Tricyclic Indole Research Articles

Cobalamin-dependent radical S-adenosyl-L-methionine protein functions with a partner to successively methylate tricyclic indole alkaloid for chuangxinmycin maturation and derivatization

Cobalamin-dependent radical S-adenosyl-L-methionine protein functions with a partner to successively methylate tricyclic indole alkaloid for chuangxinmycin maturation and derivatization

Synthesis and Antitumour Evaluation of Tricyclic Indole-2-Carboxamides against Paediatric Brain Cancer Cells.

Antitumour properties of some cannabinoids (CB) have been reported in the literature as early as 1970s, however there is no clear consensus to date on the exact mechanisms leading to cancer cell death. The indole-based WIN 55,212-2 and SDB-001 are both known as potent agonists at both CB1 and CB2 receptors, yet we demonstrate herein that only the former can exert in vitro antitumour effects when tested against a paediatric brain cancer cell line KNS42. In this report, we describe the synthesis of novel 3,4-fused tricyclic indoles and evaluate their functional potencies at both cannabinoid receptors, as well as their abilities to inhibit the growth or proliferation of KNS42 cells. Compared to our previously reported indole-2-carboxamides, these 3,4-fused tricyclic indoles had either completely lost activities, or, showed moderate-to-weak antagonism at both CB1 and CB2 receptors. Compound 23 displayed the most potent antitumour properties among the series. Our results further support the involvement of non-CB pathways for the observed antitumour activities of amidoalkylindole-based cannabinoids, in line with our previous findings. Transcriptomic analysis comparing cells treated or non-treated with compound 23 suggested the observed antitumour effects of 23 are likely to result mainly from disruption of the FOXM1-regulated cell cycle pathways.

Detection and characterisation of oxocyclohexan[b]indoles by combined application of vibrational spectroscopy and mass spectrometry

The vibrational and mass spectra of a representative set of nine oxocyclohexan[b]indoles (tricyclic indoles with a 6,5,6 ring pattern) with a carbonyl group in each of the four positions of the third non-aromatic ring and up to two methyl substituent(s) attached to the carbon atoms in the other positions of this ring are reported and discussed. Particular attention is focused on the use of infrared spectroscopy to determine whether these compounds may best be described as ketoindoles or hydroxyindolenines. Most of these spectra indicate that the tricyclic heterocycles exist preferentially at ketoindoles, but the solid state infrared spectra of oxocyclohexan[b]indoles with the oxygen function in the 4-position are highly unusual, giving the initial impression that these compounds are hydroxyindolenines. Computational modelling supports the interpretation that the 4-ketoindole tautomer has a lower energy than either of its most stable isomeric indolenines conformers. Mass spectrometry is shown to provide valuable confirmatory evidence to differentiate the isomeric ionised oxocyclohexan[b]indoles, which dissociate via distinctive and informative fragmentation routes, in which the stability of intermediate distonic ions appears to be profoundly influenced by participation of the lone pair of electrons on the nitrogen atom. Many of these fragmentations are better described by stepwise mechanisms, rather than as concerted cycloreversions.

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine.

An unusual photoredox-catalyzed radical decarboxylative cyclization cascade reaction of γ,γ-dimethylallyltryptophan (DMAT) derivatives containing unactivated alkene moieties has been developed, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This type of cyclization, which was hitherto very difficult to comprehend in ergot biosynthesis and to accomplish by more conventional procedures, enables the synthesis of ergot alkaloid precursors. In addition, this work describes a mild, environmentally friendly method to activate, reductively and oxidatively, natural carboxylic acids for decarboxylative C-C bond formation by exploiting the same photocatalyst.

Recent Advances in the Synthesis of 3,n-Fused Tricyclic Indole Skeletons via Palladium-Catalyzed Domino Reactions.

3,n-fused (n = 4-7) tricyclic indoles are pervasive motifs, embedded in a variety of biologically active molecules and natural products. Thus, numerous catalytic methods have been developed for the synthesis of these skeletons over the past few decades. In particular, palladium-catalyzed transformations have received much attention in recent years. This review summarizes recent developments in the synthesis of these tricyclic indoles with palladium-catalyzed domino reactions and their applications in the total synthesis of representative natural products.

