Series Of Β-carboline Derivatives Research Articles

Design, synthesis, and biological evaluation of harmine derivatives as topoisomerase I inhibitors for cancer treatment

A series of β-carboline derivatives were designed and synthesized by introducing the chalcone moiety into the harmine. The synthesized derivatives were evaluated their anti-proliferative activities against six human cancer cell lines (MCF-7, MDA-MB-231, HepG2, HT29, A549, and PC-3) and one normal cell line (L02). Among them, compound G11 exhibited the potent anti-proliferative activity against MCF-7 cell line, with an IC50 value of 0.34 μM. Further biological studies revealed that compound G11 inhibited colony formation of MCF-7 cells, suppressed MCF-7 cell migration by downregulating migration-associated protein MMP-2. In addition, it could induce apoptosis of MCF-7 cells by downregulating Bcl-2 and upregulating Cleaved-PARP, Bax, and phosphorylated Bim proteins. Furthermore, compound G11 can act as a Topo I inhibitor, affecting DNA synthesis and transcription, thereby inhibiting cancer cell proliferation. Moreover, compound G11 inhibited tumor growth in 4T1 syngeneic transplant mice with an inhibition rate of 43.19 % at a dose of 10 mg/kg, and 63.87 % at 20 mg/kg, without causing significant toxicity to the mice or their organs, achieving the goal of reduced toxicity and increased efficacy. All these results indicate of G11 has enormous potential as an anti-tumor agent and merits further investigation.

Synthesis and Antimicrobial and Anticancer Activity of β-Carboline Analogues

The β-carboline alkaloids possess a wide diversity of important biochemical effects and pharmacological properties. A series of β-carboline derivatives were synthesized from L-tryptophan through the Pictet-Spengler reaction and oxidation of K2Cr2O7 via sequential one-pot synthesis method. In vitro anti-bacterial, insecticidal, and cytotoxic activities of all synthesized compounds were investigated by the tablet diffusion, leaf disc, and MTT methods, respectively. Some of the compounds(1a, 1b, 1c and 1j) exhibited obvious anti-bacterial effects and some (1-3) had significant cytotoxic activities against tumor cells 3LL, MCF-7, BGC-823 and QGY-7701, with IC50 values of 7.79, 5.75, 3.53 and 4.02 μg/mL, respectively. No insecticidal activity against third stage instar larvae of Mythimnaseparata Walker were observed under the tested concentration.

Design and synthesis of β-carboline derivatives with nitrogen mustard moieties against breast cancer

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-methyl-9H-pyrido[3,4-b]indol-3-yl)methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-formamidopropanoate possessed the most potent antiproliferative activity with IC50 values of 1.79 μM and 4.96 μM, respectively, which were significantly higher than that of the parent compounds, and the efficacy was comparable to that of the positive control doxorubicin. More importantly, it showed weak cytotoxicity against human normal breast cell line MCF-10A (IC50 > 20 μM), exhibiting certain selectivity. Subsequently, further mechanism exploration indicated that it induced G2/M phase cell cycle arrest and apoptosis in MDA-MB-231 cells. The DCFH-DA fluorescent probe assay and comet assay showed that this compound could cause intracellular ROS accumulation and DNA damage. In addition, it exerted potent inhibitory effect on the migration, invasion and adhesion of MDA-MB-231 cells in vitro. In short, (1-methyl-9H-pyrido[3,4-b]indol-3-yl)methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-formamidopropanoate was considered as a promising compound for anti-breast cancer.

Design and synthesis of β-carboline and combretastatin derivatives as anti-neutrophilic inflammatory agents

A series of β-carboline derivatives was synthesized by the Pictet-Spengler reaction with or without the combretastatin skeleton. The structures of these derivatives were elucidated by spectroscopic techniques. All synthesized compounds were evaluated for their anti-inflammatory activity in human neutrophils. Among them, two compounds, NTU-228 and HK-72, showed significant inhibitory effects on N-formyl-Met-Leu-Phe (fMLF)-induced superoxide anion generation in human neutrophils with IC50 values of 5.58 ± 0.56 and 2.81 ± 0.07 μM, respectively. Neither NTU-228 nor HK-72 caused cytotoxicity in human neutrophils. NTU-228 inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and intracellular Ca2+ levels ([Ca2+]i) in fMLF-activated human neutrophils. Additionally, HK-72 selectively inhibited the fMLF-induced phosphorylation of p38 and [Ca2+]i in human neutrophils. Molecular docking analysis showed a favorable binding affinity of HK-72 toward p38 MAPK. The proposed synthetic strategy opens up new opportunities for the synthesis of novel potential candidates against neutrophilic inflammation.

