Beta-carboline Derivatives Research Articles

A Comprehensive Review on Recent Advances in Synthesis and Pharmacotherapeutic Potential of Betacarbolines

Heterocyclic analogues and their derivatives have attracted strong interest in medicinal chemistry due to their biological and pharmacological properties. s-carboline also known as nor-harmane is a nitrogen containing heterocyclic compound. It belongs to the group of indole alkaloids and consists of pyridine ring that is fused to an indole skeleton. These tricyclic nitrogen heterocyclics are formed in plants and animals as Maillard reaction products between amino acids and reducing sugars or aldehydes. These compounds have special significance in the field of Medicinal chemistry due to their remarkable pharmacological potentialities and their derivatives have attracted a great deal of interest due to their wide range of biological activities such as antimicrobial, antitumor, cytotoxic, antiplasmodial, antioxidant, antimutagenic, antigenotoxic and hallucinogenic properties. It acts on gamma-aminobutyric acid type A and monoamine oxidase A or B receptor, enhances insulin sensitivity and also produces vasorelaxant effect. Harmine prevents bone loss by suppressing osteoclastogenesis. This review is mainly an attempt to present the research work reported in the recent scientific literature focusing on different synthetic methods and pharmacological activities of betacarboline derivatives which may contribute in future to synthesize various analogs and to develop new pharmacologically less toxic medicines.

A Series of Beta-Carboline Derivatives Inhibit the Kinase Activity of PLKs

Polo-like kinases play an essential role in the ordered execution of mitotic events and 4 mammalian PLK family members have been identified. Accumulating evidence indicates that PLK1 is an attractive target for anticancer drugs. In this paper, a series of beta-carboline derivatives were synthesized and three compounds, DH281, DH285 and DH287, were identified as potent new PLK inhibitors. We employed various biochemical and cellular approaches to determine the effects of these compounds on the activity of PLK1 and other mitotic kinases and on cell cycle progression. We found that these three compounds could selectively inhibit the kinase activity of purified PLK1, PLK2 and PLK3 in vitro. They show strong antitumor activity against a number of cancer cell lines with relatively low micromolar IC50s, but are relatively less toxic to non-cancer cells (MRC5). Moreover, these compounds could induce obvious accumulation of HeLa cells in G2/M and S phases and trigger apoptosis. Although MRC5 cells show clear S-phase arrest after treatment with these compounds, the G2/M arrest and apoptosis are less insignificant, indicating the distinct sensitivity between normal and cancer cells. We also found that HeLa cells treated with these drugs exhibit monopolar spindles and increased Wee1 protein levels, the characteristics of cells treated with PLK1 inhibitors. Together, these results demonstrate that DH281, DH285 and DH287 beta-carboline compounds are new PLK inhibitors with potential for cancer treatment.

Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors

Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure–activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.

Synthesis of Novel Tadalafil Analogues and their Evaluation as Phosphodiesterase Inhibitors and Anticancer Agents

Two closely related series of novel beta-carboline derivatives, electronically similar to tadalafil (CAS 171596-29-5), were synthesized and evaluated for their inhibitory effects upon phosphodiesterase 5 (PDE5) and phosphodiesterase 11 (PDE11) and their in vitro tumor cell growth inhibitory activity versus HT29 colorectal carcinoma cell line. Interestingly, some of the synthesized compounds showed growth inhibitory properties that appear to be associated with their ability to inhibit PDE5. Moreover, the PDE5 inhibition seems relevant to the stereochemical aspects of the compounds.

