- 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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- TCCA-mediated oxidative rearrangement of tetrahydro-β-carbolines: Facile access to spirooxindoles and the total synthesis of (±)-coerulescine and (±)-horsfiline
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Multi-reactive centered reagents are beneficial in chemical synthesis due to their advantage of minimal material utilization and formation of less by-products. Trichloroisocyanuric acid (TCCA), a reagent with three reactive centers, was employed in the synthesis of spirooxindoles through the oxidative rearrangement of various N-protected tetrahydro-β-carbolines. In this protocol, low equivalents of TCCA were required to access spirooxindoles (up to 99% yield) with a wide substrate scope. Furthermore, the applicability and robustness of this protocol were proven for the gram-scale total synthesis of natural alkaloids such as (±)-coerulescine (1) and (±)-horsfiline (2) in excellent yields.
- Sathish, Manda,Sakla, Akash P.,Nachtigall, Fabiane M.,Santos, Leonardo S.,Shankaraiah, Nagula
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p. 16537 - 16546
(2021/05/19)
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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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- 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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- 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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- 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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- 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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- 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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- Novel multifunctional ascorbic triazole derivatives for amyloidogenic pathway inhibition, anti-inflammation, and neuroprotection
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Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds 2c and 5c exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds 2c and 5c were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2.
- Chauthong, Nattapong,Jiaranaikulwanitch, Jutamas,Jiranusornkul, Supat,Nilkosol, Supitcha,Pandith, Hataichanok,Tadtong, Sarin,Thammarat, Phanit,Vajragupta, Opa
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supporting information
(2021/06/15)
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- Exploration of TRPM8 Binding Sites by β-Carboline-Based Antagonists and Their in Vitro Characterization and in Vivo Analgesic Activities
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Transient receptor potential melastatin 8 (TRPM8) ion channel represents a valuable pharmacological option for several therapeutic areas. Here, a series of conformationally restricted derivatives of the previously described TRPM8 antagonist N,N′-dibenzyl
- Bertamino, Alessia,Ostacolo, Carmine,Medina, Alicia,Di Sarno, Veronica,Lauro, Gianluigi,Ciaglia, Tania,Vestuto, Vincenzo,Pepe, Giacomo,Basilicata, Manuela Giovanna,Musella, Simona,Smaldone, Gerardina,Cristiano, Claudia,Gonzalez-Rodriguez, Sara,Fernandez-Carvajal, Asia,Bifulco, Giuseppe,Campiglia, Pietro,Gomez-Monterrey, Isabel,Russo, Roberto
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p. 9672 - 9694
(2020/10/19)
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- Design and synthesis of β-carboline linked aryl sulfonyl piperazine derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability
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A series of new β-carboline linked aryl sulfonyl piperazine congeners have been synthesized by coupling various β-carboline acids with substituted aryl sulfonyl piperazines. Evaluation of their anticancer activity against a panel of human cancer cell lines such as colon (HT-29), breast (MDA-MB-231), bone osteosarcoma (MG-63), brain (U87 MG), prostate (PC- 3) and normal monkey kidney (Vero) cell line has been done. Among the series, compound 8ec and 8ed has shown most potent cytotoxicity with an IC50 values of 2.80 ± 0.10 μM and 0.59 ± 0.28 μM respectively against MG-63 cell line and also potent on other cell lines tested. Compounds 8ec and 8ed was found to inhibit Topo II that is confirmed by specific Topo II inhibition assay. DNA binding studies, cell cycle analysis, Annexin V study indicate that these compounds has potential anticancer activity. Molecular docking studies for compound 8ec and 8ed are incorporated to understand the nature of interaction with topoisomerase IIα and dsDNA.
- Alvala, Mallika,Godugu, Chandraiah,Kalle, Arunasree M.,Kiranmai, Gaddam,Lakshmi Manasa, Kesari,Nagendra Babu, Bathini,Nagesh, Narayana,Sagar, Arpita,Sigalapalli, Dilep Kumar,Thatikonda, Sowjanya
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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 0038; 0060-0062; 0063-0065
(2020/07/13)
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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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- Synthesis of Spiro-Pyrrolidinyloxindoles by Oxidative Rearrangement of N-Acyltetrahydro-β-carbolines Using an Oxone/Aqueous Acetone Mixture
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Spiro-pyrrolidinyl-2-oxindoles were prepared by the oxidative rearrangement of Na-acetyl-1,2,3,4-tetrahydro-β-carbolines (THBC) using dimethyldioxirane generated in situ. The Na-acetyl THBC substrates were obtained by Pictet-Spengler and acyl-Pictet-Spengler reactions of L-tryptophan methyl ester, followed by Na-acetylation. The stereoselectivity of the oxidative rearrangement was evaluated and 2D nuclear magnetic resonance (NMR) was used to determine the stereochemistry of the oxindole products relative to L-tryptophan. Density functional theory calculations were consistent with a face selective, substrate controlled, epoxidation of the indolic double bond. The calculations indicated that the resulting epoxide would readily rearrange at room temperature via a concerted ring opening/ring contraction process to give the 3-substituted-2-oxindole.
