,Xu, Qibing,Miao, Jiefei,Zhang, Yanan,Ling, Yong
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p. 1213 - 1219
(2017/07/11)
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- Β-Carboline alkaloid derivative, its preparation process and its medical use
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The invention provides beta-carboline alkaloid derivatives and pharmaceutically acceptable salts thereof, their preparation method, a pharmaceutical composition containing the beta-carboline alkaloid derivatives, and a medical use of the beta-carboline al
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Paragraph 0107; 0165-0167
(2016/10/10)
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- Design, synthesis, and: In vivo evaluations of benzyl N ω-nitro- N α-(9 H -pyrido[3,4- b] indole-3-carbonyl)-l-argininate as an apoptosis inducer capable of decreasing the serum concentration of P-selectin
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A series of findings suggest that the discovery of in vivo apoptosis inducers for chemotherapy is of clinical importance. Based on the analyses of the pharmacophores of in vitro apoptosis inducers, the correlation of P-selectin and apoptosis and the docki
- Xu, Wenyun,Zhao, Ming,Wang, Yuji,Zhu, Haimei,Wang, Yaonan,Zhao, Shurui,Wu, Jianhui,Peng, Shiqi
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supporting information
p. 1730 - 1737
(2016/09/28)
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- AUTOTAXIN INHIBITORS AND USES THEREOF
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Described herein are methods and compositions for the treatment of conditions, diseases, or disorders associated with autotaxin activity. The methods and compositions disclosed herein include the use of at least one autotaxin inhibitor compound.
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Paragraph 00346
(2016/12/22)
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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 0148-0150
(2016/11/28)
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- Design, Synthesis, and Biological Activities of Spirooxindoles Containing Acylhydrazone Fragment Derivatives Based on the Biosynthesis of Alkaloids Derived from Tryptophan
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On the basis of the biosynthesis of alkaloids derived from tryptophan and considering the wide use of spirooxindole in drug molecular design, a series of novel spirooxindole derivatives containing an acylhydrazone moiety were designed, synthesized, and first evaluated for their biological activities. The results of bioassays indicated that the target compounds possessed good activities against tobacco mosaic virus (TMV); especially compound 4, containing a tert-butyl at the benzene ring, exhibited the best antiviral activity in vitro and inactivation, curative, and protection activities in vivo (48.4%, 58 ± 0.4, 55.2 ± 2.3, and 49.7 ± 1.1% at 500 μg/mL, respectively) compared with ribavirin (38.2, 36.4 ± 0.2, 37.5 ± 0.2, and 36.4 ± 0.1% at 500 μg/mL, respectively) and harmine (44.6, 40.5 ± 0.2, 38.6 ± 0.8, and 42.4 ± 0.6% at 500 μg/mL, respectively). At the same time, these compounds exhibited fungicidal activity selectively against certain fungi; most of these derivatives exhibited >60% fungicidal activity against Physalospora piricola at 50 mg/kg. Additionally, compounds 25 and 14 displayed excellent insecticidal activities (60% motality against C. pipiens pallens at 0.25 mg/kg) even at very low concentrations.
- Chen, Linwei,Xie, Jialin,Song, Hongjian,Liu, Yuxiu,Gu, Yucheng,Wang, Lizhong,Wang, Qingmin
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p. 6508 - 6516
(2016/09/09)
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- Iodine-catalyzed one-pot decarboxylative aromatization of tetrahydro-β-carbolines
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A synthetic strategy was developed for the preparation of β-carbolines by one-pot decarboxylation and aromatization of tetrahydro-β-carboline-3-carboxylic acids by employing 10?mol% of iodine in presence of oxidant aqueous H2O2. The method was also successfully extended for the aromatization of tetrahydro-β-carboline-3-methyl esters. The utility of the method was demonstrated in the synthesis of β-carboline alkaloids norharmane, harmane and eudistomin N.
- Meesala, Ramu,Arshad, Ahmad Saifuddin Mohamad,Mordi, Mohd Nizam,Mansor, Sharif Mahsufi
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p. 8537 - 8541
(2016/12/09)
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- Methods for the treatment of metabolic disorders by a selective small molecule autotaxin inhibitor
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Described herein are methods and compositions for treatment or prevention of metabolic disorder(s) in an individual. The methods and compositions disclosed herein include the use of at least one autotaxin inhibitor compound.
