Indole Framework Research Articles

Advances and Strategies towards Synthesis of Aspidosperma Indole Alkaloids Goniomitine.

Goniomitine is of the aspidosperma alkaloid family, with an angularly fused tetracyclic skeleton housing an all-carbon quaternary carbon chiral center alongside an aminal functional group. This natural product has garnered attention as a synthetic target due to its intriguing molecular architecture and anti-proliferative activity in recent years. Following the first synthesis of (-)-goniomitine by Takano in 1991, synthetic chemists have developed various methods. This review provides an overview of the methodologies used in the synthesis of goniomitine in racemic and enantiopure forms via divergent construction indole framework, indole functionalization, and the integrated oxidation/reduction/cyclization (iORC) sequence from 1991 to 2023.

In(OTf)3 promoted sonochemical approach to 3-(2-chloropyrimidin-4-yl)indoles: Their in silico and in vitro evaluation against SIRT1

We report exploring the 3-(2-chloropyrimidin-4-yl)indole framework for the identification of new inhibitors of SIRT1. A library of compounds based on this framework was synthesized via an ultrasound assisted heteroarylation approach. The methodology involved In(OTf)3 mediated CC bond forming reaction between 2,4-dichloropyrimidine and indoles to give the desired products in good to acceptable yields. The regioselectivity of this approach appeared to be a key feature as the methodology involved sonochemical replacement of the (i) C-3 hydrogen of indole and (ii) C-4 chloro group of the pyrimidine ring at the same time. Its synthetic application was demonstrated by converting one of the synthesized compounds into the naturally occurring alkaloid Meridianin G. The in silico docking of 3-(2-chloropyrimidin-4-yl)indoles prepared showed promising interactions with SIRT1 in addition to probable selectivity towards this protein over SIRT2. A majority of compounds participated in H-bond interaction with GLN345 residue mainly through their indole “NH” moiety. However, higher binding affinities were observed for compounds possessing a sulfonamide moiety at C-5 position of the indole ring. Correlating the findings of in silico studies a number of synthesized compounds showed inhibition of SIRT1 in vitro. With the inhibition > 70 % the compound 3e, 3o and 3p were identified as initial hit molecules when 3p emerged as most promising among them. The SAR (Structure-Activity-Relationship) analysis also suggested that a sulfonamide moiety at C-5 position was beneficial for the high SIRT1 inhibition whereas a free NH moiety of the indole ring was essential for activity. Based on in silico and in vitro studies including ADME predictions the compound 3p appeared as a key agent for further pharmacological evaluation.

Total syntheses of certain asperversiamides, linearly-fused and prenylated indole alkaloids

Biogenetically-patterned total syntheses of seven prenylated alkaloids embodying the pyrano[3,2-f]indole framework have been realised alongside the preparation of several potential natural products.

Enhanced Cytotoxicity and Antimelanoma Activity of Novel Semisynthetic Derivatives of Betulinic Acid with Indole Conjugation.

The prevalence and severity of skin cancer, specifically malignant melanoma, among Caucasians remains a significant concern. Natural compounds from plants have long been explored as potential anticancer agents. Betulinic acid (BI) has shown promise in its therapeutic properties, including its anticancer effects. However, its limited bioavailability has hindered its medicinal applications. To address this issue, two recently synthesized semisynthetic derivatives, N-(2,3-indolo-betulinoyl)diglycylglycine (BA1) and N-(2,3-indolo-betulinoyl)glycylglycine (BA2), were compared with previously reported compounds N-(2,3-indolo-betulinoyl)glycine (BA3), 2,3-indolo-betulinic acid (BA4), and BI. These compounds were evaluated for their effects on murine melanoma cells (B164A5) using various in vitro assays. The introduction of an indole framework at the C2 position of BI resulted in an increased cytotoxicity. Furthermore, the cytotoxicity of compound BA4 was enhanced by conjugating its carboxylic group with an amino acid residue. BA2 and BA3, with glycine and glycylglycine residues at C28, exhibited approximately 2.20-fold higher inhibitory activity compared to BA4. The safety assessment of the compounds on human keratinocytes (HaCaT) has revealed that concentrations up to 10 µM slightly reduced cell viability, while concentrations of 75 µM resulted in lower cell viability rates. LDH leakage assays confirmed cell membrane damage in B164A5 cells when exposed to the tested compounds. BA2 and BA3 exhibited the highest LDH release, indicating their strong cytotoxicity. The NR assay revealed dose-dependent lysosome disruption for BI and 2,3-indolo-betulinic acid derivatives, with BA1, BA2, and BA3 showing the most cytotoxic effects. Scratch assays demonstrated concentration-dependent inhibition of cell migration, with BA2 and BA3 being the most effective. Hoechst 3342 staining revealed that BA2 induced apoptosis, while BA3 induced necrosis at lower concentrations, confirming their anti-melanoma properties. In conclusion, the semisynthetic derivatives of BI, particularly BA2 and BA3, show promise as potential candidates for further research in developing effective anti-cancer therapies.