Investigation into the in vivo effects of five novel tacrine/ferulic acid and β-carboline derivatives on scopolamine-induced cognitive impairment in rats using radial maze paradigm

Two tacrine-ferulic acid hybrids (1 A, 1 B) and three beta-carboline derivatives (BCs; 2A, 2B, 2C) were tested in vivo on 3-month-old female rats as multi-potent anti-Alzheimer drug candidates. In vitro, the two tacrine-ferulic acid hybrids show higher acetylcholinesterase (AChE) inhibitory activity and comparable butyrylcholinesterase (BChE) inhibitory activity compared to tacrine (CAS 1684-40-8). However, in vivo both substances have no beneficial effect on scopolamine (CAS 51-34-3) induced cognition impairment. On the contrary, 1B even worsen the scopolamine induced cognition impairment. The beta-carboline derivatives 2A, 2B, and 2 C, the inhibitory potency of which at AChE reaching tacrine activity does not antagonize scopolamine induced impairment of cognition in rats measured in radial maze paradigm. Compounds 2A and 1B might act as positive allosteric modulators of scopolamine action at the muscarinic acetylcholine receptors. On the basis of these results it can be concluded that both ferulic acid- (CAS 537-98-4) and BC-derivatives are not qualified as cognition improving drugs and further studies in this field should be focussed on other pharmaceutical leads to find effective anti-Alzheimer drugs.

β-Carboline alkaloids bind DNA

β-Carboline alkaloids present in Peganum harmala ( harmal) have recently drawn attention due to their antitumor activities. The mechanistic studies indicate that beta-carboline derivatives inhibit DNA topoisomerases and interfere with DNA synthesis. They interact with DNA via both groove binding and intercalative modes and cause major DNA structural changes. The aim of this study was to examine the interactions of five β-carboline alkaloids (harmine, harmane, harmaline, harmalol and tryptoline) with calf-thymus DNA in aqueous solution at physiological conditions, using constant DNA concentration (6.25 mM) and various alkaloids/polynucleotide (phosphate) ratios of 1/240, 1/160, 1/80, 1/40, 1/20, 1/10, 1/5, 1/2 and 1/1. Fourier transform infrared (FTIR) and UV–visible spectroscopic methods were used to determine the ligand binding modes, the binding constants, and the stability of alkaloids–DNA complexes in aqueous solution. Spectroscopic evidence showed major binding of alkaloids to DNA with overall binding constants of K harmine − DNA = 3.44 × 10 7 M −1, K harmane − DNA = 1.63 × 10 5 M −1, K harmaline − DNA = 3.82 × 10 5 M −1, K harmalol − DNA = 6.43 × 10 5 M −1 and K tryptoline − DNA = 1.11 × 10 5 M −1. The affinity of alkaloids–DNA binding is in the order of harmine > harmalol > harmaline > harmane > tryptoline. No biopolymer secondary structural changes were observed upon alkaloid interaction and DNA remains in the B-family structure in these complexes.

DH166, a beta-carboline derivative, inhibits the kinase activity of PLK1

A better way to treat complex diseases such as cancer is to aim for several targets at once. Beta-carboline derivatives have been shown to have anticancer activity, but these compounds may target several enzymes required for cell division. Polo-like kinases (PLKs) are well conserved serine/threonine kinases and PLK1 plays multiple roles in cell proliferation. Thus, PLK1 is one of the attractive mitotic targets for anticancer drugs. We found that DH166, a beta-carboline derivative, inhibits the growth of cdc5-2 temperature-sensitive mutant more profoundly than wild-type yeast cells. Because Cdc5 is the human PLK1 homologue in budding yeast, this observation indicates that DH166 might be a PLK1 inhibitor. Indeed, DH166 inhibits the kinase activity of purified PLK1 at low micromolar concentration in an ATP-competitive manner, which is consistent with the docking result based on the crystal structure of PLK1. In addition, DH166 blocks cancer cell proliferation, causes a mitotic arrest, increases cyclin B1 accumulation, induces aberrant mitotic spindles and apoptosis, presumably due to the down-regulation of PLK1. Although beta-carboline derivatives have been demonstrated to show antitumor activities through multiple mechanisms, our data indicate for the first time that their cytotoxicity to tumor cells might be attributable to the inhibition of PLK1 as well.

