Simultaneous determination of tetrahydro-β-carbolines and β-carbolines

Summary Reversed-phase ion-pair HPLC with fluorimetric detectors connected in series was studied for the simultaneous determination of two tetrahydro--carbolines and two -carbolines. After additon of internal standards the samples were reacted with fluorescamine, and then subjected to serial extractions to remove their precursor (tryptamine) from the analytical system. This treatment not only suppressed the artefactual formation of tetrahydro--carbolines and -carbolines during analysis, but also effectively purified them. Under optimum conditions, using trifluoroacetic acid as counter ion, all analytes were separated within 14 min and without major interfering peaks. The quantitative ranges were 0.25–80.0 ng mL^–1 for both tetrahydro--carbolines and 0.1–30.0 ng mL^–1 for both -carbolines. Replicate spiking experiments showed that recovery from most of the samples tested was over 90% and the relative standard deviation ranged from 0.7 to 10.4% within and between assays. The proposed method was applicable to various materials such as soy sauce, vinegar, ketchup, tabasco, beer, wine, sake, whisky, brandy, cows' milk, coffee, cocoa, cheese, cigarette smoke and urine.     

Synthesis of β-carbolines via a silver-mediated oxidation of tetrahydro-β-carbolines

The oxidation of tetrahydro-β-carbolines to β-carbolines using silver carbonate was developed as an alternative to current methods. The oxidation is extremely mild and provides the products in modest to good yields after purification. A number of functional groups are tolerated by this methodology, including reduction-sensitive groups which are often cleaved with other methods. Though the mechanism is not fully understood, the reaction proceeds in an open flask, is not sensitive to light or moisture, and provides a viable synthetic route to compounds that are not easily prepared via other methodologies.     

Use of the Pictet-Spengler reaction for the synthesis of 1,4-disubstituted-1,2,3,4-tetrahydro-β-carbolines and 1,4-disubstituted-β-carbolines: formation of γ-carbolines

Microwave-assisted conjugate addition of indole on nitro-olefins furnished nitro compounds, which were reduced to tryptamines. Further, by using Pictet-Spengler condensation, new 1,4-disubstituted-1,2,3,4-tetrahydro-β-carbolines were synthesized in diastereoselective manner. Dehydrogenation of the tetrahydro-β-carbolines produced new 1,4-disubstituted-β-carbolines. As a new observation, in some of the cases, Pictet-Spengler condensation and dehydrogenation gave two products, namely 1,4-disubstituted-β-carbolines and 1,4-disubstituted-γ-carbolines. A mechanism is proposed for this observation.     

Biocatalytic asymmetric formation of tetrahydro-β-carbolines

Strictosidine synthase triggers the formation of strictosidine from tryptamine and secologanin, thereby generating a carbon-carbon bond and a new stereogenic center. Strictosidine contains a tetrahydro-β-carboline moiety—an important N-heterocyclic framework found in a range of natural products and synthetic pharmaceuticals. Stereoselective methods to produce tetrahydro-β-carboline enantiomers are greatly valued. We report that strictosidine synthase from Ophiorrhiza pumila utilizes a range of simple achiral aldehydes and substituted tryptamines to form highly enantioenriched (ee >98%) tetrahydro-β-carbolines via a Pictet-Spengler reaction. This is the first example of aldehyde substrate promiscuity in the strictosidine synthase family of enzymes and represents a first step toward developing a general biocatalytic strategy to access chiral tetrahydro-β-carbolines.     

Spectroscopic study of molecular associations between FMN and β-carbolines

The spectrophotometric and thermodynamic properties of molecular complexes of flavin mononucleotide (FMN) (riboflavin 5′-phosphate) with some β-carboline derivatives have been investigated in aqueous solution. The molecular associations have been examined by means of electronic absorption spectra, since in each a new charge-transfer band has been located, and also the variation of the fluorescence emission of FMN on the solutions has been observed. The formation constants for the molecular complexes were determined from absorption data using the Foster—Hammick—Wardley method. The quenching phenomenon observed in FMN fluorescence is related to the concentration of the β-carboline derivatives, allowing the calculation of the quenching constants for FMN-β-carboline complexes. Thermodynamic parameters have been determined from the values of association constants for the molecular complexes at various temperatures. The influence of substituents in the β-carboline molecule on the stability of the complexes formed was also investigated.     