- Mar?al, Luisa L.,Garden, Simon J.
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- Design, synthesis and evaluation of novel bivalent β-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease
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To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent β-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC50 = 1.7 and 2.7 μM, respectively), Aβ1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aβ1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25 μM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H2O2, okadaic acid (OA) and Aβ1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.
- Zhao, Yifan,Ye, Feng,Xu, Jian,Liao, Qinghong,Chen, Lei,Zhang, Weijia,Sun, Haopeng,Liu, Wenyuan,Feng, Feng,Qu, Wei
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p. 3812 - 3824
(2018/06/30)
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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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p. 767 - 780
(2018/09/25)
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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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- 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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- Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4-b)indoles
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The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED50 = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC50 = 6.7 μM), CRP-XL (IC50 = 53.5 μM), and convulxin (CVX) (IC50 = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC50 = 10.4 μM; CRP-XL, IC50 = 158 μM; CVX, IC50 = 11 μM) than any of its enantiomers S (6c) (collagen, IC50 = 25.3 μM; CRP-XL, IC50 = 181.4 μM; CVX, IC50 = 9 μM) and R (6d) (collagen, IC50 = 126.3 μM; CRP-XL, IC50 > 500 μM; CVX, IC50 = 86.8 μM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies.
- Bhunia, Shome S.,Misra, Ankita,Khan, Imran A.,Gaur, Stuti,Jain, Manish,Singh, Surendra,Saxena, Aaruni,Hohlfield, Thomas,Dikshit, Madhu,Saxena, Anil K.
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p. 322 - 337
(2017/04/26)
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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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- [...] - 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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- Neuritogenic activity of bi-functional bis-tryptoline triazole
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Alzheimer's disease (AD) is a common neurodegenerative disorder, one of the hallmarks of which is the deposition of aggregated β-amyloid peptides (Aβ40,42) as plaques in the brain. Oligomers of these peptides have been reported to be toxic and to inhibit neurite outgrowth, as evidenced by neurite dystrophy and significant loss of synaptic connectivity of neurons in the AD brain resulting in cognitive decline. These peptides also react with biological metal in the brain to generate free radicals, thereby aggravating neuronal cell injury and death. Herein, multifunctional triazole-based compounds acting on multiple targets, namely β-secretase (BACE1), β-amyloid peptides (Aβ) as well as those possessing metal chelation and antioxidant properties, were developed and evaluated for neuritogenic activity in P19-derived neurons. At the non-cytotoxic concentration (1?nM), all multifunctional compounds significantly enhanced neurite outgrowth. New bis-tryptoline triazole (BTT) increased the neurite length and neurite number, by 93.25% and 136.09% over the control, respectively. This finding demonstrates the ability of multifunctional compounds targeting Aβ to enhance neurite outgrowth in addition to their neuroprotective action.
- Jiaranaikulwanitch, Jutamas,Tadtong, Sarin,Govitrapong, Piyarat,Fokin, Valery V.,Vajragupta, Opa
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p. 1195 - 1201
(2017/02/05)
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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 0109; 0165; 0168; 0169
(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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p. 1730 - 1737
(2016/09/28)
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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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- Macrocyclic analogues of the diuretic insect neuropeptide helicokinin I show strong receptor-binding
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Abstract Helicokinin I, a diuretic neuropeptide of the relevant cotton pest Helicoverpa zea represents a promising target for the design of insect neuropeptide mimetics. Using a ring-closing metathesis reaction, N-terminal bridged macrocyclic helicokinin
- Tran Van, Chien,Nennstiel, Dirk,Scherkenbeck, Jürgen
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p. 3278 - 3286
(2015/08/03)
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- Isolation and total synthesis of stolonines A-C, unique taurine amides from the Australian marine tunicate Cnemidocarpa stolonifera
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Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to subtropical East Coast of Australia, with only two pyridoacridine compounds reported previously. Qualitative analysis of the lead-like enhanced fractions of C. stolonifera by LC-MS dual electrospray ionization coupled with PDA and ELSD detectors led to the identification of three new natural products, stolonines A-C (1-3), belonging to the taurine amide structure class. Structures of the new compounds were determined by NMR and MS analyses and later verified by total synthesis. This is the first time that the conjugates of taurine with 3-indoleglyoxylic acid, quinoline-2-carboxylic acid and β-carboline-3-carboxylic acid present in stolonines A-C (1-3), respectively, have been reported. An immunofluorescence assay on PC3 cells indicated that compounds 1 and 3 increased cell size, induced mitochondrial texture elongation, and caused apoptosis in PC3 cells.
