Tetracyclic Indole Research Articles

NHC-Catalyzed Umpolung Driven Intramolecular Cyclizations for the Generation of 3,4-Cycloheptanone Annulated Tetracyclic Indole Derivatives.

In this Letter, we disclose the development and exploitation of umpolung reactivity of N-heterocyclic carbene (NHC) organocatalysts in generating tetracyclic indole derivatives with the introduction of a cycloheptane ring forming event. The NHC-catalyzed intramolecular vinylogous Stetter, Stetter, benzoin, and formal cross-dehydrogenative coupling transformations have been executed, enabling the construction of 3,4-cycloheptannulated indole derivatives in good to excellent yields. The developed protocols utilize an inexpensive catalyst and feature operational simplicity, atom economy, gram-scale syntheses, and postsynthetic availability.

A Novel C3/C4-Fused Indole Scaffold through Acid-Catalyzed Cascade Reaction.

3,4-bridged indoles are underrepresented among the vast number of indoles described in the literature. Attempts to access 3,4-macrocyclized indoles led to the unexpected formation of a novel tetracyclic indole through intramolecular acid-catalyzed ring contraction. The herein-established one-step synthetic route provides an excellent medicinal chemistry platform for the construction of screening libraries covering a unique chemical space of indoles.

Mechanism of isorhynchophylline in lipopolysaccharide-induced acute lung injury based on proteomic technology.

Isorhynchophylline (IRN), a tetracyclic indole alkaloid, has anti-inflammatory and antioxidant activities against cardiovascular diseases and central nervous system disorders. Acute lung injury (ALI) is a manifestation of inflammation concentrated in the lungs and has a high incidence rate and mortality The purpose of this study is to explain the mechanism of IRN in the treatment of acute lung injury and to provide a new scheme for clinical treatment. The experimental mice were divided into three groups: CTRL, LPS, LPS+IRN. The mouse model of ALI was established by inhaling LPS solution through nose. After continuous administration of IRN solution for 7 days, the mice in LPS+IRN group were killed and the lung tissue was collected for detection. Proteomic (Data are available via ProteomeXchange with identifier PXD050432) results showed that 5727 proteins were detected in mouse lung tissues, and 16 proteins were screened out. IRN could reverse the trend of these differential proteins. In addition, IRN can act on integrin αM to reduce neutrophil recruitment and thereby produce anti-inflammatory effects and may suppress neutrophil migration through the leukocyte transendothelial migration pathway. TUNEL and RT-PCR experiments revealed that LPS-induced ALI in mice increases the apoptosis of lung tissues, damage to alveolar epithelial cells and levels of inflammatory factors. Treatment with IRN can repair tissues, improve lung tissue pathology and reduce lung inflammation.

Synthesis of N-Fused Polycyclic Indole Derivatives via Ru(II)-Catalyzed C-H Bond Activation and Intramolecular Hydroarylation.

A new synthesis of N-fused tetracyclic indole derivatives and their related polycyclic analogues has been developed based on ruthenium(II)-catalyzed C-H activation and intramolecular hydroarylation. A series of polycyclic indoles with a 3-formyl group have been prepared in good to high yields. Various aliphatic and aromatic amines have been studied to form a transient directing group with the aldehyde for the catalytic process. A significant impact of the structures of the aromatic amines was identified, and 1-naphthylamine was shown to enable the catalytic process. DFT computations were performed to gain further insight into the role of the transient directing groups.

Catalytic asymmetric dearomative azo-Diels–Alder reaction of 2-vinlyindoles

Due to the high electrophilic nature of azo-dienophiles, azo-Diels–Alder proceeds rapidly even without the need of a catalyst and is therefore regarded as the “click reaction”. This spontaneity causes strong background reaction and poses a daunting challenge to chemists for developing the catalytic asymmetric version. Reported herein is the first catalytic asymmetric dearomative azo-Diels–Alder reaction between 2-vinylindoles and triazoledione. This protocol makes use of the high energy barrier of dearomatization to avert the strong background reaction of azo-Diels–Alder reaction, allowing the implementation of the projected reaction at ambient temperature. Density functional theory calculations have been performed to gain insights into the reaction mechanism and the origins of the enantioselectivity. By using this method, a variety of tetracyclic indole derivatives have been readily prepared in good to excellent yields and with excellent diastereo- and enantio‑selectivities (33 examples, up to 97% yield and >99% ee, >20:1 dr).