An overview on synthetic entries to tetrahydro-β-carbolines

The tetrahydro-β-carboline (THBC) nucleus is a predominant feature of a vast array of naturally occurring alkaloids. Most of these alkaloids have been found to exhibit significant biological activities, which promote to develop a plethora of synthetic methods for the construction of THBCs. In this review, we focus on the recent developments and studies related to the synthesis of THBCs including total syntheses of related alkaloids mainly over the period of 2000–2017. In addition, a brief account of some significant THBC alkaloids with their sources and bioactivities is also presented in tabular format.     

Sequential one-pot five-component synthesis of tetrazole-based spirotetrahydro-β-carbolines

A one-pot five-component two-step sequential synthesis of tetrazole-based tetrahydrospiro[indene-2,1′-pyrido[3,4-b]indole]-1,3-diones in moderate to good yields is described. The reaction consists of four-component condensation of aromatic aldehydes with tryptamine, trimethylsilyl azide (TMSN₃) and isocyanides, followed by addition of ninhydrin. These reactions presumably proceeded through Ugi-azide/Pictet–Spengler processes, respectively.     

Synthesis of tetrahydro-β-carbolines from phthalic anhydrides and tryptamine

Tetrahydro-b-carbolines with strictosamide skeleton have been synthesized via intermolecular condensation, selective reduction, and intramolecular cyclization starting from phthalic anhydrides and tryptamine. The reactions are carried out under mild conditions with a wide range of substrates and functional groups.     

Novel domino reactions in β-carbolines with triple bonded dienophiles

Vinylpyrrolo-[2,1-a]-β-carbolines 1 give different products upon reaction with dienophiles. With dimethyl acetylenedicarboxylate (DMAD), a novel domino process takes place, involving Michael attack and rearrangement, affording complex polycycles like 3, 4, and 5. Diels-Alder cycloadditions are favored in the presence of Lewis acids and are the only reactions with dimethyl maleate. When 3-butyn-2-one is used as dienophile, a Stevens rearrangement is observed giving product 9.     

Synthesis of 1,1-disubstituted tetrahydro-β-carbolines from 2-methyleneaziridines

Ring opening of indole functionalised methyleneaziridines (3a-c, 7) with alcohols in the presence of boron trifluoride etherate leads to the formation of 1,1-disubstituted tetrahydro-β-carbolines in moderate to good yields (37-83%).     

Synthesis of β-carbolines using microwave-assisted aza-Wittig methodology in ionic liquids

The improved preparation of 1-substituted-β-carbolines is reported using microwave-assisted aza-Wittig/electrocyclic ring-closure reaction with ionic liquids as solvent. In all cases an unprecedented N-methoxymethyl group (MOM) deprotection is observed.     

Recent advances on the synthesis and application of tetrahydro-γ-carbolines

Tetrahydro-γ-carbolines(THγ Cs) constitute one of the most important subtypes of indole alkaloids. In addition to being substructures of natural products, these structural motifs and moieties can often be found in pharmaceuticals due to their diverse bioactivities such as antiviral, antibacterial, antifungal,antiparasitic, antitumor, anti-inflammatory, and neuropharmacological activities. Beyond the pharmacological and biological aspects of these scaffolds, they have considerable synthetic appli...     

Novel chemistry of β-carbolines. Expedient synthesis of polycyclic scaffolds

Functionalization of β-carbolines is a challenge as numerous natural alkaloids with different biological activities present this heterocycle. The RCM is used herein with allyl-, vinyl-, ethynyl-, and propargyl-β-carbolines to generate additionally fused hetero- and carbocycles, and it is combined with other cyclization processes to achieve great molecular complexity in one synthetic step. Thus, an RCM-Diels-Alder sequence gives pentacyclic compounds related with certain alkaloids. On the other hand, vinylpyrrolo[2,1-a]-β-carbolines and vinyl-β-carbolines give different products upon reaction with activated dienophiles. Thus, a novel domino processes affords complex polycycles like 35-38. Other alkynes like 3-butyn-2-one give a Stevens rearrangement.     

Synthesis and cytotoxic activity of 3-phenyl-4-substituted-β-carbolines

A new class of 3-phenyl-4-substituted-β-carbolines via iodine-mediated electrophilic cyclization as key step were synthesized and their inhibitory activity against three tumor cell lines was evaluated in vitro.It was found that some of the tested compounds showed better cytotoxicity against HeLa and MCF-7 cells than harmine.     

