Α-carboline Derivatives Research Articles

Chemoselective synthesis of α-carboline derivatives via hypervalent iodine-catalyzed [3+3] annulation under metal-free conditions

A strategy for the synthesis of α-carboline derivatives from indole-3-carboxaldehydes and 3-aminocyclohex-2-enones under metal-free conditions has been developed. The combination use of phenyliodine (III) diacetate (PIDA) and benzoic acid could significantly facilitate the corresponding [3 ​+ ​3] annulation process. This newly developed strategy featured unextraordinary chemoselectivity, good functional group tolerance and the preservation of the carbonyl group of the ketone substrates, which offers the possibility for further transformation of the products.

Discovery of novel α-carboline derivatives as glycogen synthase kinase-3β inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss, and behavioral disturbances, ultimately resulting in death. The critical roles of glycogen synthase kinase-3β (GSK-3β) in tau pathology have also received considerable attention. Based on molecular docking studies, a series of novel α-carboline derivatives were designed, synthesized, and evaluated as GSK-3β inhibitors for their various biological activities. Among them, compound ZCH-9 showed the most potent inhibitory activity against GSK-3β, with an IC50 value of 1.71 ± 0.09 µM. The cytotoxicity assay showed that ZCH-9 had low cytotoxicity toward the cell lines SH-SY5Y, HepG2, and HL-7702. Moreover, Western blot analysis indicated that ZCH-9 effectively inhibited hyperphosphorylation of the tau protein in okadaic acid-treated SH-SY5Y cells. The binding mode between ZCH-9 and GSK-3β was analyzed and further clarified throughout the molecular dynamics simulations. In general, these results suggested that the α-carboline-based small-molecule compounds could serve as potential candidates targeting GSK-3β for the treatment of AD.

Design, synthesis, and in vitro protective effect evaluation of α-carboline derivatives against H2O2-induced cardiomyocyte injury

As one of the most important features of myocardial ischemia reperfusion (MI/R) injury, the overproduction of reactive oxygen species (ROS) overwhelms the intrinsic antioxidant and impairs the function of mitochondria and, finally, leads to cardiomyocyte death. To improve the damage of cardiomyocyte caused by oxidative stress, a series of α-carboline derivatives were designed and synthesized in this study. The biological studies revealed that most of the α-carbolines exhibited obvious protective activities against H2O2-induced cardiomyocyte injury. Among them, compound 14b significantly increased the cell viability in H2O2-induced oxidative stress in H9c2 cardiomyoblasts with a concentration-dependent manner, which was more potent than polydatin. Pretreatment of 14b obviously inhibited H2O2-induced lactate dehydrogenase (LDH) leakage, enhanced the capacity of endogenous antioxidant defenses, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and reduced the formation of the toxic product of lipid peroxidation (malondialdehyde, MDA). In addition, 14b effectively reduced the overproduction of ROS and restored the mitochondrial membrane potential ΔΨm, better than that of polydatin. Flow cytometry analysis demonstrated that 14b markedly reduced both necrosis and apoptosis in H9c2 cells after the exposure to H2O2. Further Western blot analysis revealed that 14b obviously decreased the ratio of Bax/Bcl-2 and reduced the expression of cytochrome c. Overall, these results revealed the potential of α-carboline 14b as a promising cardioprotective agent against H2O2-induced oxidative injury.

Asymmetric Synthesis of α-Carboline Derivatives

Asymmetric Synthesis of α-Carboline Derivatives

Pd-NHC catalyzed Suzuki–Miyaura couplings on 3-bromo-9H-pyrido[2,3-b]indole-6-sulfonamide

A series of novel α-carboline derivatives such as 3-aryl-9H-pyrido[2,3-b]indole-6-sulfonamides have been synthesized from the readily available low-cost raw material, benzotriazole which is subjected to nucleophilic aromatic substitution with 5-bromo-2-chloropyridine followed by sequential steps of cyclization, sulfonation, amidation, and finally Suzuki–Miyaura coupling reactions. The C–C bond formation between 3-bromo-9H-pyrido[2.3-b]indole-6-sulfonamide and various boronic acids was achieved with more accessible palladium pre-catalyst, Pd-PEPPSI-IPr via Suzuki coupling under microwave condition in a short reaction time with excellent yields.

Synthesis and photophysical properties of carboline derivatives and their applications in OLEDs

ABSTRACTFour novel meta-linked carboline derivatives, two δ-carboline-based, 1, 3-bis (5H-pyrido[3,2-b]- indol-5-yl)benzene (mCdP) and 2,6-bis(5H-pyrido[3,2-b]indol-5-yl)pyridine (26mCdPy) were synthesized, as well as two α-carboline derivatives, 1,3-bis(9H-pyrido[2,3-b]indol-9-yl) benzene (mCaP) and 2,6-bis(9H-pyrido[2,3-b]indol-9-yl)pyridine (26mCaPy) as comparison. The triplet energy of four compounds was higher than 2.70 eV, which was enough to be the host materials for FIrpic-doped (2.65 eV) blue PhOLEDs. The structure-properties relationship of four host materials was investigated and the efficiencies of blue PhOLED were 42.6 cd A−1, 32.3 lm W−1 and 21.4% of external quantum efficiency at 1 cd m−2 for mCaP.