- Tran, Trong D.,Pham, Ngoc B.,Ekins, Merrick,Hooper, John N.A.,Quinn, Ronald J.
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p. 4556 - 4576
(2015/08/06)
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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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- 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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- 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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- (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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supporting information
p. 2617 - 2626
(2013/10/21)
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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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- Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents
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Callophycin A was originally isolated from the red aμgae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and se
- Shen, Li,Park, Eun-Jung,Kondratyuk, Tamara P.,Guendisch, Daniela,Marler, Laura,Pezzuto, John M.,Wright, Anthony D.,Sun, Dianqing
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experimental part
p. 6182 - 6195
(2011/12/15)
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- Facile and efficient one-pot synthesis of β-carbolines
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Initial formation of tetrahydrocarboline 3 from tryptophan methyl ester 1 and aldehyde 2 by Pictet-Spengler reaction, followed by treatment with trichlorocyanuric acid, provides a facile and efficient route for a one-pot synthesis of-carbolines with excellent yields. Copyright Taylor & Francis Group, LLC.
- Tang, Jian-Guo,Liu, Han,Zhou, Zhong-Yu,Liu, Ji-Kai
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experimental part
p. 1411 - 1417
(2010/07/06)
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- A class of 3 S -2-aminoacyltetrahydro-β-carboline-3-carboxylic acids: Their facile synthesis, inhibition for platelet activation, and high in vivo anti-thrombotic potency
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3S-Tetrahydro-β-carboline-3-carboxylic acid (TCCA) effectively inhibits ADP-induced platelet activation. This paper used TCCA as a lead, modified its 2-position with amino acids, and provided 20 novel 3S-2-aminoacyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acids (5a-t). With the in vitro assay, it was demonstrated that this modification diminished the IC50 values from 701 nM of TCCA to 10 nM of 5a-t. With the in vivo assay, it was demonstrated that this modification reduced the efficacious dose from 5.0 μmol/kg of TCCA to 0.1 μmol/kg of 5a-t. Comparing the Cerius2 based conformation of them with that of their analogues, the 3-position modified TCCA, it was suggested that the comparatively unfolded conformation was one of the important factors of enhancing the in vivo antithrombotic potency.
- Liu, Jiawang,Jiang, Xueyun,Zhao, Ming,Zhang, Xiaoyi,Zheng, Meiqing,Peng, Li,Peng, Shiqi
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experimental part
p. 3106 - 3116
(2010/09/05)
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- Triazolyl tryptoline derivatives as β-secretase inhibitors
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Tryptoline, a core structure of ochrolifuanine E, which is a hit compound from virtual screening of the Thai herbal database against BACE1 was used as a scaffold for the design of BACE1 inhibitors. The tryptoline was linked with different side chains by 1
- Jiaranaikulwanitch, Jutamas,Boonyarat, Chantana,Fokin, Valery V.,Vajragupta, Opa
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supporting information; experimental part
p. 6572 - 6576
(2010/12/18)
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- Toward breast cancer resistance protein (BCRP) inhibitors: design, synthesis of a series of new simplified fumitremorgin C analogues
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In this study, we report the design and synthesis of a series of new simplified fumitremorgin C analogues. The preliminary biological study indicated some of these simplified fumitremorgin C might be developed into breast cancer resistance inhibitors.
- Wu, Guofeng,Liu, Jiawang,Bi, Lanrong,Zhao, Ming,Wang, Chao,Baudy-Floc'h, Miche?le,Ju, Jingfang,Peng, Shiqi
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p. 5510 - 5528
(2008/02/07)
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- ENZYME INHIBITORS
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Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R2is the side chain of a natural or non-natural alpha amino acid; Y is a bond, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(O)NR3-, -C(=S)-NR3 , -C(=NH)NR3 or -S(=O)2NR3- wherein R3 is hydrogen or optionally substituted C1-C6 alkyl; L1 is a divalent radical of formula -(Alk1)m(Q)n(Alk2)p- wherein m, n and p are independently 0 or 1 , Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula -X2-Q1- or -Q1-X2- wherein X2 is -O-, S- or NRA- wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, AIk1 and AIk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, C1-C6 alkylene, C2-C6 alkenylene ,or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl; X1 represents a bond; -C(=O); or -S(=O)2-; -NR4C(=O)-, -C(=O)NR4-, -NR4C(=O)NR5- , -NR4S(=O)2-, or -S(=O)2NR4-wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; z is 0 or 1 ; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals R1R2NH-Y-L1-X1-[CH2]Z- and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONHOH, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms.