Sonochemical replacement of C-3 hydrogen of indole by a pyridine ring: Docking, synthesis and in vitro evaluation of 3-(6-aryl pyridin-2-yl)indoles against SIRT1

As an emerging pharmacological target for cancer, SIRT1 attracted our attention while searching unique approaches or strategies for the identification of new anticancer agents. Accordingly, the 3-(6-aryl pyridin-2-yl)indole framework was pursued for the design of new and possible inhibitors of SIRT1. Initially, the in silico docking of a number of molecules based on this framework was conducted that showed their promising interactions with SIRT1 in addition to probable selectivity towards this protein over SIRT2. The study also suggested VAL412, PHE414, ILE347, ALA262, ILE411, HIS363, GLN345, ASN346, ILE270, ILE316, PHE273 and PHE297 as the common interacting residues. A majority of compounds participated in non-H bonding interactions through their aromatic rings with the hydrophobic active site pocket of hSIRT1. A convenient access to these 3-(6-aryl pyridin-2-yl)indoles (3) was established via the first ultrasound assisted heteroarylation approach involving a CC bond forming reaction between 6-aryl substituted 2-chloropyridine and indoles in the presence of AlCl3. Indeed, the current approach revealed sonochemical replacement of the C-3 hydrogen of indole by the pyridine ring in a regioselective manner. The compounds obtained were assessed for their SIRT1 inhibitory potential in vitro. Correlating the outcome of in silico studies the compound 3c, 3d, 3f and 3g were emerged as the best active molecules (with ≥ 70% inhibition) whereas compound 3a, 3e, 3i, 3j and 3o showed good inhibition (> 55%) of SIRT1 at 10 μM. According to the Structure-Activity-Relationship (SAR) the promising SIRT1 inhibitory activities were noted when a OMe or NO2 group was present at C-6 position of the indole ring. Based on IC50 values the order of activity of compounds was found to be 3g > 3f > 3c > 3d when 3g being the most potent seemed to be better than nicotinamide.

Molecular engineering and bioimaging applications of C2-alkenyl indole dyes with tunable emission wavelengths covering visible to NIR light

As an important member of dyes, small-molecule fluorescent dyes show indispensable value in biomedical fields. Although various molecular dyes have been developed, full-color dyes covering blue to red region derived from a single chromophore are still in urgent demand. In this work, a series of dyes based on C2-alkenyl indole skeleton were synthesized, namely AI dyes, and their photophysical properties, cytotoxicity, and imaging capacity were verified to be satisfactory. Particularly, the maximal emission wavelengths of these dyes could cover a wide range from visible to NIR light with large Stokes shifts. Besides, the optical and structural discrepancies between the C2- and C3- alkenyl AI dyes were discussed in detail, and the theoretical calculations were conducted to provide insights on such structure–activity relationship. Finally, as a proof-of-concept, a fluorescent probe AI-Py-B capable of imaging endogenous ONOO− was presented, demonstrating the bioimaging potentials of these alkenyl indole dyes. This work is anticipated to open up new possibilities for developing dye engineering and bio-applications of natural indole framework.

Recent Progress in Gold‐Catalyzed Reactions of Alkynes for the Construction of Indole Frameworks

AbstractIndole heterocycles hold an important position in chemical landscape because of their prominence in natural products and pharmaceuticals. Consequently, development of new and efficient strategies to access indole scaffold are of continuous interest. For the past few years, gold‐catalyzed activation of alkyne has emerged as a powerful strategy for constructing the heterocyclic skeleton. The present review highlights recent advances (2018–2023) toward synthesis of indole skeletons via gold‐catalyzed annulations of alkynes. A variety of alkynes, such as, ynamides, azido alkynes, ortho‐alkynyl anilines, propargylic alcohols, ortho‐alkynyl phenylimines, and miscellaneous alkynes are employed affording various indole architectures under gold catalysis. Moreover, mechanisms are included in most of the cases for better understanding of the reaction pathway.