Synthesis,in vitroAntiproliferative and Anti-Mycobacterium tuberculosisActivities of Novel β-Carboline Derivatives

A series of β-carboline derivatives with amino or guanidinium were synthesized and evaluated in vitro against anti-Mycobacterium tuberculosis and for antiproliferative activities against nine human cancer cell lines. The compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline (24.9 µg mL-1) and 1-(4-methoxyphenyl)-3-carboxamide(ethylamine) β-carboline (26.9 µg mL-1) were the most active against M. Tuberculosis (MTB). Compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline and 1-(4-methoxyphenyl)-3-carboxamide(propylamine) β-carboline, which had the same substituted groups, inhibited the growth of all human tumor cell lines with growth inhibitory activity (GI50) values from 1.37 to 9.20 mmol L-1. Also in this series, compounds 1-(4-hydroxyphenyl)-3-carboxamide(propylamine) β-carboline and 1-(3-nitrophenyl)-3-carboxamide(propylamine) β-carboline demonstrated significant activity against NCI/ADR cells. Among compounds with a terminal guanidine group, compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethyl)guanidine β-carboline (27.8 µg mL-1) and 1-(3-nitrophenyl)-3-carboxamide(ethyl)guanidine β-carboline (37.4 µg mL-1) demonstrated the greatest activity against MTB. Additionally, compounds 1-(4-methoxyphenyl)-3-carboxamide(ethyl)guanidine β-carboline (GI50 = 0.45 mmol L-1) effectively inhibited growth and was highly selective against NCI/ADR. The in silico study revealed that 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline, 1-(4-methoxyphenyl)-3-carboxamide(ethylamine) β-carboline, 1-(4-hydroxyphenyl)-3-carboxamide(propylamine) β-carboline, 1-(4-methoxyphenyl)-3-carboxamide(propylamine) β-carboline and 1-(3-nitrophenyl)-3-carboxamide(propylamine) β-carboline compounds follow the rules established by Lipinski, suggesting that this compound has no problems with oral bioavailability.

Synthesis and Fungicidal Activity of β-Carboline Alkaloids and Their Derivatives.

A series of β-Carboline derivatives were designed, synthesized, and evaluated for their fungicidal activities in this study. Several derivatives electively exhibited fungicidal activities against some fungi. Especially, compound F5 exhibited higher fungicidal activity against Rhizoctonia solani(53.35%) than commercial antiviral agent validamycin (36.4%); compound F16 exhibited high fungicidal activity against Oospora citriaurantii ex Persoon(43.28%). Some of the alkaloids and their derivatives (compounds F4 and F25) exhibited broad-spectrum fungicidal activity. Specifically, compound F4 exhibited excellent high broad-spectrum fungicidal activity in vitro, and the curative and protection activities against P. litchi in vivo reached 92.59% and 59.26%, respectively. The new derivative, F4, with optimized physicochemical properties, obviously exhibited higher activities both in vitro and in vivo; therefore, F4 may be used as a new lead structure for the development of fungicidal drugs.

Design, synthesis of new β-carboline derivatives and their selective anti-HIV-2 activity.

In the present study, a new series of β-carboline derivatives were synthesized and evaluated for inhibition activity against both HIV-1 and HIV-2 strains. Among these reported analogues, surprisingly (1-phenyl-9H-pyrido[3,4-b]indol-3-yl)(4-p-tolylpiperazin-1-yl)methanone (7b), (4-(2-methoxyphenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7f), (4-(4-fluorophenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7k), (4-(2-fluorophenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7l) displayed selective inhibition of HIV-2 strain with EC50 values of 3.3, 3.2, 2.6 and 5.4μM, respectively, which are comparable with nucleoside reverse transcriptase inhibitors lamivudine and dideoxyinosine. As these analogues have not shown in vitro HIV-2 reverse transcriptase inhibition, it could be excluded as potential target for their specific anti-HIV-2 activity.

3D-QSAR and Docking Studies of a Series ofβ-Carboline Derivatives as Antitumor Agents of PLK1

An alignment-free, three dimensional quantitative structure-activity relationship (3D-QSAR) analysis has been performed on a series ofβ-carboline derivatives as potent antitumor agents toward HepG2 human tumor cell lines. A highly descriptive and predictive 3D-QSAR model was obtained through the calculation of alignment-independent descriptors (GRIND descriptors) using ALMOND software. For a training set of 30 compounds, PLS analyses result in a three-component model which displays a squared correlation coefficient (r2) of 0.957 and a standard deviation of the error of calculation (SDEC) of 0.116. Validation of this model was performed using leave-one-out,q2looof 0.85, and leave-multiple-out. This model gives a remarkably highr2pred(0.66) for a test set of 10 compounds. Docking studies were performed to investigate the mode of interaction betweenβ-carboline derivatives and the active site of the most probable anticancer receptor, polo-like kinase protein.

