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The p-TsOH-catalyzed Diels-Alder reaction of 3-(indol-3-yl)maleimides with chalcone in toluene at 60 °C afforded two diastereoisomers of tetrahydropyrrolo[3,4-c]carbazoles, which can be dehydrogenated by DDQ oxidation in acetonitrile at room temperature to give the aromatized pyrrolo[3,4-c]carbazoles in high yields. On the other hand, the one-pot reaction of 3-(indol-3-yl)-1,3-diphenylpropan-1-ones with chalcones or benzylideneacetone in acetonitrile in the presence of p-TsOH and DDQ resulted in polyfunctionalized carbazoles in satisfactory yields. The reaction mechanism included the DDQ oxidative dehydrogenation of 3-(indol-3-yl)-1,3-diphenylpropan-1-ones to the corresponding 3-vinylindoles, their acid-catalyzed Diels-Alder reaction and sequential aromatization process.
Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC50 values from 67 to >10,000 nM. Measures of the activity of modified carbazoles with tubulin and microtubules coupled to molecular docking studies show that these compounds bind to the colchicine site of tubulin in a unique low interaction space that inhibits tubulin assembly. The modified carbazoles reported here represent novel chemical tools to better understand how small molecules disrupt MT functions and kill devastating cancers such as GBM.
The preparation and characterization of 12 azaindolo[3,2,1-jk]carbazoles is presented. Ring-closing C-H activation allowed for the convenient preparation of six singly and six doubly nitrogen-substituted indolo[3,2,1-jk]carbazole derivatives in which ten of the materials have not been described in the literature before. The detailed photophysical and electrochemical characterization of the developed materials revealed a significant impact of the incorporation of pyridine-like nitrogen into the fully planar indolo[3,2,1-jk]carbazole backbone. Furthermore, the nitrogen position decisively impacted intermolecular hydrogen bonding and thus the solid-state alignment. Ultimately, the versatility of the azaindolo[3,2,1-jk]carbazoles scaffold makes this class of materials an attractive new building block for the design of functional organic materials.
In this work, a set of structurally diverse synthetic carbazoles was screened for their anticancer activities. According to structure-activity relationship studies, carbazoles with an N-substituted sulfonyl group exhibited better anticancer activity. Moreover, compound 8h was discovered to show the most potent anticancer effects on Capan-2 cells by inducing apoptosis and cell cycle arrest in G2/M phase. Finally, the in vivo study demonstrated that 8h prevented the tumor growth in PANC-1 and Capan-2 xenograft models without apparent toxicity.
Mitochondrial targeting plays an important role in anticancer therapy. The Mn(III)-promoted cyclization of 5-(1H-indol-3-yl)-3-oxopentanoic acid allow to obtain novel substituted carbazole derivatives that can act as mitochondria-disruptive agents. The starting materials used for the synthesis of these new aminocarbazoles are oxopentanoate derivatives of tryptophan. The scope and limitation of this method of synthesis are determined by a series of experiments. The prepared carbazole derivatives are screened for their in vitro anticancer activity against a broad panel of human cancer cells and normal cell lines. Among the tested compounds, the most active ones are examined further against human colon cancer cells (HCT-116) and human bone osteosarcoma (U-2 OS), in complex in vitro cellular assays, including studies on cell cycle distribution, intracellular compartmentalization, antimigratory properties, mitochondrial generation of reactive oxygen species, DNA damage, and type of cellular death. The results reveal that the synthesized compounds display potent oxidative activity inducing massive accumulation of DNA double-strand breaks, which lead to a parallel change in the assembly of mitochondria causing their dysfunction. These findings provide new leads for the treatment of colon cancer and osteosarcoma.
A modular approach to prepare tri- and tetracyclic carbazoles by a sequential [3 + 2]heteroannulation is described. First, optimization of Pd-catalyzed Buchwald-Hartwig amination followed by C/N-arylation in a one-pot process is established. Second, mechanistic analyses identified the origins of chemo- and regioselective sequential control of both bond-forming steps. Finally, the substrate scope is demonstrated by the preparation of a range of tri- and tetracyclic carbazoles, including expedient access to several natural products and anti-cancer agents.