Anti-Tobacco Mosaic Virus Indole Alkaloids from the Nicotiana tabacum-Derived Fungus Aspergillus versicolor

To explore the active metabolites from Aspergillus, we have discovered five undescribed tricyclic or tetracyclic indole alkaloids aspergillines K–O (1–5) and four known analogues (6–9) from the strain of Nicotiana tabacum-derived Aspergillus versicolor YNCA0363. The α-amino group derived from tryptophan in isolates 1–6 was changed to an oxygen atom, which is uncommon in the reported analogues. To the best of our knowledge, 4 and 5 represent the first examples of indole alkaloids possessing an isochromene moiety. Compounds 1 and 3 showed obvious anti-tobacco mosaic virus (TMV) activities with inhibition rates of 43.6% ± 2.2 and 58.5% ± 2.8 at the concentration of 20 μM, respectively, which were significantly higher than that of the positive control. Compound 3 also showed excellent potential of inducing systemic acquired resistance. Furthermore, compound 3 can increase the activities of two reactive oxygen species-scavenging enzymes, peroxidase and superoxide dismutase, and enhance tobacco resistance to TMV. Molecular docking results showed that compound 3 exhibits a stronger interaction with TMV-helicase, and showed higher antiviral activities than others. This work revealed that the above indole alkaloids, especially 3, could induce resistance in tobacco plants against the viral pathogen TMV.

A Convergent Synthesis of Tetracyclic Indole Compounds by a ­Palladium-Catalyzed Cross-Coupling and Tandem Cyclization ­Reaction

AbstractA new strategy for the convergent synthesis of the ABCD ring system of indole terpene alkaloids has been developed based on a Sonogashira coupling of an o-iodoaniline (the A ring) with an alkyne bearing the D ring. After a tandem palladium-catalyzed cyclization, the tetracyclic ABCD ring structure found in the terpene indole alkaloids was obtained in good yield.

Cellular Stress-Induced Metabolites in Escherichia coli.

Escherichia coli isolates commonly inhabit the human microbiota, yet the majority of E. coli's small-molecule repertoire remains uncharacterized. We previously employed erythromycin-induced translational stress to facilitate the characterization of autoinducer-3 (AI-3) and structurally related pyrazinones derived from "abortive" tRNA synthetase reactions in pathogenic, commensal, and probiotic E. coli isolates. In this study, we explored the "missing" tryptophan-derived pyrazinone reaction and characterized two other families of metabolites that were similarly upregulated under erythromycin stress. Strikingly, the abortive tryptophanyl-tRNA synthetase reaction leads to a tetracyclic indole alkaloid metabolite (1) rather than a pyrazinone. Furthermore, erythromycin induced two naphthoquinone-functionalized metabolites (MK-hCys, 2; and MK-Cys, 3) and four lumazines (7-10). Using genetic and metabolite analyses coupled with biomimetic synthesis, we provide support that the naphthoquinones are derived from 4-dihydroxy-2-naphthoic acid (DHNA), an intermediate in the menaquinone biosynthetic pathway, and the amino acids homocysteine and cysteine. In contrast, the lumazines are dependent on a flavin intermediate and α-ketoacids from the aminotransferases AspC and TyrB. We show that one of the lumazine members (9), an indole-functionalized analogue, possesses antioxidant properties, modulates the anti-inflammatory fate of isolated TH17 cells, and serves as an aryl-hydrocarbon receptor (AhR) agonist. These three systems described here serve to illustrate that new metabolic branches could be more commonly derived from well-established primary metabolic pathways.

