Indole C2 Research Articles

Triflic Acid-Mediated Chemoselective Indole C2-Heteroarylation of Peptide Tryptophan Residues by Triazine.

Peptide modification provides opportunities to afford peptides with designed functions. Among the proteogenic amino acids, tryptophan represents an ideal and attractive target for peptide modification because of the exclusive chemical reactivity of its unique indole structure. Herein, we reported an indole C2 position-selective and transition-metal-free modification approach for indole derivatives and tryptophan-containing peptides by triazine derivatives via triflic acid activation and that the incorporated functional group could act as an orthogonal handle for further bioconjugation via an inverse electron demand Diels-Alder reaction.

Rhodium-Catalyzed C-H Arylation of Indoles with Arylsilanes at Room Temperature.

The Cp*Rh-catalyzed C-H arylation of indoles with arylsilanes is developed. This C-H activation transformation allows for the Rh-catalyzed indole C2 arylation to overcome the limitations of requiring strong directing group assistance and high-temperature conditions, achieving a room-temperature transformation driven by a weak directing group. Cp*Rh/MeOH catalytic media are considered a key factor enabling this transformation to occur under mild conditions, and experimental studies and theoretical calculations were performed to rationalize the reaction mechanisms and the influence of methanol as a solvent in promoting the reaction.

Unconventional Ligand‐to‐Catalyst Ratio for the Distal C−C Bond Formation via C−H Activation and Chain‐Walking

AbstractA mechanism‐navigated enantioselective alkylation of an indole C2 C−H bond with an internal alkene was developed. Under the unconventional ligand‐to‐metal catalyst ratio, a moderate enantiomeric ratio (er), ranging from 70:30 to 88:12, was achieved with our original ligand. We propose that chain‐walking and bond formation are mechanistically independent and suggest that hydridoiridium generated from the C−H source does not play a role in the chain‐walking process.

One‐Pot Gold/Acid‐Catalyzed Synthesis of Indolo[1,2‐a]quinolin‐5(6H)‐ones from 1‐(2‐Ethynylphenyl)‐1H‐indoles

AbstractWe present a method for the synthesis of substituted indolo[1,2‐a]quinoline‐5(6H)‐ones starting from 1‐(2‐ethynylphenyl)‐1H‐indoles. The transformation involves gold‐catalyzed oxidation of the triple bond followed by acid‐promoted intramolecular cyclization at the indole C2 position. Demonstrating noteworthy versatility, the reaction tolerates a wide array of substituents on the indole core and proceeds in good to excellent yields (up to 93 %).

Late-stage modification of complex drug: Base-controlled Pd-catalyzed regioselective synthesis and bioactivity of arylated osimertinibs.

Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed C─H arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (K2CO3) promoted the arylation of acrylamide terminal C(sp2)-H, affording 34 derivatives. Conversely, sodium tert-butoxide (t-BuONa) mediated the aryl C(sp2)-H arylation of the indole C2 position, providing 27 derivatives. The derivative 3r containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFRT790M/L858R and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a "one substrate-multi reactions-multiple products" strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.

An attempted oxidative coupling approach to the scholarinine A framework

In this manuscript, an oxidative carbon–carbon bond forming reaction to construct the framework of alkaloids such as scholarinine A is explored using a constrained substrate. Instead of the desired carbon–carbon bond formation between an indole C3 position and a malonate group, a competing carbon–nitrogen bond between the malonate and indole C3 position was observed to form. This work adds to the growing body of substrates for oxidative carbon–carbon bond formation and importantly, demonstrates that these reactions are challenging for some conformationally constrained substrates.

The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors.