A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC90 values ranging from 1.5 to 3.7μM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50μM.
The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1-3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1-3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.
Development of an efficient and scalable synthesis of 6-formylindolo[3,2-b]carbazole (FICZ), a naturally-occurring aryl hydrocarbon receptor (AhR) ligand, allowed its biological and physical properties to be studied. FICZ was shown to be the most potent among a series of 6-substituted indolo[3,2-b]carbazoles for activation of AhR in cells. Photostability studies of FICZ revealed a non-enzymatic mechanism for its conversion to a biologically active quinone. These results further support the hypothesis that FICZ is a light-dependent hormone that links sun exposure to regulation of biological pathways in peripheral tissues.
We report herein the synthesis of siloxane-functionalized CBP molecules (4,4'-bis(carbazole)-1,1'-biphenyl) for liquid optoelectronic applications. The room-temperature liquid state is obtained through a convenient functionalization of the molecules with heptamethyltrisiloxane chains via hydrosilylation of alkenyl spacers. The synthesis comprises screening of metal-catalyzed methodologies to introduce alkenyl linkers into carbazoles (Stille and Suzuki Miyaura cross-couplings), incorporate the alkenylcarbazoles to dihalobiphenyls (Ullmann coupling), and finally introduce the siloxane chains. The used conditions allowed the synthesis of the target compounds, despite the high reactivity of the alkenyl moieties bound to π-conjugated systems toward undesired side reactions such as polymerization, isomerization, and hydrogenation. The features of these solvent-free liquid CBP derivatives make them potentially interesting for fluidic optoelectronic applications.
We report in this work the discovery of novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening. Two out of 13 virtual hit compounds were identified as MEK kinase inhibitors using a MEK1 binding assay. Structural derivations on the hit compound M100 (IC50 = 27.2 ± 4.5 μM in RAF-MEK cascading assay) by substituent transformation and bioisosterism replacement have led to the synthesis of a small library of carbazoles. The enzymatic studies revealed the preliminary structure-activity relationships and the derivative 22k (IC50 = 12.8 ± 0.5 μM) showed the most potent inhibitory effect against Raf-MEK cascading. Compound 7 was discovered as toxic as M100 to tumor cells whereas safer to HEK293 cells (IC50 > 100 μM) than M100 (IC50 = 8.9 ± 2.0 μM). It suggests that carbazole is a good scaffold for the design of novel MEK inhibitors for therapeutic uses. More importantly, the developed pharmacophore model can serve as a reliable criterion in novel MEK inhibitor discovery.
There is increasing evidence that ingested diet-borne components are involved in the pathogenesis of disorders such as inflammatory bowel diseases, atherosclerosis, and type 2 diabetes. Nutrients can have short- and long-term effects in shaping the composition of the microbiota. Western diets (enriched in fat, phosphatidylcholine, and L-carnitine) promote inflammation and atherosclerosis through specific fatty acids and degradation products such as trimethylamine N-oxide. Other dietary factors such as carbazoles or tryptophan-enriched proteins have anti-inflammatory properties-partly via activation of aryl hydrocarbon receptors. The microbiota and its metabolic machinery produce a myriad of metabolites that serve as important messengers between the diet, microbiota, and host. Short-chain fatty acids affect immune responses and epithelial integrity via G-protein-coupled receptors and epigenetic mechanisms. By increasing our understanding of interactions between diet, immunity, and the microbiota, we might develop food-based approaches to prevent or treat many diseases. There now is scientific evidence to support the adage "we are what we eat," and this process begins in early life.