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Page/Page column 48
(2008/06/13)
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- Modified Pictet-Spengler reaction. A highly diastereoselective approach to 1,2,3-trisubstituted-1,2,3,4-tetrahydro-β-carbolines using perhydro-1,3-heterocycles
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A flexible variant of the Pictet-Spengler reaction employing oxazinanes as synthetic equivalents of several carbonyl compounds has been developed. Using acid catalyzed one pot condensation of perhydro-1,3-heterocycles various 1,3-disubstituted and 1,2,3-trisubstituted-1,2,3,4-tetrahydro-β-carbolines (THBCs) have been synthesized diastereoselectively.
- Singh, Kamaljit,Deb, Prasant K,Venugopalan
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p. 7939 - 7949
(2007/10/03)
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- Microwave assisted stereospecific synthesis of (S)-3-substituted 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido [3,4-b]indole-1,4-diones
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A new easy way of preparing (S)-3-substituted 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b] indole-1,4-diones, an important intermediate compound, is described using microwave irradiation supported on silica gel. The reaction is generalised and good to excellent yields of enantiomerically pure products are obtained.
- Pandey, Suresh K.,Awasthi, Keshav K.,Saxena, Anil K.
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p. 4437 - 4442
(2007/10/03)
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- Synthesis, molecular modeling and QSAR studies in chiral 2,3-disubstituted-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indoles as potential modulators of opioid antinociception
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In view of coexistence of opioid and cholecystokinin (CCK) in the brain areas concerned with pain processing, some semirigid racemic and chiral anlogues of a potent CCK receptor antagonist (benzotript) have been synthesized and tested for their modulatory
- Saxena, Anil K,Pandey, Suresh K,Tripathi, Ravish C,Raghubir, Ram
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p. 1559 - 1570
(2007/10/03)
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- The fate of the tryptophan stereocenter in the synthesis of 7,10,16,16a-tetrahydro-11H-quinazolino[2',3':3,4]pyrazino[1,2-b]β-carboline-5,8-diones
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Condensation reactions of anthranilic acid with iminoethers 14-17 derived from tetracycles 9-13 to give the title hexacyclic compounds reflect a preferred trans-relationship for H(10)-H(16a) protons in C(7)-unsubstituted products and a cis-relatioship for
- Madrigal, Antonio,Grande, Mercedes,Avendao, Carmen
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p. 3515 - 3526
(2007/10/03)
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- Fumitremorgin C analogs that reverse mitoxantrone resistance in human colon carcinoma cells
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A series of diketopiperazines (1a) that mimic the natural product, fumitremorgin C (1), were synthesized. This class of compounds enhanced the sensitivity of a mitoxantrone-selected colon carcinoma cell line, S1-M1-3.2, to various antitumor agents, thereb
- He, Haiyin,Rabindran, Sridhar G.,Greenberger, Lee M.,Carter, Guy T.
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p. 424 - 437
(2007/10/03)
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- Method for determining the therapeutic activity of metalloproteinase inhibitor compounds, new inhibitor compounds, and the therapeutic use thereof
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A method for determining the activity as pharmacological agents of zinc-dependent metalloproteinase inhibiting peptidomimetic chemical compounds extracted from snake venom for the therapeutic treatment of disturbances created in mammals by metalloproteinases of endogenous origin produced in the organism of the mammals themselves, along with new inhibitor compounds determined in this way and their pharmaceutical use in a variety of important human pathologies connected with endogenous metalloproteinase activation.
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- Tetrahydro-β-carboline dithioic acid derivatives and treatment of liver diseases
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Tetrahydro-β-carboline derivatives of the formula: STR1 wherein R1 is hydrogen atom, a lower alkyl group, a cycloalkyl group, phenyl group or a hydroxy-substituted lower alkyl group, R2 is hydrogen atom, an alkyl group, or a group of
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- Some 3-carboxamides of β-carboline and tetrahydro-β-carboline
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A series of tetrahydro-β-carboline-3-carboxamides (L- and D-series) was made by the interaction of the respective amine with the appriopriate methyl tetrahydro-β-carboline-3-carboxylate.The β-carboline-3-carboxamides were prepared by a similar route from methyl β-carboline-3-carboxylate or by aromatization of the respective tetrahydro-β-carboline-3-carboxamide.The diastereomers of N-sec-butyl tetrahydro-β-carboline-3-carboxamide (L- and D-series) were separated by chromatography.
- Couts, Ronald T.,Micetich, Ronald G.,Baker, Glen B,Benderly, Abraham,Dewhurst, Tim,et al.
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p. 131 - 142
(2007/10/02)
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