As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 μM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

Functions of Protein <i>C</i>-Mannosylation in Physiology and Pathology

Protein C-mannosylation is a unique type of protein glycosylation in which a single α-mannose is attached to the indole C2 of tryptophan (Trp) through a C–C bond. The Trp-x-x-Trp (WxxW) sequences, whose first Trp residue may be C-mannosylated, constitute the consensus motifs of this rare glycosylation modification. Dpy-19 was recognized as a gene encoding C-mannosyltransferase in Caenorhabditis elegans. DPY19L1 and DPY19L3 were later confirmed as mammalian C-mannosyltransferases. The consensus motif can be found in the thrombospondin type 1 repeat and cytokine receptor type I families as well as in many other proteins, and recent studies suggest critical roles of C-mannosylation in the folding, sorting, and/or secretion of the substrate proteins. We successfully synthesized C-mannosylated Trp-containing Trp-Ser-Pro-Trp (WSPW) peptides. As a result of using these peptides in our investigations, we proposed that C-mannosylation may have biological functions in addition to contributing to the folding and stability of the substrate proteins. In this mini-review, we discuss the biological roles of C-mannosylation in physiology and pathology as based on our recent findings.

Metabolism-Guided Optimization of Tryptophanol-Derived Isoindolinone p53 Activators.

For the first time, the pharmacokinetic (PK) profile of tryptophanol-derived isoindolinones, previously reported as p53 activators, was investigated. From the metabolites' identification, performed by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-HRMS/MS), followed by their preparation and structural elucidation, it was possible to identify that the indole C2 and C3 are the main target of the cytochrome P450 (CYP)-promoted oxidative metabolism in the tryptophanol-derived isoindolinone scaffold. Based on these findings, to search for novel p53 activators a series of 16 enantiopure tryptophanol-derived isoindolinones substituted with a bromine in indole C2 was prepared, in yields of 62-89%, and their antiproliferative activity evaluated in human colon adenocarcinoma HCT116 cell lines with and without p53. Structural optimization led to the identification of two (S)-tryptophanol-derived isoindolinones 3.9-fold and 1.9-fold more active than hit SLMP53-1, respectively. Compounds' metabolic stability evaluation revealed that this substitution led to a metabolic switch, with the impact of Phase I oxidative metabolism being minimized. Through differential scanning fluorimetry (DSF) experiments, the most active compound of the series in cell assays led to an increase in the protein melting temperature (Tm) of 10.39 °C, suggesting an effective binding to wild-type p53 core domain.

Iridium catalysed C2 site-selective methylation of indoles using a pivaloyl directing group through weak chelation-assistance.

Here we present an iridium catalysed C2-selective methylation of indoles using methyltrifluoroborate as a source of methyl group. The iridium catalyst selectively discriminates the indole C2 and C4 C-H bonds by coordination with a pivaloyl directing group.

Total Synthesis of (+)-Alstonlarsine A: Old Reactions in Modern Alkaloids Synthesis

Abstract(+)-Alstonlarsine A is a recently isolated monoterpenoid indole alkaloid, possessing a novel pentacyclic skeleton and interesting biological activity, making it an attractive target for synthetic chemists. In this article we focus on its total synthesis, grounded on enamine formation/Diels–Alder reaction domino sequence, as well as a novel methodology for indole C2 functionalization via carbenoid insertion, which could also allow for the synthesis of other indole alkaloids possessing cycloalka[b]indole subunits.1 Introduction2 Diels–Alder Reaction3 Methodology Studies4 Total Synthesis of (+)-Alstonlarsine A by Bihelovic and Ferjancic5 Total Synthesis of (+)-Alstonlarsine A by Zhai6 Summary

Diastereoselective Synthesis of Indoline- and Pyrrole-Embedded Tetracycles via an Unprecedented Dearomative Indole-C3-Alkylation/Aza-Friedel-Crafts Cascade Reaction.

Dearomative indole C3-alkylation─intramolecular iminium trapping cascade reaction of indole-C3-tethered nucleophiles is a well-known blueprint for accessing 2,3-fused indolines. In exploring this strategy, synthetic chemists have utilized diverse classes of electrophilic reagents. However, the tethered nucleophiles have mainly been limited to heteronucleophiles and enolates; exploitation of tethered arenes/heteroarenes remains unknown. We herein describe the first examples of pyrrole-intercepted dearomative indole C3-allylation and benzylation of indole-tethered pyrroles toward the synthesis of 2,3-cis-fused tetracyclic indolines featuring a C3 all-carbon quaternary stereocentre. Our methodology capitalizes on the capability of NaOtBu/Et3B combination to direct the intermolecular alkylation to take place regioselectively at the indole C3 position over the other reactive sites (indole N and C2 and pyrrole C2 positions) and leverages the high nucleophilicity of the pyrrole template for the concomitant aza-Friedel-Crafts ring closure that traditionally would require an additional acid-catalyzed synthetic step. This cascade reaction is accomplished with broad substrate scope and excellent yields and chemo-, regio-, and diastereoselectivities.