N-Propargyltetrahydrocarbazoles and N-propargyltetrahydro-γ-carbolines in 1,3-cycloaddition with azide-containing pharmacophores

Russian Chemical Bulletin - A modification of tetrahydrocarbazoles and tetrahydro-γ-carbolines with pharmacophore ligands was performed based on the copper-catalyzed 1,3-dipolar cycloaddition...     

Catalytic asymmetric synthesis of 1,1-disubstituted tetrahydro-β-carbolines by phase-transfer catalyzed alkylations

Efficient catalytic asymmetric synthesis of 1,1-disubstituted tetrahydro-β-carbolines has been achieved via asymmetric alkylation of 1-cyanotetrahydro-β-carbolines using a binaphthyl-modified N-spiro-type chiral phase-transfer catalyst. This is a valuable example of hitherto difficult highly enantioselective alkylations at α-carbon of the cyano group under phase-transfer conditions.     

Annulated 1,2,3,4-tetrahydro-β-carbolines by intramolecular Mannich-type amino- and amidoalkylations of N(9)-(ω-nitroalkyl)-3,4-dihydro-β-carbolines

2-[1-(ω-Nitroalkyl)-1H-indol-3-yl]ethylformamides 11 were transformed to the corresponding 9-(ω-nitroalkyl)-4,9-dihydro-3H-β-carbolines 5 and through a diastereoselective intramolecular aminoalkylation to the annulated tetrahydro-β-carbolines 13, in high yields. Intramolecular N-acyliminium cyclisation of compounds 5 afforded the tetracyclic diazacycloalkano[jk]fluorenes in two diastereoisomeric forms 18 and 19 with moderate selectivity. Conjugate addition reactions performed on compounds 18 and 19 led to pentacyclic indolo[3,2,1-de]pyrido[3,2,1-jk]naphthyridinone 26a or diazabenzo[a]naphtho[2,1,8-cde]azulenone 26b.     

Photosensitization of DNA by β-carbolines: kinetic analysis and photoproduct characterization

β-Carbolines (βCs) are a group of alkaloids present in many plants and animals. It has been suggested that these alkaloids participate in a variety of significant photosensitized processes. Despite their well-established natural occurrence, the main biological role of these alkaloids and the mechanisms involved are, to date, poorly understood. In the present work, we examined the capability of three important βCs (norharmane, harmane and harmine) and two of its derivatives (N-methyl-norharmane and N-methyl-harmane) to induce DNA damage upon UV-A excitation, correlating the type and extent of the damage with the photophysical characteristics and DNA binding properties of the compounds. The results indicate that DNA damage is mostly mediated by a direct type-I photoreaction of the protonated βCs after non-intercalative electrostatic binding. Reactive oxygen species such as singlet oxygen and superoxide are not involved to a major extent, as indicated by the only small influence of D(2)O and of superoxide dismutase on damage generation. An analysis with repair enzymes revealed that oxidative purine modifications such as 8-oxo-7,8-dihydroguanine, sites of base loss and single-strand breaks (SSB) are generated by all βCs, while only photoexcited harmine gives rise to the formation of cyclobutane pyrimidine dimers as well.     

Regiodivergent annulation of alkynyl indoles to construct spiro-pseudoindoxyl and tetrahydro-β-carbolines

Regiodivergent annulations of 3-phenoxy alkynyl indoles have been developed and tuned by protective groups through gold catalysis. With electron-donating protective groups, the substrate followed a C3-selective annulation and gave structurally interesting tetrahydro-β-carboline derivatives possessing potential bioactivity. Using electron-withdrawing protective groups, the substrate underwent a C2-selective annulation and afforded the structurally useful spiro-pseudoindoxyl found in natural indole alkaloids. Notably, an interesting and unusual 1, 2-migration of the phenoxy group was found in the C3-selective process.     

Medium-sized and strained heterocycles from non-catalysed and gold-catalysed conversions of β-carbolines

2-Allyl-1-vinyl-β-carbolines and dihydropyrrolo-β-carbolines react with activated internal alkynes through novel rearrangement reactions leading to complex polycyclic structures. Favored reaction pathways depend on reaction conditions and on the presence of gold catalysts. In particular, upon reaction with 2 equiv. of the alkyne, new hexacyclic structures 10 are formed with total stereocontrol.