The molecular structure and conformational characteristics of some specific benzodiazepine receptor ligands: A molecular orbital study of C3-substituted betacarboline derivatives

The molecular structures of the benzodiazepine receptor ligands {beta}-carboline-3-carboxylic acid (BCCA), its methyl, ethyl, and propyl esters (BCCM, BCCE, and BCCP, respectively), and 3-CN-{beta}-carboline (BC-3-CN) have been investigated on a minimal basis STO-3G level of accuracy. For BCCM, BCCE, and BCCP semiempirical AM 1 calculations have also been performed. Fully optimized molecular geometries are reported. Comparisons with available experimental structures indicate that minimal basis results may have a useful predictive value. For the mobile ester side chains, a study of chosen points on the conformational surface was made. Both the STO-3G and the AM 1 results give the planar conformers is the most stable structures with small barriers to internal rotation, provided the ester side chain remains extended. The calculated STO-3G rotational barriers are higher than are the corresponding AM 1 barriers. Partial optimization, i.e., of side-chain structure parameters only, seems sufficient to map the conformational characteristics of these compounds. The orientation of the dipole moment vector and its magnitude may have consequences for possible interaction with a receptor. On the basis of the sidechain internal dynamics, the intramolecular flexibility tends to be confined to certain regions of conformational space.

Floral nectar composition of Peganum harmala L.

Chemical composition of the floral nectar of Peganum harmala, a herbaceous medicinal perennial of the family Zygophyllaceae, was analysed using high-performance liquid chromatography technique. The nectar sugar detection experiments resulted in 33.1, 39.8 and 27.4%, respectively, for fructose, glucose and sucrose, upon which the nectar was classified as hexose rich. In addition, 11 proteinaceous amino acids were recognised and quantified in the nectar. Concentration of the insects’ favoured amino acid, prolin, was markedly high. Furthermore, among four detected alkaloids, harmalol and harmine as the two beta-carboline derivatives were identified. These findings may confer a better understanding upon outcrossing processes and favour the plant–pollinator relationships.

Furan Oligomers and β-Carbolines from Terrestrial Streptomycetes

2,5-Bis(hydroxymethyl)furan monoacetate (3) and 2,5-bis(hydroxymethyl)furan diacetate (4) were obtained as new natural products from an ethyl acetate extract of the terrestrial Streptomyces sp. isolate GW11/1695. Another Streptomyces isolate, GW21/1313, delivered a dimer (6) and a trimer (7) of (hydroxymethyl)furfural. The latter strain also produced 4-hydroxy-2-(5-(hydroxymethyl)furan-2-ylmethylene)-5-methylfuran-3-one (5), perlolyrin (8), and two new beta-carboline derivatives, 9 and 10. 2,5-Bis(hydroxymethyl)furan diacetate (4) exhibited weak cytotoxic activity against brine shrimp larvae.

Coupled hydrogen‐bonding interactions between β‐carboline derivatives and acetic acid

In this work, we have analysed the tendency of two beta-carboline derivatives, harmane and norharmane, in the formation of hydrogen bonds. We obtained the (1)H and (13)C NMR spectra of different mixtures of these derivatives with acetic acid (AcOH) in CDCl(3). A cyclic 1:3 complex is proposed between harmane and AcOH, while a 1:2 complex is proposed for norharmane. Chemical shifts at temperatures between 233 and 323 K were measured: lowering the temperature produces the same effect as increasing the amount of AcOH in solution. The (13)C data confirm a delocalisation of the pi electron density towards the pyridinic ring that occurs when AcOH is added.

Effect of nanocavity confinement on the rotational relaxation dynamics: 3-acetyl-4-oxo-6,7-dihydro-12H indolo-[2,3-a] quinolizine in micelles

In continuation of our recent study on the steady state photophysics of a biologically active beta-carboline derivative, 3-acetyl-4-oxo-6,7-dihydro-12H indolo-[2,3-a] quinolizine (AODIQ), in the present article we have investigated the effect of nanocavity confinement on the excited state dynamics and rotational relaxation of the probe using picosecond time resolved fluorescence and fluorescence anisotropy techniques. The polarity dependent intramolecular charge transfer process is responsible for the remarkable sensitivity of this biological fluorophore in micellar environments. The fluorescence anisotropy decay of AODIQ incorporated inside the micelle is biexponential. The rotational motion of the probe was interpreted on the basis of a two step model consisting of a fast restricted rotation of the probe and a slow lateral diffusion of the probe in the micelle; both coupled to the overall rotation of the micelle. Experimental results reveal that micellar environment causes significant retardation of both the wobbling as well as the translational motion of the probe.