In silico, synthesis and anticancer evaluation of benzamide tryptamine derivatives as novel eEF2K inhibitors

Eukaryotic elongation factor 2 kinase (eEF2K), a member of the atypical α-kinase family, is highly expressed in a variety of tumor tissues. Inhibition of eEF2K function can effectively kill cancer cells without affecting the function of normal cells. Therefore, eEF2K is a promising new target for cancer therapy. In this study, a series of benzamide tryptamine derivatives were designed and synthesized as novel eEF2K inhibitors. The druggability properties of the synthesized compounds were predicted in silico and performed well. The MTT assay indicated that most of these compounds displayed good antiproliferative activity against human leukemia CCRF-CEM and K562 cell lines. The structure–activity relationship (SAR) revealed that substituents with different electronic effects on the C5 position of indole ring or C2′, C4′ positions of benzene ring have a great influence on the anti-proliferative activity. Among them, 5j demonstrated the highest anti-proliferative activity with IC50 value of 1.63–3.54 μM. this compound displayed an effective eEF2K inhibition by down-regulated the level of phosphorylated eEF2 in CCRF-CEM cells. Additionally, the western blot analysis further revealed that 5j also significantly affected eEF2K-related signaling pathways. Anticancer mechanism studies have shown that 5j arrested the cell cycle in G0/G1 and induced CCRF-CEM cells apoptosis. Furthermore, 5j activated cleaved caspase-9, 8, 3 and cleaved PARP in a time-dependent manner, which suggesting that 5j induced cancer cells apoptosis through both intrinsic and extrinsic pathways. In summary, benzamide tryptamine derivative 5j represents a novel and promising lead structure for the development of eEF2K inhibitors in cancer therapy.

Regioselectivity of the SEAr-based cyclizations and SEAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles.

Indole-3,4- and 4,5-fused carbo- and heterocycles are ubiquitous in bioactive natural products and pharmaceuticals, and hence, a variety of synthetic approaches toward such compounds have been developed. Among these, cyclization and annulation of 3,5-unsubstituted, 4-substituted indoles involving an electrophilic aromatic substitution (SEAr) as the ring closure are particularly attractive, because they avoid the use of 3,4- or 4,5-difunctionalized indoles as starting materials. However, since 3,5-unsubstituted, 4-substituted indoles have two potential ring-closure sites (indole C3 and C5 positions), such reactions in principle can furnish either or both of the indole 3,4- and 4,5-fused ring systems. This Commentary will briefly highlight the issue by summarizing recent relevant literature reports.

Visible Light‐Mediated Dearomative Hydrogen Atom Abstraction/ Cyclization Cascade of Indoles

AbstractThe photochemical synthesis of yet unknown 2‐oxospiro[azetidine‐3,3′‐indolines] (17 examples, 80–95 % yield), 2,4‐dioxospiro[azetidine‐3,3′‐indolines] (eight examples, 87–97 % yield), and 1‐oxo‐1,3‐dihydrospiro[indene‐2,3′‐indolines] (17 examples, 85–97 % yield) is described. Starting from readily accessible 3‐substituted indoles, a dearomatization of the indole core was accomplished upon irradiation at λ=420 nm in the presence of thioxanthen‐9‐one (10 mol%) as the sensitizer. Based on mechanistic evidence (triplet energy determination, deuteration experiments, by‐product analysis) it is proposed that the reaction proceeds by energy transfer via a 1,4‐ or 1,5‐diradical intermediate. The latter intermediates are formed by excited state hydrogen atom transfer from suitable alkyl groups within the C3 substituent to the indole C2 carbon atom. Subsequent ring closure proceeds with pronounced diastereoselectivity to generate a 4‐ or 5‐membered spirocyclic dearomatized product with several options for further functionalization.