A microporous organic polymer (Cz-pyr-P) was prepared from a monomer of pyridine-imides, flanked by four carbazoles, and its application as an adsorbent for both CO2 and methylene blue dye in wastewater was investigated. The polymer was synthesised by oxidative polymerisation facilitated by FeCl3 and comprehensively characterised using routine spectroscopic, thermal, textural, and morphological analyses. With a high surface area of 1065 m2/g and a median pore width of 8.06 Å, the nitrogen-enriched Cz-pyr-P reversibly adsorbed 19.41 wt% (273 K) and 12.78 wt% (295 K) CO2 at 1 bar, with a good isosteric heat value of CO2 adsorption (28.5 kJ/mol). For the removal of methylene blue dye from wastewater, Cz-pyr-P exhibited excellent partition coefficient of 380.10 mg/g μM with an equilibrium time of 6 min which is shorter than previously reported values for other materials. The results indicate that Cz-pyr-P with desirable functionality could be utilised for reaching CO2 emission reduction targets as well as for wastewater treatment.
Herein, a new series of N-substituted 1,2,3-triazolylmethyl indole derivatives 4(a-u) was synthesized by rationally incorporating a pharmacophoric active heterocyclic ring containing indole and triazole moieties in one molecular frame via the conventional and microwave irradiation methods. Briefly, the new compounds 4(a-u) were synthesized via the N-alkylation of tetrahydro-1H-carbazoles followed by click reaction and copper-catalyzed Huisgen [3 + 2] cycloaddition in the presence of copper sulphate and sodium ascorbate with various aromatic azides 3(a-m). All the newly synthesized compounds were characterized via 1H and 13C NMR, mass, and IR spectroscopy and evaluated for their antimicrobial, antioxidant and anticancer activities. Among the synthesized compounds, 4d, 4j, 4n, 4p, 4s and 4r were found to exhibit good antimicrobial, antioxidant, anticancer activities. The biological activity of the synthesized compounds was further supplemented by molecular docking studies against the target receptors caspase-3 and 17-beta-hydroxy steroid dehydrogenase type 1, revealing that the reported structures best fit into the active site pocket of the target molecules.
A total of three carbazole alkaloids and essential oil from the leaves of Murraya koenigii (Rutaceae) were obtained and examined for their effects on the growth of five antibiotic resistant pathogenic bacteria and three tumor cell lines (MCF-7, P 388 and Hela). The structures of these carbazoles were elucidated based on spectroscopy data and compared with literature data, hence, were identified as mahanine (1), mahanimbicine (2) and mahanimbine (3). The chemical constituents of the essential oil were identified using Gas Chromatography-Mass Spectroscopy (GCMS). These compounds exhibited potent inhibition against antibiotic resistant bacteria such as Staphylococcus aureus (210P JTU), Psedomonas aeruginosa (ATCC 25619), Klebsiella pneumonia (SR1-TU), Escherchia coli (NI23 JTU) and Streptococcus pneumoniae (SR16677-PRSP) with significant minimum inhibition concentration (MIC) values (25.0-175.0 mg/mL) and minimum bacteriacidal concentrations (MBC) (100.0-500.0 mg/mL). The isolated compounds showed significant antitumor activity against MCF-7, Hela and P388 cell lines. Mahanimbine (3) and essential oil in particular showed potent antibacteria and cytotoxic effect with dose dependent trends (≤5.0 μg/mL). The findings from this investigation are the first report of carbazole alkaloids' potential against antibiotic resistant clinical bacteria, MCF-7 and P388 cell lines.
Drug-like molecules are known to contain many different building blocks with great potential as pharmacophores for drug discovery. The continued search for unique scaffolds in our laboratory led to the isolation of a novel Ghanaian soil bacterium, Streptomyces sp. MA37. This strain produces many bioactive molecules, most of which belong to carbazoles, pyrrolizidines, and fluorinated metabolites. Further probing of the metabolites of MA37 has led to the discovery of a new naphthacene-type aromatic natural product, which we have named accramycin A 1. This molecule was isolated using an HPLC-photodiode array (PDA) guided isolation process and MS/MS molecular networking. The structure of 1 was characterized by detailed analysis of LC-MS, UV, 1D, and 2D NMR data. Preliminary studies on the antibacterial properties of 1 using Group B Streptococcus (GBS) produced a minimum inhibitory concentration (MIC) of 27 µg/mL. This represents the first report of such bioactivity amongst the naphthacene-type aromatic polyketides, and also suggests the possibility for the further development of potent molecules against GBS based on the accramycin scaffold. A putative acc biosynthetic pathway for accramycin, featuring a tridecaketide-specific type II polyketide synthase, was proposed.