Partial least squares-based multivariate spectral calibration method for simultaneous determination of beta-carboline derivatives in Peganum harmala seed extracts

The partial least squares regression method has been applied for simultaneous spectrophotometric determination of harmine, harmane, harmalol and harmaline in Peganum harmala L. (Zygophyllaceae) seeds. The effect of pH was optimized employing multivariate definition of selectivity and sensitivity and best results were obtained in basic media (pH > 9). The calibration models were optimized for number of latent variables by the cross-validation procedure. Determinations were made over the concentration range of 0.15–10 μg mL −1. The proposed method was validated by applying it to the analysis of the β-carbolines in synthetic quaternary mixtures of media at pH 9 and 11. The relative standard errors of prediction were less than 4% in most cases. Analysis of P. harmala seeds by the proposed models for contents of the β-carboline derivatives resulted in 1.84%, 0.16%, 0.25% and 3.90% for harmine, harmane, harmaline and harmalol, respectively. The results were validated against an existing HPLC method and it no significant differences were observed between the results of two methods.

A Selective Small Molecule IκB Kinase β Inhibitor Blocks Nuclear Factor κB-Mediated Inflammatory Responses in Human Fibroblast-Like Synoviocytes, Chondrocytes, and Mast Cells

IkappaB kinase (IKK) beta is essential for inflammatory cytokine-induced activation of nuclear factor kappaB (NF-kappaB). NF-kappaB plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKKbeta inhibitor N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a beta-carboline derivative, on NF-kappaB signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKKbeta with an IC50 of 60 nM when evaluated in an IkappaBalpha kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor alpha (TNFalpha)-stimulated NF-kappaB signaling via inhibition of IkappaBalpha phosphorylation, degradation, and NF-kappaB translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNFalpha- or interleukin (IL)-1beta-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKKbeta-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide- or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKKbeta-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1beta-induced matrix metalloproteinase production with an IC50 of approximately 1 microM. ML120B also blocked IL-1beta-induced prostaglandin E2 production. In summary, ML120B blocked numerous NF-kappaB-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKKbeta inhibitors as anti-inflammatory agents for the treatment of RA.

Design, Synthesis and in vitro and in vivo Antitumor Activities of Novel β‐Carboline Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access the actual ChemInform Abstract, please click on HTML or PDF.

A New Efficient Synthetic Methodology for Tetrahydroisoquinoline and Tetrahydro‐β‐carboline Derivatives Using the Pictet—Spengler Reaction.

A new solution-phase methodology microwave-assisted for improving the Pictet-Spengler reaction in the synthesis of the tetrahydroisoquinoline and beta-carboline derivatives has been reported. This methodology was applied to obtain a small library of tetrahydroisoquinoline and beta-carboline derivatives using L-Dopa, dopamine, and tryptophan, as well as a variety of commercially available aldehydes as starting material. The use of such nonconventional reaction conditions reveals several features like a short reaction time compared to conventional eating, ease of isolation of the products after work-up, and improvement of the yields. This new one-pot protocol would be an ideal and rapid method to synthesize compounds in a combinatorial context.

Isolation of Mutagenic β-Carboline Derivatives after Nitrite Treatment of Maillard Reaction Mixtures and Analysis of These Compounds from Foodstuffs and Human Urine

Mixtures of carbohydrate decomposition products and L-tryptophan were incubated at pH 7.0 and 37 degrees C for 4 weeks. These mixtures exhibited mutagenic activity toward S. typhimurium TA 100 without metabolic activation after a nitrite treatment at pH 4.0. Four beta-carboline derivatives were isolated as premutagens from mixtures of methylglyoxal and furfural. These premutagens were also found to be contained in daily foodstuffs and human urine samples.