Metabolites identification and pharmacokinetic profile of hirsuteine, a bioactive component in Uncaria in rats by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Hirsuteine is one of the major bioactive tetracyclic indole alkaloids found in Uncaria rhynchophylla (Miq.) Jacks, possessing a wide range of pharmacological activities including neuroprotective, anticonvulsant, antihypertensive, sedative and hypnotic, and so forth. The present study was undertaken to assess the metabolism and plasma pharmacokinetics of hirsuteine in rats. After oral administration of hirsuteine at the dose of 30 mg/kg, 13, 21, and 8 metabolites were detected in rat plasma, urine, and bile by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, respectively. Furthermore, plasma concentrations of hirsuteine and its four metabolites, 4-hirsuteine N-oxide, 3,4-dehydrohirsuteine, 11-hydroxyhirsuteine, and 11-hydroxyhirsuteine-11-O-glucuronide were simultaneously quantified in rat plasma, using carbamazepine as the internal standard. The linear calibration curve of hirsuteine was in the concentration range of 0.005-5.0 μg/ml. The lower limit of quantitation in the rat plasma was 5 ng/ml for hirsuteine. This study is the first to comprehensively investigate the metabolism process of hirsuteine and the pharmacokinetic profiles of hirsuteine and its major metabolite, and will provide a scientific basis to further elucidate the pharmacodynamic material basis and therapeutic mechanism of Uncaria prescriptions.

Total synthesis of (\xb1)-decursivine via BINOL-phosphoric acid catalyzed tandem oxidative cyclization

The synthesis of tetracyclic indole alkaloid (±)-decursivine was accomplished using BINOL-phosphoric acid catalyzed tandem oxidative cyclization as a key step with (bis(trifluoroacetoxy)iodo)benzene (PIFA) as an oxidizing agent. This represents one of the shortest and highest yielding routes for the synthesis of (±)-decursivine from readily available starting materials.

Tandem Nenitzescu Reaction/Nucleophilic Aromatic Substitution to Form Novel Pyrido Fused Indole Frameworks

Abstract5‐Hydroxyindoles are privileged structures that form part of various bioactive compounds. The Nenitzescu reaction of quinones and enamines is one of the most powerful methods to obtain 5‐hydroxyindoles. In this work, we have applied the Nenitzescu reaction to 2‐(2‐chloropyrid‐3‐yl)benzoquinones. Mixtures of regioisomers were obtained that could be separated in the 4‐ and 6‐substituted analogues, and then cyclized separately in a metal‐free base‐catalyzed reaction, affording novel tetracyclic indole derivatives. These are indeed the first examples reported in the literature of the linear pyrido[3′,2′ : 4,5]furo[3,2‐b]indole and angular 1H‐pyrido[2′,3′ : 4,5]furo[2,3‐c]indole systems. The regioselectivity and the yield of the Nenitzescu reaction were found to be dependent on the N‐substituent at the enamine. Furthermore, we analyzed the UV‐Vis and PL spectra of the new systems, and this was supported by DFT calculations, allowing us to compare the properties of angular compared to linearly shaped compounds.

Discovery of a tetracyclic indole alkaloid that postpones fibrillation of hen egg white lysozyme protein

Protein aggregation, such as amyloid fibril formation, is molecular hallmark of many neurodegenerative disorders including Alzheimer's, Parkinson's, and Prion disease. Indole alkaloids are well-known as the compounds having the ability to inhibit protein fibrillation. In this study, we experimentally and computationally have investigated the anti-amyloid property of a derivative of a synthesized tetracyclic indole alkaloid (TCIA), possessing capable functional groups. The fibrillation reaction of Hen White Egg Lysozyme (HEWL) was performed in absence and presence of the indole alkaloid. For quantitative analysis, we used Thioflovin T binding assay which showed ~50% reduction in fibril formation in the presence of 20 μM TCIA. Using TEM imaging, we observed a significant morphological change in our model protein in the presence of TCIA. In addition, we exploited FT-IR assay by which Amide I peak's shifting toward lower wavenumber was clearly observed. Using Molecular Docking, the interaction of the inhibitor (TCIA) with the protein's amyloidogenic region was modeled. Also, different biophysical parameters were calculated by Molecular Dynamics (MD) simulation. Various biochemical assays, conformational change, and hydrophobicity exposure of the protein during amyloid formation indicated that the compound assists HEWL to keep its native structure via destabilizing β-sheet structure.