Synthesis of a Novel Series of 1,6-Disubstituted-3-(cyclohexylmethoxy)-β-carboline Derivatives via Minisci Reaction

A facile and efficient route for the synthesis of 1,6-disubstituted-3-cyclohexylmethoxy-β-carboline derivatives via the Minisci reaction has been described with good yields and selectivity. A novel series of β-carboline derivatives with various substituents at 1-, 3-, and 6-positions were designed and synthesized from the starting material (±)-tryptophan on the basis of harmine chemical structure. The mechanism of the 1-substituted β-carboline derivatives by means of a nucleophilic radical was also described, and the x-ray analysis confirmed the structures of 11-7.

Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors

Previous studies have shown that harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with harmine has been recently solved. This crystal structure shows that close to the methoxy group of the harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the β-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of β-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their K(i) values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a K(i) against MAO-A of 3.6nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a K(i) value of 221.6nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a K(i) value of 4.3nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.

Synthesis and Bioactivity of β-Carboline Derivatives

The β-carboline alkaloids possess a wide diversity of important biochemical effects and pharmacological properties. A series of β-carboline derivatives were synthesized from L-tryptophan through the Pictet-Spengler reaction and oxidation of K2Cr2O7 by a sequential one-pot synthesis method. In Vitro antibacterial, insecticidal, and cytotoxic activities of all synthesized compounds were investigated by the tablet diffusion, leaf disc, and MTT methods, respectively. Some of the compounds (1-1, 1-2, 1-3 and 1-12) exhibited obvious antibacterial effects and some (1-3) had significant cytotoxic activities against tumor cells 3LL, MCF-7, BGC-823 and QGY-7701, with IC50 values of 7.79, 5.75, 3.53 and 4.02 μg/mL, respectively. No insecticidal activity against third stage instar larvae of Mythimna separata Walker were observed under the tested concentration.

Synthesis and evaluation of β-carboline derivatives as inhibitors of human immunodeficiency virus

A series of β-carboline derivatives were synthesized by utilizing aromatization and chemoselective alkylation method recently reported from our laboratory. Synthesized derivatives were evaluated for anti-HIV activity in human CD4+ T cell line (CEM-GFP) infected with HIV-1 NL4.3 virus. 1-Formyl-β-carboline-3-carbxylic acid methyl ester (15) showed inhibition of human immunodeficiency virus at IC50=2.9μM.

Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents

In a continuing effort to develop novel β-carbolines endowed with better pharmacological profiles, a series of β-carboline derivatives were designed and synthesized based on the previously developed SARs. Cytotoxicities in vitro of these compounds against a panel of human tumor cell lines were also investigated. The results demonstrated that the N 2-benzylated β-carbolinium bromides 56– 60 represented the most potent compounds with IC 50 values lower than 10 μM. The application of 3D-QSAR to these compounds explored the structural basis for their biological activities. CoMFA ( q 2 = 0.513, r 2 = 0.862) and CoMSIA ( q 2 = 0.503, r 2 = 0.831) models were developed for a set of 47 β-carbolines. The results indicated that the antitumor pharmacophore of these molecules were marked at position-1, -2, -3, -7 and -9 of β-carboline ring.

Design, synthesis and in vitro and in vivo antitumor activities of novel β-carboline derivatives

To further our SAR study on the chemistry and antitumor activity/neurotoxicity of β-carboline alkaloids, several series of β-carboline derivatives with various substituents were designed and synthesized from the starting material l-tryptophan on the basis of harmine chemical structure. Cytotoxic activities of these compounds were investigated in vitro. The results showed that some β-carboline derivatives had significant cytotoxic activities against human tumor cell lines. Among all the synthesized β-carboline derivatives, the compounds 27, 28 and 32, having a benzyl substituent at both position-2 and 9, respectively, were found to be the most potent compounds with IC 50 value lower than 50 μM against all human tumor cell lines examined. Acute toxicities and antitumor activities of the selected β-carboline derivatives in mice were also evaluated. The results demonstrated that a benzyl substituent at position-2 increased the antitumor activity as well as acute toxicity significantly. However an (ethoxycarbonyl)amino substituent at position-3 reduced the acute toxicity as well as antitumor activity remarkedly. These data suggested that ( 1) the antitumor potencies of β-carboline derivatives were enhanced by the introduction of benzyl substituent into the position-2; ( 2) the acute toxicity of β-carboline derivatives reduced dramatically by the introduction of an appropriate substituent into the position-3 and 9; ( 3) the β-carboline structure might be an important basis for the design and synthesis of new antitumor drugs with significant antitumor activity and low toxicity.