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Paragraph 0247
(2015/06/16)
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- T3P-Promoted, Mild, One-Pot Syntheses of Constrained Polycyclic Lactam Dipeptide Analogues via Stereoselective Pictet-Spengler and Meyers Lactamization Reactions
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A new convenient, mild, one-pot procedure is described for the diastereoselective synthesis of constrained 7,5- and 7,6-fused azabicycloalkanes. Using 2-formyl-L-tryptophan and 2-formyl-l-phenylalanine as bielectrophilic building blocks, T3P-mediated Pict
- Jida, Mouhamad,Van Der Poorten, Olivier,Guillemyn, Karel,Urbanczyk-Lipkowska, Zofia,Tourwé, Dirk,Ballet, Steven
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supporting information
p. 4482 - 4485
(2015/09/28)
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- TETRACYCLIC AUTOTAXIN INHIBITORS
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Described herein are compounds that are autotaxin inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with autotaxin activity.
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Paragraph 00292; 00297
(2015/06/08)
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- An efficient one-pot decarboxylative aromatization of tetrahydro-β-carbolines by using N-chlorosuccinimide: total synthesis of norharmane, harmane and eudistomins
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A facile method for the synthesis of a variety of β-carbolines and their natural products such as norharmane (2a), harmane (2b), eudistomins I, N, T, and U (6, 7, 9 and 10, respectively) has been successfully developed via a decorboxylative aromatization tool by employing N-chlorosuccinimide (NCS) as a mild and efficient reagent. Gratifyingly, this reagent system proceeds in a one-pot manner and converted all the tetrahydro-β-carboline acids into their corresponding decorboxylative aromatic products with good to excellent yields. Additionally, this system works well in the case of tetrahydro-β-carboline esters to produce their aromatic partners in high yields.
- Kamal, Ahmed,Sathish, Manda,Prasanthi,Chetna, Jadala,Tangella, Yellaiah,Srinivasulu, Vunnam,Shankaraiah, Nagula,Alarifi, Abdullah
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p. 90121 - 90126
(2015/11/10)
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- Novel β-carboline/hydroxamic acid hybrids targeting both histone deacetylase and DNA display high anticancer activity via regulation of the p53 signaling pathway
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A novel series of hybrids from β-carboline and hydroxamic acid were designed and synthesized. Several compounds (5m, 11b-d, and 11h) not only exerted significant antiproliferation activity against four human colorectal cancer (CRC) cell lines but also sho
- Zhang, Yanan,Ling, Yong,Xu, Chenjun,Luo, Lin,Cao, Jingyi,Feng, Jiao,Xue, Yu,Zhu, Qing,Ju, Caoyun,Li, Fengzhi,Zhang, Yihua,Ling, Xiang
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p. 9214 - 9227
(2015/12/23)
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- Copper(II)-containing C2-symmetric bistetracarboline amides in enantioselective Henry reactions
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A series of new C2-symmetric chiral diamides were synthesized from l-tryptophan and used as chiral ligands chelated with Cu(II) in enantioselective Henry reactions. Ligand 4a with CuCl2·2H2O (5%) showed effective catalytic
- Li, Jin-Liang,Liu, Li,Pei, Yu-Ning,Zhu, Hua-Jie
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p. 9077 - 9083
(2015/03/05)
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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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- Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease
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A series of tacrine-(β-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced β-amyloid (Aβ) aggregation, Cu2+-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, 11l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Aβ aggregation (65.8% at 20 μM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11l might be an excellent multifunctional agent for AD treatment.