Visible Light-Mediated Dearomative Hydrogen Atom Abstraction/ Cyclization Cascade of Indoles.

The photochemical synthesis of yet unknown 2‐oxospiro[azetidine‐3,3′‐indolines] (17 examples, 80–95 % yield), 2,4‐dioxospiro[azetidine‐3,3′‐indolines] (eight examples, 87–97 % yield), and 1‐oxo‐1,3‐dihydrospiro[indene‐2,3′‐indolines] (17 examples, 85–97 % yield) is described. Starting from readily accessible 3‐substituted indoles, a dearomatization of the indole core was accomplished upon irradiation at λ=420 nm in the presence of thioxanthen‐9‐one (10 mol%) as the sensitizer. Based on mechanistic evidence (triplet energy determination, deuteration experiments, by‐product analysis) it is proposed that the reaction proceeds by energy transfer via a 1,4‐ or 1,5‐diradical intermediate. The latter intermediates are formed by excited state hydrogen atom transfer from suitable alkyl groups within the C3 substituent to the indole C2 carbon atom. Subsequent ring closure proceeds with pronounced diastereoselectivity to generate a 4‐ or 5‐membered spirocyclic dearomatized product with several options for further functionalization.

Gold(I)‐Catalyzed Selective Cyclization and 1,2‐Shift to Prepare Pseudorutaecarpine Derivatives

AbstractA variety of pseudorutaecarpine derivatives were prepared in good to excellent yields through a gold(I)‐catalyzed selective cyclization and 1,2‐shift of N‐alkynyl quinazolinone‐tethered indoles. Mechanistic study revealed that spiroindolenines generated in situ by cyclization at the the indole C3 position underwent an alkenyl 1,2‐shift to generate pseudorutaecarpine. The reaction proceeds under mild reaction conditions, has a broad substrate scope, good functional group tolerance, and gram‐scalable application. Furthermore, biological evaluation showed that most of the pseudorutaecarpine scaffolds prepared exhibit anti‐inflammatory activity.magnified image

Synthesis, Molecular Pharmacology, and Structure-Activity Relationships of 3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists.

Synthetic indole cannabinoids characterized by a 2',2'-dimethylindan-5'-oyl group at the indole C3 position constitute a new class of ligands possessing high affinity for human CB2 receptors at a nanomolar concentration and a good selectivity index. Starting from the neutral antagonist 4, the effects of indole core modification on the pharmacodynamic profile of the ligands were investigated. Several N1 side chains afforded potent and CB2-selective neutral antagonists, notably derivatives 26 (R1 = n-propyl, R2 = H) and 35 (R1 = 4-pentynyl, R2 = H). Addition of a methyl group at C2 improved the selectivity for the CB2 receptor. Moreover, C2 indole substitution may control the CB2 activity as shown by the functionality switch in 35 (antagonist) and 49 (R1 = 4-pentynyl, R2 = CH3, partial agonist).

Rapid Synthesis of Functionalized Hydrocarbazolones via Indole C2−H Activation Using Enone Functionality as a Directing Group/Electrophilic Species

AbstractHydrocarbazolones are a key structural unit in many natural bioactive compounds and are thus a valuable synthetic target. A rhodium‐catalyzed C−H functionalization reaction with acceptor/acceptor diazo compounds was developed for synthesizing 2,3‐fused indole variants. An α,β‐unsaturated enone was utilized as a directing group for site‐selective C−H activation and as an electrophile for the subsequent cyclization. Overall, the developed annulation enabled the rapid assembly of synthetically valuable hydrocarbazolones from readily available indoles. Additionally, computational investigations were conducted to elucidate the reaction pathway and rationalize the experimentally observed site‐selectivity.magnified image

Regioselective cascade annulation of indoles with alkynediones for construction of functionalized tetrahydrocarbazoles triggered by Cp*RhIII-catalyzed C–H activation

An efficient regioselective and stereoselective cascade annulation of indoles with alkynediones has been developed for construction of free (NH) tetrahydrocarbazoles with continuous quaternary carbons via Cp*RhIII-catalyzed indole C2–H activation.