2-Indolymethanols as 4-atom-synthons in oxa-Michael reaction cascade: access to tetracyclic indoles

The first Brønsted acid-catalyzed oxa-Michael reaction cascade of 2-indolylmethanols as four-atom synthons with trione alkenes was accomplished.

Gold/scandium bimetallic relay catalysis of formal [5+2]- and [4+2]-annulations: access to tetracyclic indole scaffolds.

Regiodivergent formal [5+2]- and [4+2]-annulation reactions of indole derivatives with 2-(2-alkynyl)aryl cyclopropane-1,1-diesters (ACPs) have been developed. A series of tetracyclic indole derivatives were delivered in a 77% average yield with excellent regioselectivities enabled by Au(I)/Sc(III) bimetallic relay catalysis. A gram-scale reaction and further transformation of the resulting tetracyclic indoles demonstrated the practical utility of this protocol. Moreover, the photophysical properties of the obtained multicyclic compounds were also investigated.

Atropselective Synthesis of N,C-Bis(diphenylphosphanes) from Bridged 2-Arylindoles Based on Effective Point-to-Axial Asymmetric Inductions after an Unusual Dilithiation ⊥.

An asymmetric methanolysis of glutaric anhydride and 6 ensuing steps gave veratrol-annulated dimethylcyclo-heptenone diastereomers with 99% ee; ring closures occurred by Friedel-Crafts acylations of carboxylic acids obtained by stereospecific hydrogenolyses of a pair of diastereomeric δ-lactones. The mentioned cycloheptenones and Ph-NH-NH2 underwent Fischer indole syntheses providing the tetracyclic indoles cis- and trans-14a, respectively. Double lithiations with BuLi and quenchings with ClPPh2 furnished the diphosphanes cis- and trans-15 with perfect (P)- and (M)-atropselectivity, respectively.

Diastereoselective pot-and atom-economical synthesis of densely-substituted polycyclic 1,2- and 1,2,3-fused indole scaffolds

A simple, efficient, one-pot sequential process for the preparation of a family of 8,9-dihydropyrido[1,2–a]indol-6(7H)-one scaffolds in acceptable yields has been established under mild conditions. The Michael-hemiaminalization-oxidation reaction proceeds between methyl 2-(3-formyl-1H-indol-2-yl) acetate and trans-β-aryl/alkyl-substituted acroleins using pyrrolidine-BzOH as an efficient organocatalyst, followed by oxidation of in situ generated of C,N-fused hemiaminal adducts in the presence of PDC at room temperature. Excitingly, organobase-catalyzed highly diastereoselective (up to ≤9:1 dr) construction of a series of pharmacologically attractive 1,2,3-fused tetracyclic indole scaffolds with five contiguous chiral centers including an all-carbon stereogenic center has been realized through our developed method. Moreover, pyrrolidine-BzOH and PTSA as combined catalytic systems promote the uninterrupted sequential Michael-cyclization reaction, followed by N-alkylation reaction with carbazole to produce interesting class of 6-(9H-carbazol-9-yl)-6,7,8,9-tetrahydropyrido[1,2–a]indole derivatives in a diastereoselective manner.

Room-Temperature and Transition-Metal-Free Intramolecular α-Arylation of Ketones: A Mild Access to Tetracyclic Indoles and 7-Azaindoles.

A novel approach for the synthesis of tetracyclic indoles and 7-azaindoles is reported. The strategy involves four steps, with a fast rt intramolecular α-arylation of ketones as key step. The reaction was inspected synthetically to achieve the synthesis of 11 novel tetracyclic structures with moderate to very good yields (39-85%). Theoretical combined with experimental studies led us to propose a probable polar mechanism (concerted SNAr).

8-Oxo-9-Dihydromakomakine Isolated from Aristotelia chilensis Induces Vasodilation in Rat Aorta: Role of the Extracellular Calcium Influx.