Abstract 5066: Impact of Brk-inhibitors on nondirectional and directed migration of breast cancer cells

Abstract The non-receptor tyrosine kinase Brk (breast tumor kinase, PTK-6) has been linked to various effects in tumor cells including cell proliferation, differentiation and migration. Modulation of cellular signaling occurs due to protein scaffolding and substrate phosphorylation, while effects depend on cell type and molecular context. Recent findings suggest, that some hallmark effects of cancer may be linked to the active kinase whereas inactive Brk seems to be involved in different physiological processes of epithelial cells. Novel α-carboline derivatives were described previously and identified as Brk inhibitors in in-vitro testing. We examined the effect of four candidates MK5, MK136, MK138 and MK150 in breast cancer cell lines regarding Brk as a modulator of cell migration. Cell lines MDA-MB-231 and MDA-MB-468 were cultivated as indicated by the distributor. Inhibition of non-directional migration over a given period of time was determined by scratch assays barring proliferation by addition of 50 mM hydroxyurea. The gap was created using silicon inserts and TScratch software was used to evaluate cell free surface area. Directional migration was investigated by trans-well assay utilizing FCS as attractant and an 8 μm pore membrane in combination with xCellingence real time measurement. Statistical evaluation was conducted using 1-way ANOVA followed by Dunnett's test. In scratch assays samples incubated with 1 μM of each substance showed a larger cell free area after 24 hours for MDA-MB-231 cells and after 30 hours for MDA-MB-46 cells. The increase was significant in MDA-MB-231 cells for substance MK136 (32.07±17.21%, p<0.1) and highly significant for MK138 (52.37±7.00%, p<0.001) compared to DMSO treated control (7.73±3.22%). Furthermore, the effect of MK138 increased in a concentration-dependent manner yielding consistently highly significant differences at a concentration of 1 μM (36.77±14.53%, N = 8 vs. 9.870±1.12%, N = 4). MK138 displayed a significant difference in MDA-MB-468 cells as well (37.27±12.56% vs. 10.07±3.04%, p<0.01). In transwell experiments MDA-MB-231 cells showed significantly impaired migration when incubated with MK138 and MK150. For MK138 a concentration-dependent effect was found similar to the scratch assay. In cell line MDA-MB-468 the inhibitor MK138 accounted for a significant decrease in directional migration as well. Our findings indicate an influence of pharmacological Brk-inhibition on the migratory ability of breast cancer cells. These effects were evident for all tested substances and constantly significant and concentration-dependent for MK138 making unspecific effects unlikely. The mechanism of Brk activity in modulation of migratory processes needs to be further addressed to better understand and exploit its influence on tumor cell migration, dissemination and metastasis. This work was supported by the German Research Foundation (DFG, Grant No. RI1196/4-1). Citation Format: Markus Oelze, Franziska I. Kluwe, Tom Wersig, Wolfgang Sippl, Andreas Hilgeroth, Christoph A. Ritter. Impact of Brk-inhibitors on nondirectional and directed migration of breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5066.

α-Carboline derivative TJY-16 inhibits tumor growth by inducing G2/M cell cycle arrest in glioma cells.

BackgroundGlioblastoma multiforme (GBM) is the most lethal primary brain tumors which remains difficult to cure despite advances in surgery, radiotherapy and chemotherapy. Therefore, the development of new drug is urgently needed. α-carboline derivatives were usually isolated from marine animals such as Britannia marine tunicate Dendrodoa grossularia and Indonesian ascidian Polycarpa aurata. In this study, we have synthesized several α-carboline compounds and examined their anti-glioma activities.ResultsWe report that among α-carboline derivatives TJY-16 (6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2,3-b] indole) is the most potent α-carboline analog to induce glioma cell death with IC50 value of around 50 nM. TJY-16 decreased cell viability of glioma cells in a concentration- and time-dependent manner. Trypan blue exclusion assay showed that the reduction of cell viability was due to both cell growth inhibition and cell death. Flow cytometric analysis showed that TJY-16 induced G2/M cell cycle arrest followed by induction of sub-G1 phase. Hoechst staining detected the apoptotic features such as nuclear shrinkage and DNA condensation. Western blot analysis showed the increased level of cleaved caspase-3. The activation of caspase-8 and depolarization of mitochondrial membrane potential (ΔΨm) indicated that both extrinsic and intrinsic apoptotic pathways were involved in TJY-16-induced apoptosis. TJY-16 effectively inhibited tumor growth and induced caspase-3 activation in the xenograft tumor model of U87 glioma cells.ConclusionsOur results suggest that TJY-16 may kill glioma cells by inducing G2/M cell cycle arrest followed by apoptosis. Thus, TJY-16 is a promising agent for the treatment of malignant gliomas.

Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells

In our continued focus on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesized a novel series of 3,9-substituted α-carboline derivatives and evaluated the new compounds for antiproliferactive effects. Structure activity relationships revealed that a COOCH3 or CH2OH group at position-3 and substituted benzyl group at position-9 of the α-carboline nucleus were crucial for maximal activity. The most active compound, 11, showed high levels of cytotoxicity against HL-60, COLO 205, Hep 3B, and H460 cells with IC50 values of 0.3, 0.49, 0.7, and 0.8 μM, respectively. The effect of compound 11 on the cell cycle distribution demonstrated G2/M arrest in COLO 205 cells. Furthermore, mechanistic studies indicated that compound 11 induced apoptosis by activating death receptor and mitochondria dependent apoptotic signaling pathways in COLO 205 cells. The new 3,9-substituted α-carboline derivatives exhibited excellent anti-proliferative activities, and compound 11 can be used as a promising pro-apoptotic agent for future development of new antitumor agents.

Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells

Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells

Synthesis and biological evaluation of novel 3,9-substituted β-carboline derivatives as anticancer agents

In our previous studies on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesised numerous substituted carbazole and α-carboline derivatives, which exhibited anticancer activity. In this study, we designed and synthesised a series of 3,9-substituted β-carbolines, by replacing the tricyclic rings of carbazole and α-carboline derivatives with isosteric β-carboline, and evaluated anticancer activity. We observed that 9-(2-methoxybenzyl)-β-carboline-3-carboxylic acid (11a) inhibited the growth of HL-60 cells by inducing apoptosis, with a half maximal inhibitory concentration of 4.0 μM. Our findings indicate that β-carboline derivatives can be used as lead compounds for developing novel antitumor agents.

Three-Component Tandem Reaction Involving Acid Chlorides, Terminal Alkynes, and 2-Aminoindole Hydrochlorides: Synthesis of α-Carboline Derivatives in Aqueous Conditions via Regioselective [3 + 3] Cyclocondensation

An efficient synthesis toward highly diversified α-carboline derivatives via a three-component tandem reaction using acid chlorides, terminal alkynes, and 2-aminoindole hydrochlorides has been described. The salient feature of the one-pot strategy involves regioselective [3 + 3]-cyclocondensation and the presence of water in the reaction medium to facilitate cyclization. Nonaqueous conditions furnished products in poor yields.

Synthesis and Cytotoxicity of 1,6,8,9-Substituted α-Carboline Derivatives

α-Carboline (pyrido[2,3-b]indole) was selected as the basic scaffold for development of antileukemic agents by structural modification. From the structure-activity study, it was found that sequential introduction of 6-acetyl and 9-substituted benzyl groups onto an α-Carboline scaffold resulted in 6-acetyl-9-(3,5-dimethoxybenzyl)-9H-pyrido[2,3-b]indole and 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2,3-b]indole with potent cytotoxicity against the HL-60 cell line. These two compounds will be used as new lead compounds for further investigation.

A one-pot, four-component synthesis of α-carboline derivatives

A one-pot method for the efficient and simple synthesis of novel 1 H-indolo[2,3- b]pyrazolo[4,3- e]pyridines via a four-component condensation reaction of indolin-2-one, 3-oxo-3-phenylpropanenitrile, and various hydrazines and aldehydes in the ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br) is reported.

2-Amidinylindole-3-carbaldehydes: Versatile Synthons for the Preparation of α-Carboline Derivatives

The 2-amidinylindole-3-carbaldehydes 1 are the key starting materials for the preparation of three classes of carbolines 2, 6 and 7 in which the pyridine ring is characterised by a different substitution patterns. The carbolines 2 which are functionalized with an amino group in position 2, were obtained directly by heating 1 in presence of SiO 2. The condensation of amidines 1 with arylmethylketones afforded unsaturated ketones 5 which on heating were transformed into 2,9-dialkyl-3-aroyl-9 H-pyrido[2,3- b]indoles 7. Instead, prolonged reaction of amidines 1 with arylmethylketones in t-BuOH/ t-BuOK gave 2-aryl-9 H-pyrido[2,3- b]indoles 6.

ChemInform Abstract: C=C‐Conjugated Carbodiimides as 2‐Azadienes in Intramolecular (4 + 2) Cycloadditions. One‐Pot Preparation of Quinoline, α‐Carboline, and Quinindoline Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and spectroluminescent properties of 4-oxo-1,2,3,3a-tetrahydropyrimido[1,2,3-Z,m]-?-carbolines

The reaction of 1-acetyl-2-arylpyrazolidines with the DMF-POCl3 complex and subsequent treatment of the iminium salts formed with the potassium enolates of α-substituted acetate esters yielded a series of previously unknown α-carboline derivatives. The spectroluminescent properties of these compounds were studied. Some of the α-carbolines synthesized have a laser effect.