Asymmetric synthesis of 7-membered-ring-bridged 3,4-fused tricyclic indoles via Friedel–Crafts alkylation/annulation

Regio- and enantioselective Friedel–Crafts alkylation/N-hemiacetalization and dehydration sequence were reported using Ni(ii)-PyBPI complex as catalyst, affording chiral 7-membered-ring-bridged 3,4-fused tricyclic indoles in good results.

Anti-proliferating and apoptosis-inducing activity of chemical compound FTI-6D in association with p53 in human cancer cell lines

Compounds with 3,4-fused tricyclic indole (FTI) frameworks are attractive scaffolds for drug discovery. We synthesized FTI-6D, a compound with this framework, which was cytotoxic in several human cancer cell lines. FTI-6D induced apoptosis via activation of the p53 downstream mitochondria-related apoptotic pathway, characterized by an increased ratio of pro-apoptotic Bcl-2 family members to anti-apoptotic members. This change was followed by caspase-9 and caspase-3 cleavage and activation in two cancer cell lines, RKO and AGS. The anti-proliferating effect of FTI-6D was remarkably detected in eight cancer cells with wild-type TP53 (TP53_wt), including RKO and AGS, but not in seven cancer cells with mutated TP53 (TP53_mut). Additionally, p53 protein levels increased after FTI-6D treatment in TP53_wt cancer cells, and the cytotoxic effect of FTI-6D was decreased by TP53 knockdown. Accordingly, the expression of p53 downstream genes involved in apoptotic signaling pathways, such as BBC3 and TP53INP1, and those involved in cell growth inhibition, such as CDKN1A, was upregulated in TP53_wt cancer cells. These results suggest that the anti-proliferative and apoptosis-inducing activities of FTI-6D rely on p53 and the corresponding signaling processes. This study demonstrated that FTI-6D shows anti-cancer activity against TP53_wt cancer cells. FTI-6D may have potential as a prototype compound for a new drug to utilize a functional p53 pathway in TP53_wt cancer cells.

Discovery of a New Mcl‐1 Protein Inhibitor through the QSAR Approach and Molecular Docking Study

AbstractIn this study, a quantitative structure‐activity relationship (QSAR) model of anticancer activity against myeloid cell leukemia 1 (Mcl‐1) for a series of 41 tricyclic indole diazepinone derivatives is established. Three different modeling methods, multiple linear regression (MLR), partial least square (PLS), and artificial neural network (ANN) are investigated to perform a QSAR model with significant predictiveness. A clustering method is also used for dividing all compounds into training and external test (ET) sets. Component principal analysis is used to eliminate the redundancy between descriptors. The accuracy and predictability of the proposed models are proven by comparing their key statistical terms. The good results obtained with the internal and external validations (EV) show that the proposed models can predict high‐performance activities and that the selected descriptors are pertinent. This model is also validated using internal validation (IV), mainly using cross‐validation (leave‐many‐out (LMOCV)). The applicability domain (AD) is identified. Based on the SAR map analysis, a novel Mcl‐1 inhibitor with a good predicted activity using the best model is proposed, the interaction of the designed compound with the binding site of Mcl‐1 protein is evaluated and its docking score is found high.

Silver-Catalyzed Carbon Dioxide Fixation on Alkynylindoles.

A silver-catalyzed carbon dioxide fixation reaction into 2-alkynylindole derivatives was developed to afford tricyclic indoles. Carbon dioxide was selectively fixed on the N atom of the indole, and only 6-endo-dig cyclization proceeded under mild reaction conditions. Carboxylation on C3 of the indole was not observed. This method was applicable for a variety of 2-alkynylindoles, and the corresponding products were obtained in high yields without the production of side products.