- Lan, Jin-Shuai,Xie, Sai-Sai,Li, Su-Yi,Pan, Long-Fei,Wang, Xiao-Bing,Kong, Ling-Yi
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p. 6089 - 6104
(2015/02/02)
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- Synthesis and in vitro biological evaluation of hybrids from tetrahydro-β-carboline and hydroxylcinnamic acid as antitumor carcinoma agents
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Novel hybrids 8a-j and 9a-j were designed and synthesized by coupling the carboxyl group of hydroxylcinnamic acids with tetrahydro-β-carboline alkaloids which were linked with different substituted nitrogen-containing heterocycles at the positions-N9, and
- Lin, Ying,Xia, Xuanping,Yao, Rongxin,Ni, Li,Hu, Jie,Guo, Wenjian,Zhu, Baoling
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p. 343 - 349
(2014/04/17)
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- (R/S)-BINOL-α-phosphoryloxy enecarbamate-mediated and (R/S)-Titanium(IV) BINOLates-catalyzed enantioselective intramolecular heck/aza-diels-alder cycloaddition (IHADA): An expedient methodology
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An (R/S)-titanium(IV) BINOLate-catalyzed highly enantioselective intramolecular Heck/aza-Diels-Alder cycloaddition (IHADA) cascade was developed to prepare tetrahydropyridoindoles (tHPs) and octahydropyrazinopyridoindoles (oHPPs) from in situ generated (R/S)-BINOL α-phosphoryloxy carbamate (αPPC2) in one pot. Chiral cooperativity between (R/S)-αPPC2 and (R/S)-titanium(IV) BINOLate was observed and successfully utilized for the construction of various tHPs (7 examples) and oHPPs (17 examples). Copyright
- Khan, Imran A.,Saxena, Anil K.
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p. 2617 - 2626
(2013/10/21)
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- Novel antitumor indolizino[6,7-b]indoles with multiple modes of action: DNA cross-linking and topoisomerase i and II inhibition
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A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of β-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro. Treatment of human breast carcinoma MX-1 xenograft-bearing nude mice with compounds 18b and 28c achieved more than 99% tumor remission. We also observed that 18a displayed potent therapeutic efficacy against human lung adenocarcinoma A549 and colon cancer HT-29 xenografts. These results revealed that compound 18a was more potent than irinotecan against HT-29 cells and was as potent as irinotecan against A549 cells in xenograft models. Furthermore, we demonstrated that these derivatives possess multiple modes of action, such as induction of DNA cross-linking, inhibition of topoisomerase I and II, and cell-cycle arrest at the S-phase.
- Chaniyara, Ravi,Tala, Satishkumar,Chen, Chi-Wei,Zang, Xiuguo,Kakadiya, Rajesh,Lin, Li-Fang,Chen, Ching-Huang,Chien, Shin-I,Chou, Ting-Chao,Tsai, Tung-Hu,Lee, Te-Chang,Shah, Anamik,Su, Tsann-Long
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p. 1544 - 1563
(2013/04/10)
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- Synthesis and biological evaluation of novel β-carboline derivatives as antiproliferative agents
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A series of novel β-carboline derivatives was synthesized and evaluated for their cytotoxic activities in vitro against two human tumor cell lines. Most of the compounds showed moderate to potent cytotoxic activities against the tested cell lines, in whic
- Chen, Jing,Du, Wenting,Tao, Xuefen,Huang, Jiawei,Song, Yuliang,Ying, Huazhou
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p. 879 - 885
(2013/12/04)
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- Design, synthesis, and evaluation of a novel class of 2,3-disubstituted- tetrahydro-β-carboline derivatives
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Several novel tetrahydro-β-carboline derivatives with amino acid residues at the 2-position and a glucosamine group at the 3-position of the tetrahydro-β-carboline nucleus were synthesized from a readily available starting material, tryptophane, and were evaluated for their anti-inflammatory activity in the present study. Our results showed that all of the derivatives tested exhibited a significant inhibition of xylene-induced inflammation in mice.
- Zeng, Li,Zhang, Jianwei
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supporting information; scheme or table
p. 3718 - 3722
(2012/07/17)
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- Structure-activity relationship in the antitumor activity of 6-, 8- or 6,8-substituted 3-benzylamino-β-carboline derivatives
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We synthesized 47 kinds of 3-amino- or 3-benzylamino-β-carboline derivatives with a substituent on the 6-, 8-, or 6,8-carbon atoms and evaluated their antitumor activities for Hela S-3 and Sarcoma 180 cell lines using a 3-(4,5-dimethylthiazol-2-yl)-2,5-di
- Ikeda, Reiko,Kimura, Takanori,Tsutsumi, Tatsuya,Tamura, Syunsuke,Sakai, Norio,Konakahara, Takeo
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supporting information; experimental part
p. 3506 - 3515
(2012/07/03)
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