New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death-modulating effects of the telmisartan-derived lead 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid (3 b) was investigated. Inspired by the pharmacodynamics of HYL-6d and the selective PPARγ ligand VSP-51, the benzimidazole was replaced by a carbazole or an indole core. The results indicate no correlation between PPARγ activation and sensitization of resistant CML cells to imatinib. The 2-COOH derivatives of the carbazoles or indoles achieved low activity at PPARγ, while the benzimidazoles showed 60-100 % activation. Among the 2-CO2 CH3 derivatives, only the ester of the lead (2 b) slightly activated PPARγ. Sensitizing effects were further observed for this non-cytotoxic 2 b (80 % cell death), and to a lesser extent for the lead 3 b or the 5-Br-substituted ester of the benzimidazoles (5 b).
The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as "anticancer compounds" and "anticancer epi-compounds" and PK083 a "damage-corrective" compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.
Agricultural soils are becoming contaminated with synthetic chemicals like polyaromatic compounds, petroleum hydrocarbons, polychlorinated biphenyls (PCBs), phenols, herbicides, insecticides and fungicides due to excessive dependency of crop production systems on the chemical inputs. Microbial degradation of organic pollutants in the agricultural soils is a continuous process due to the metabolic multifunctionalities and enzymatic capabilities of the soil associated communities. The plant rhizosphere with its complex microbial inhabitants and their multiple functions, is amongst the most live and dynamic component of agricultural soils. We analyzed the metatranscriptome data of 20 wheat rhizosphere samples to decipher the taxonomic microbial communities and their multifunctionalities linked with the degradation of organic soil contaminants. The analysis revealed a total of 21 different metabolic pathways for the degradation of aromatic compounds and 06 for the xenobiotics degradation. Taxonomic annotation of wheat rhizosphere revealed bacteria, especially the Proteobacteria, actinobacteria, firmicutes, bacteroidetes, and cyanobacteria, which are shown to be linked with the degradation of aromatic compounds as the dominant communities. Abundance of the transcripts related to the degradation of aromatic amin compounds, carbazoles, benzoates, naphthalene, ketoadipate pathway, phenols, biphenyls and xenobiotics indicated abundant degradation capabilities in the soils. The results highlighted a potentially dominant role of crop rhizosphere associated microbial communities in the remediation of contaminant aromatic compounds.
The signalling pathway of Janus tyrosine Kinases-Signal Transducers and Activators of Transcription (JAK-STAT) is activated by a number of cytokines, hormones (GH, erythropoietin and prolactin), and growth factors. JAK-STAT signalling is involved in regulation of cell proliferation, differentiation and apoptosis. These activities are due to different members of JAK-STAT family consisting of: JAK1, JAK2, JAK3, Tyk2 and STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6. Recent studies suggest a key role for STAT family proteins, in particular for STAT3, in selectively inducing and maintaining a pro-carcinogenic inflammatory microenvironment, that promote tumour cells transformation. Moreover, a striking correlation between cancer development/progression and STAT3 persistent activation exists, probably due to STAT3 promoting of the pro-oncogenic inflammatory pathways, like NF-kB, IL-6 and JAK family kinases. Recent study demonstrated that carbazoles can inhibit STAT3 mediated transcription. From these evidences, STAT3 represents a therapeutic target, so we have synthesized a new set of N-alkylcarbazole derivatives substituted in positions 2, 4 and 6, to evaluate their activity on STAT3. Some of these compounds showed an interesting activity as STAT3 selective inhibitors; in particular, compounds 9a 9b and 9c revealed to inhibit the STAT3 activation for the 50%, 90% and 95%, respectively.
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