BiCl3‐Mediated Tandem Cyclization of Tryptamine‐Derived Ynamide: Concise Synthesis of Pentacyclic Spiroindolines and Tricyclic Indole Derivatives

AbstractCatalytic tandem cyclization of ynamides has attracted considerable interest in organic synthesis because of its atom economy in the rapid formation of polycyclic compounds. However, examples on the construction of pentacyclic spiroindolines are quite scarce. Herein, we described a BiCl3‐mediated tandem cyclization reaction of tryptamine‐ynamides, which led to the formation of appealing pentacyclic spiroindoline scaffolds in moderate to excellent yields. In addition, such a reaction can lead to the divergent synthesis of tricyclic indole derivatives with moderate yields by engineering substrate structures. The synthetic utility of this methodology has also been demonstrated by further interesting transformations.magnified image

Selective C(sp3)−N Bond Cleavage of N,N‐Dialkyl Tertiary Amines with the Loss of a Large Alkyl Group via an SN1 Pathway

AbstractPolar disconnection of the C(sp3)−N bond of N,N‐dialkyl‐substituted tertiary amines via ammonium species conventionally favored the loss of the smaller alkyl group by an SN2 displacement, while selective C(sp3)−N bond cleavage by cutting off the larger alkyl group is still underdeveloped. Herein, we present a novel Pd0‐catalyzed [2+2+1] annulation, proceeding through an alkyne‐directed palladacycle formation and consecutive diamination with a tertiary hydroxylamine by cleaving its N−O bond and one C(sp3)−N bond, for the rapid assembly of tricyclic indoles in a single‐step transformation. Noteworthy, experimental results indicated that large tert‐butyl and benzyl groups were selectively cleaved via an SN1 pathway, in the presence of a smaller alkyl group (Me, Et, iPr). Under the guidance of this new finding, tricyclic indoles bearing a removable alkyl group could be exclusively obtained by using a (α‐methyl)benzyl/benzyl or tert‐butyl/2‐(methoxycarbonyl)ethyl mixed amino source.

Selective C(sp3)−N Bond Cleavage of N,N‐Dialkyl Tertiary Amines with the Loss of a Large Alkyl Group via an SN1 Pathway

AbstractPolar disconnection of the C(sp3)−N bond of N,N‐dialkyl‐substituted tertiary amines via ammonium species conventionally favored the loss of the smaller alkyl group by an SN2 displacement, while selective C(sp3)−N bond cleavage by cutting off the larger alkyl group is still underdeveloped. Herein, we present a novel Pd0‐catalyzed [2+2+1] annulation, proceeding through an alkyne‐directed palladacycle formation and consecutive diamination with a tertiary hydroxylamine by cleaving its N−O bond and one C(sp3)−N bond, for the rapid assembly of tricyclic indoles in a single‐step transformation. Noteworthy, experimental results indicated that large tert‐butyl and benzyl groups were selectively cleaved via an SN1 pathway, in the presence of a smaller alkyl group (Me, Et, iPr). Under the guidance of this new finding, tricyclic indoles bearing a removable alkyl group could be exclusively obtained by using a (α‐methyl)benzyl/benzyl or tert‐butyl/2‐(methoxycarbonyl)ethyl mixed amino source.

Synthesis of Tricyclic Indoles by Enantioconvergent Substitution of Alcohols

Synthesis of Tricyclic Indoles by Enantioconvergent Substitution of Alcohols

Palladium-Catalyzed Synthesis of Tricyclic Indoles via a N-S Bond Cleavage Strategy.

In palladium/norbornene (Pd/NBE) chemistry, the "ortho effect" has been proven to be a key factor in the process of β-carbon elimination to extrude NBE. Herein, we found that the o-iodoaniline protected by a p-methoxybenzenesulfonyl group can recover the "ortho effect" and then undergo N-S bond cleavage with vinyl palladium, thus achieving a highly selective C-N coupling reaction in the Catallani-Lautens reaction system. On the basis of this discovery, a one-step synthesis of highly functionalized tricyclic indole derivatives was realized.