A New Method for the Introduction of an Acylsulfonamide Moiety Applied to a 3-Substituted Functionalized Indole Framework ­Related to the Welwitindolinone Alkaloids

AbstractThe one-pot reaction between an α-formylcyclohexanone derivative and tosyl azide in the presence of rhodium trifluoroacetate dimer afforded an acylsulfonamide derivative. This transformation is proposed to arise from a domino mechanism involving the in situ generation, through the Regitz method, of an α-diazoketone, followed by its transformation into a rhodium carbenoid and its combination with N-tosylformamide, generated as a side product of the first step of the mechanism. Overall, this transformation leads to the generation of a C–N bond between the formyl carbon and the azide nitrogen adjacent to the sulfonyl group.

Synthesis of Thienyl Polycyclic Fused Indoles Based on the Indium Catalyzed Prins/Friedel‐Crafts Tandem Reaction

AbstractAn indium catalyzed Prins/Friedel‐Crafts tandem cyclization reaction has been developed. This reaction provides an efficient and practical method to construct a variety of polycyclic indole frameworks with high diastereoselectivity and good functional group tolerance (30 examples, up to 98% yield with >95 : 5 dr). The resulting products are easily accessible for further chemical transformations.

Biomimetic Total Synthesis of Clavicipitic Acid: A DDQ-Mediated Intramolecular Cross-Dehydrogenative Coupling Approach

Clavicipitic acid, a communesin alkaloid precursor, has attracted significant attention due to its unique azepino[5,4,3-cd]indole framework. Herein, we report a novel biomimetic synthesis of clavicipitic acid diastereomers by utilizing a DDQ-mediated cross-dehydrogenative coupling (CDC) reaction. The synthesis involves Suzuki coupling for the prenylation of a 4-bromotryptophan derivative, followed by an intramolecular CDC reaction to construct the azepinoindole core. The trans isomer was obtained as the major product, and the two diastereomers were separable. The CDC reaction conditions, including temperature, solvent, and protecting groups, were investigated, and a plausible mechanism for the observed diastereoselectivity was proposed.

Pd(0)-embedded-lignocellulosic nanomaterials: A bio-tailored reusable catalyst for selective C2–H arylation of free N–H indoles

Lignocellulose-a carbon-neutral renewable source has been utilized as a convenient support material for Pd nanoparticles, without disturbing its natural bio-structure. Herein, we demonstrated a green and rapid assessment of lignocellulosic nanomaterials derived from waste fibrous-feedstock of pomegranate peels using a simple extraction process in aqueous medium. The formation of lignocellulose bio-support has been authenticated by standard spectroscopic analyses. The newly developed features of Pd bio-nanomaterials were exhibited towards directing-group-free catalytic C2–H arylation of indoles with arylboronic acids. Access to vital C2-arylated indoles (62–91%) were achieved with high regioselectivity, reusability for at least five reaction cycles and admirable functionality tolerance of free N–H indole moieties. Further applicability of the catalyst was noted for selective double-functionalization of indole frameworks in a one-pot system.

Weakly coordinating tert-amide assisted Rh(III)-catalyzed C4-cyanation of indoles: application in photophysical studies.

A rhodium(III)-catalyzed indole C4-selective cyanation is described using the bench-stable, user-friendly electrophilic cyanation agent N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) as a coupling partner. A suitably positioned weakly coordinating tert-amide group was utilized for this site selectivity. The developed protocol proceeded with a broad scope. [Cp*Rh(MeCN)3][SbF6]2 was found to be an effective Rh(III) catalyst for this transformation. An initial study was carried out to know the photophysical properties of the C4-cyanated indole frameworks.

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.

Meridianins Inhibit GSK3β In Vivo and Improve Behavioral Alterations Induced by Chronic Stress.

Major depression disorder (MDD) is a severe mental alteration with a multifactorial origin, and chronic stress is one of the most relevant environmental risk factors associated with MDD. Although there exist some therapeutical options, 30% of patients are still resistant to any type of treatment. GSK3β inhibitors are considered very promising therapeutic tools to counteract stress-related affectations. However, they are often associated with excessive off-target effects and undesired secondary alterations. Meridianins are alkaloids with an indole framework linked to an aminopyrimidine ring from Antarctic marine ascidians. Meridianins could overcome several of the aforementioned limitations since we previously demonstrated that they can inhibit GSK3β activity without the associated neurotoxic or off-target effects in rodents. Here, we show that meridianins delivered into the lateral ventricle inhibited GSK3β in several brain regions involved with stress-related symptoms. We also observed changes in major signaling pathways in the prefrontal cortex (Akt and PKA) and hippocampus (PKC and GluR1). Moreover, meridianins increased synaptic activity, specifically in the CA1 but not in the CA3 or other hippocampal subfields. Finally, we chronically treated the mice subjected to an unpredictable mild chronic stress (CUMS) paradigm with meridianins. Our results showed improvements produced by meridianins in behavioral alterations provoked by CUMS. In conclusion, meridianins could be of therapeutic interest to patients with stress-related disorders such as MDD.