8-Oxo-9-dihydromakomakine is a tetracyclic indole alkaloid extracted from leaves of the Chilean tree Aristotelia chilensis. The present study investigated the effects of this alkaloid on vascular response in tissues isolated from aortic segments obtained from normotensive rats. Our results showed that 8-oxo-9-dihydromakomakine induced a dose-dependent relaxation of aortic rings pre-contracted with phenylephrine (PE; 10−6 M). The vasorelaxation induced by 8-oxo-9-dihydromakomakine in rat aortic rings is independent of endothelium. The pre-incubation of aortic rings with 8-oxo-9-dehydromakomakine (10−4 M) significantly reduced the contractile response to KCl (p < 0.001) more than PE (p < 0.05). The highest dose of 8-oxo-9-dehydromakomakine (10−4 M) drastically reduced the contraction to KCl (6·10−2 M), but after that, PE (10−6 M) caused contraction (p < 0.05) in the same aortic rings. The addition of 8-oxo-9-dihydromakomakine (10−5 M) decreased the contractile response to tetraethylammonium (a voltage-dependent potassium channels blocker; TEA; 5 × 10−3 M; p < 0.01) and BaCl2 (a non-selective inward rectifier potassium channel blocker; 5 × 10−3 M; p < 0.001) in rat aorta. 8-oxo-9-dihydromakomakine (10−5 M) decreased the contractile response to PE in rat aorta in the presence or absence of ouabain (an inhibitor of Na,K-ATPase; 10−3 M; p < 0.05). These results could indicate that 8-oxo-9-dihydromakomakine partially reduces plasma membrane depolarization-induced contraction. In aortic rings depolarized by PE, 8-oxo-9-dihydromakomakine inhibited the contraction induced by the influx of extracellular Ca2+ in a Ca2+ free solution (p < 0.01). 8-oxo-9-dihydromakomakine reduced the contractile response to agonists of voltage-dependent calcium channels type L (Bay K6844; 10−8 M; p < 0.01), likely decreasing the influx of extracellular Ca2+ through the voltage-dependent calcium channels. This study provides the first qualitative analysis indicating that traditional folk medicine Aristotelia chilensis may be protective in the treatment of cardiovascular pathologies.

Two Distinct Substrate Binding Modes for the Normal and Reverse Prenylation of Hapalindoles by the Prenyltransferase AmbP3

AbstractThe cyanobacterial prenyltransferase AmbP3 catalyzes the reverse prenylation of the tetracyclic indole alkaloid hapalindole U at its C‐2 position. Interestingly, AmbP3 also accepts hapalindole A, a halogenated C‐10 epimer of hapalindole U, and catalyzes normal prenylation at its C‐2 position. The comparison of the two ternary crystal structures, AmbP3‐DMSPP/hapalindole U and AmbP3‐DMSPP/hapalindole A, at 1.65–2.00 Å resolution revealed two distinct orientations for the substrate binding that define reverse or normal prenylation. The tolerance of the enzyme for these altered orientations is attributed to the hydrophobicity of the substrate binding pocket and the plasticity of the amino acids surrounding the allyl group of the prenyl donor. This is the first study to provide the intimate structural basis for the normal and reverse prenylations catalyzed by a single enzyme, and it offers novel insight into the engineered biosynthesis of prenylated natural products.

Two Distinct Substrate Binding Modes for the Normal and Reverse Prenylation of Hapalindoles by the Prenyltransferase AmbP3.

The cyanobacterial prenyltransferase AmbP3 catalyzes the reverse prenylation of the tetracyclic indole alkaloid hapalindole U at its C-2 position. Interestingly, AmbP3 also accepts hapalindole A, a halogenated C-10 epimer of hapalindole U, and catalyzes normal prenylation at its C-2 position. The comparison of the two ternary crystal structures, AmbP3-DMSPP/hapalindole U and AmbP3-DMSPP/hapalindole A, at 1.65-2.00 Å resolution revealed two distinct orientations for the substrate binding that define reverse or normal prenylation. The tolerance of the enzyme for these altered orientations is attributed to the hydrophobicity of the substrate binding pocket and the plasticity of the amino acids surrounding the allyl group of the prenyl donor. This is the first study to provide the intimate structural basis for the normal and reverse prenylations catalyzed by a single enzyme, and it offers novel insight into the engineered biosynthesis of prenylated natural products.