Tandem Catalytic Indolization/Enantioconvergent Substitution of Alcohols by Borrowing Hydrogen to Access Tricyclic Indoles

AbstractAn efficient tandem catalysis method is achieved for the direct conversion of alcohol‐containing alkynyl anilines to valuable chiral 2,3‐fused tricyclic indoles. This method relies on a tandem indolization followed by enantioconvergent substitution of alcohols via borrowing hydrogen to construct two rings in one step, enabled by relay and cooperative catalysis of a chiral iridium complex with a chiral phosphoric acid. Highly diastereoselective transformations of the tricyclic indole products also provide efficient access to a diverse array of complex polycyclic indoline compounds.

Tandem Catalytic Indolization/Enantioconvergent Substitution of Alcohols by Borrowing Hydrogen to Access Tricyclic Indoles.

An efficient tandem catalysis method is achieved for the direct conversion of alcohol-containing alkynyl anilines to valuable chiral 2,3-fused tricyclic indoles. This method relies on a tandem indolization followed by enantioconvergent substitution of alcohols via borrowing hydrogen to construct two rings in one step, enabled by relay and cooperative catalysis of a chiral iridium complex with a chiral phosphoric acid. Highly diastereoselective transformations of the tricyclic indole products also provide efficient access to a diverse array of complex polycyclic indoline compounds.

Mechanistic Studies of the Pd- and Pt-Catalyzed Selective Cyclization of Propargyl/Allenyl Complexes

Following the discovery of an unusual transition-metal-catalyzed reaction, the elucidation of the underlying mechanism is essential to understand the characteristic reactivity of the metal. We previously reported a synthetic method for tricyclic indoles using Pt-catalyzed Friedel-Crafts-type C-H coupling. In this reaction, the Pt catalyst selectively formed a seven-membered ring, but the Pd catalyst only afforded a six-membered ring. However, the reasons for the different selectivities caused by Pd and Pt were unclear. We performed density functional theory (DFT) calculations and experimental studies to reveal the origin of the different behaviors of the two metals. The calculations revealed that the formation of the six- and seven-membered rings proceeds via η1-allenyl and η3-propargyl/allenyl complexes, respectively. A molecular orbital analysis of the η3-propargyl/allenyl complex revealed that, for the platinum complex, the energy required to convert the unoccupied molecular orbital on the reactive carbon into the lowest unoccupied molecular orbital (LUMO) was lower than that for the palladium complex. In addition, DFT calculations revealed that the combination of platinum and bis[2-(diphenylphosphino)phenyl] ether (DPEphos) reduced the activation energy of the seven-membered cyclization in comparison with palladium or PPh3. Additional experimental studies, including NMR studies and stoichiometric reactions, support the aforementioned examination.

Rhodium-Catalyzed Synthesis of Chiral 3,4-Fused Tricyclic Indoles

Key words enones - diazomalonates - rhodium catalysis - cycloheptindoles - asymmetric catalysis

Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

AbstractUhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.1 Introduction2 Synthesis2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation3 Reactivity3.1 Use of Uhle’s Ketone for Lysergic Acid3.2 Use of Uhle’s Ketone for Rearranged Clavines3.3 Use of Uhle’s Ketone for Medicinal Chemistry4 Conclusion and Outlook

A novel and robust heterogeneous Cu catalyst using modified lignosulfonate as support for the synthesis of nitrogen-containing heterocycles.

A waste biomass, sodium lignosulfonate, was treated with sodium 2-formylbenzenesulfonate, and the phenylaldehyde condensation product was then used as a robust supporting material to immobilize a copper species. The so-obtained catalyst was characterized by many physicochemical methods including FTIR, EA, FSEM, FTEM, XPS, and TG. This catalyst exhibited excellent catalytic activity in the synthesis of nitrogen-containing heterocycles such as tricyclic indoles bearing 3,4-fused seven-membered rings, 2‑arylpyridines, aminonaphthalenes and 3-phenylisoquinolines. In addition, this catalyst showed to be recyclable and could be reused several times without significant loss in activity during the course of the reaction process.