Total Synthesis of the Proposed Structure of (-)-Novofumigatamide, Isomers Thereof, and Analogues. Part I.

The total synthesis of the suggested structure of (−)-novofumigatamide, a natural product containing a C3-reverse prenylated N-acetyl-exo-hexahydropyrrolo[2,3-b]indole motif fused to a 10-membered ring lactam, was achieved using the macrolactam formation in advance of a diastereoselective bromocyclization and reverse prenylation steps. Since the NMR data of the synthetic sample did not match those of the natural product, the endo-bromo precursor of a N-Boc analogue and additional diastereomers derived from l-Trp were also synthesized. Five alternative synthetic routes, which differed in the order of final key steps used for the construction of the 10-membered ring lactam and the hexahydropyrrolo[2,3-b]indole framework within the polycyclic skeleton and also in the amide bond selected for the ring-closing of the macrolactam, were thoroughly explored. Much to our dismay, the lack of spectroscopic correlations between the proposed structure of natural (−)-novofumigatamide and the synthetic products suggested a different connectivity between the atoms. Additional synthetic efforts to assemble alternative structures of the natural product and isomers thereof (see accompanying paper; DOI: 10.1021/acs.joc.2c01228) further highlighted the frustrating endeavors toward the identification of a natural product.

Pd/Et3N·HI-Catalyzed Intramolecular C-H Alkylation to Access [a]-Annulated Indoles via Highly Regioselective Ring-Opening of Epoxides.

A Pd/Et3N·HI-catalyzed intramolecular C-H alkylation of indoles with epoxides was achieved to furnish N-fused indole frameworks (5-, 6-, and 7-membered rings) bearing an alcohol group. The conversion proceeded smoothly in the presence of a catalytic amount of Et3N·HI together with a palladium catalyst and exhibited great functional group tolerance. The employment of Et3N·HI not only avoids the prior preparation of alkyl halide substrates but also is the key to the high chemoselective ring-opening of epoxides. Preliminary mechanism explorations strongly support a radical pathway, and the catalytic cycle was established tentatively according to the mechanism investigation experiments.

Cu(I)-Catalyzed and Base-Promoted [5 + 2 + 1] Cascade Cyclization of 2-Nitrochalcones with Aliphatic Primary Amines to 5H-Pyrimido[5,4-b]indole Frameworks.

An unprecedented [5 + 2 + 1] cascade cyclization to the preparation of 5H-pyrimido[5,4-b]indole derivatives has been disclosed. The novel protocol of 2-nitrochalcones reacted with aliphatic primary amines catalyzed by CuI and promoted by Cs2CO3, which underwent a critical intermediate 2,3-disubstituted indole, providing structurally diverse 5H-pyrimido[5,4-b]indoles in generally high yields (77-90%) and broad substrate scopes (34 examples).

Rh(III)‐Catalysed Switchable and Chemoselective Synthesis of Difluorinated Pyrazolo[1,2‐a]indazolone and Indole Frameworks

AbstractDifferent from the classical defluorinated process for gem‐difluoromethylene alkynes, described herein is the chemodivergent synthesis of difluorinated pyrazolo[1,2‐a]indazolone and indole frameworks via Rh(III)‐catalysed regioselective C−H functionalization of phenidone with gem‐difluoromethylene alkynes in a switchable manner. The detailed reaction pathways and the origin of chemoselectivity were clarified through a combined experimental and computational mechanistic study, which involves different quench modes of C−Rh bond via protonolysis or C−N bond reductive elimination switched by the solvent

Copper-Catalyzed Annulation of Indolyl α-Diazocarbonyl Compounds Leads to Structurally Rearranged Carbazoles.

Indolyl α-diazocarbonyl compounds have proven to be effective starting materials for the construction of various 2,3-ring fused indole frameworks. Activation of the diazo functional group under metal catalysis generates a spiro-cyclic indolenine-type intermediate which rearranges to provide two distinct carbazoles upon oxidation. The current study investigates the effects of the catalyst as well as the substituents on the migratory group involved in controlling the selectivity of the rearrangement.

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