Dopamine transporter-mediated cytotoxicity of beta-carbolinium derivatives related to Parkinson's disease: relationship to transporter-dependent uptake.

Endogenous or exogenous beta-carboline (betaC) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease (PD). We addressed the importance of the dopamine transporter (DAT) for selective dopaminergic toxicity by testing the differential cytotoxicity and cellular uptake of 12 betaCs in human embryonic kidney HEK-293 cells ectopically expressing the DAT gene. Cell death was measured using [4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion assays, and uptake by a fluorescence-based uptake assay. All betaCs and MPP(+) showed general cytotoxicity in parental HEK-293 cells after 72 h with half-maximal toxic concentrations (TC(50) values) in the upper micromolar range. Besides MPP(+), only 2[N]-methylated compounds showed enhanced cytotoxicity in DAT expressing HEK-293 cells with 1.3- to 4.5-fold reduction of TC(50) values compared with parental cell line. The rank order of selectivity was: MPP(+) >> 2[N],9[N]-dimethyl-harminium > 2[N]-methyl-harminium > 2[N],9[N]-dimethyl-harmanium = 2[N]-methyl-norharmanium > 2[N]-methyl-harmanium > 2[N],9[N]-dimethyl-norharminium. Consistently, only 2[N]-methylated betaCs were transported into the cell through the DAT with up to five times greater K(m) and 12-220 times smaller V(max) values compared with dopamine and MPP(+). There was a weak relation of DAT-mediated selectivity with the affinity of betaCs at the DAT (K(m)), but not with V(max). Our data suggest that DAT-mediated cellular uptake of 2[N]-methylated betaCs represents a potential mechanism for selective toxicity towards dopaminergic neurons and may be relevant for the pathogenesis of Parkinson's disease.

A new efficient synthetic methodology for tetrahydroisoquinoline and tetrahydro- -carboline derivatives using the Pictet–Spengler reaction

A new solution-phase methodology microwave-assisted for improving the Pictet-Spengler reaction in the synthesis of the tetrahydroisoquinoline and beta-carboline derivatives has been reported. This methodology was applied to obtain a small library of tetrahydroisoquinoline and beta-carboline derivatives using L-Dopa, dopamine, and tryptophan, as well as a variety of commercially available aldehydes as starting material. The use of such nonconventional reaction conditions reveals several features like a short reaction time compared to conventional eating, ease of isolation of the products after work-up, and improvement of the yields. This new one-pot protocol would be an ideal and rapid method to synthesize compounds in a combinatorial context.

Biochemical aspects of Parkinson's disease.

The importance of the striatal dopamine (DA) deficiency and the DA substituting property of levodopa for the pathophysiology and therapy of Parkinson's disease (PD) is reiterated. In addition, it is shown that in PD, significantly reduced DA levels are also found in the nucleus accumbens, external and internal segments of the globus pallidus, the substantia nigra reticulata, and the subthalamic nucleus. It is proposed that, in addition to the critical role played by the striatal DA loss, the DA changes in the extrastriatal nuclei of the basal ganglia are importantly involved in the pathophysiologic mechanisms resulting in the parkinsonian movement disorder, and that the therapeutic and/or side effects of DA substitution therapy may, in part, be mediated through these brain regions which, like the striatum, suffer DAergic deafferentation in PD. From observations in brain of patients with secondary parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine parkinsonism in the rhesus monkey, as well as the regional DA transporter distribution in the primate substantia nigra, it is concluded that PD may be caused by any exogenous and/or endogenous toxin using the transporter system for DA and to some degree the other brain monoamines (noradrenaline, serotonin), to enter, and damage, the respective monoamine neurons. Based on converging evidence, the view is advanced that endogenous, genetically based (excessive) formation, or accumulation, of toxic DA transporter substrates, such as isoquinoline or beta-carboline derivatives, may in fact represent the primary cause of substantia nigra cell degeneration in patients with PD.