Indole

Recent Advancement of Synthesis of Isatins as a Versatile Pharmacophore: A review.[Pubmed:33296925]

Drug Res (Stuttg). 2020 Dec 9.

Isatin (1 H-Indole-2, 3-Dione) and its derivatives are versatile compounds which acts as a precursor for a large number of pharmacologically active compounds. Therefore isatins have a significant importance in the synthesis of different heterocyclic compounds. Isatins show variety of biological activities. In this review we focus on synthetic methods of isatins and their biological activities such as antimicrobial, anticonvulsant, anti-inflammatory and analgesic activity, antitubercular activity.

Liquid chromatography-mass spectrometry untargeted metabolomics reveals increased levels of tryptophan indole metabolites in urine of metabolic syndrome patients.[Pubmed:33295818]

Eur J Mass Spectrom (Chichester). 2020 Dec;26(6):379-387.

Metabolic syndrome (MetS) is a multifactor condition predisposing for diabetes, cardiovascular diseases and other degenerative disorders. Although several diagnostic criteria have been established, none of them is specific and there is a call for better pathophysiological explanation of MetS and for the discovery of molecular biomarkers. Phenotype characterization at metabolome level might be useful for both purposes. To this end, our aim was to perform comparative untargeted metabolomics of urines from MetS patients and from the control group. The study participants included 52 diagnosticated and 50 healthy individuals from Leon city in central Mexico; 23 anthropometric and clinical parameters were measured and submitted to Principal Component Analysis (PCA). The obtained PCA model allowed us for selection of 11 MetS patients and 13 control subjects, correspondingly representative for each of the two groups (clearly separated in PCA). The first morning urines from these subjects were ambulatory collected and, after methanol extraction and acidification, were submitted to capillary liquid chromatography-high resolution mass spectrometry (LC-HRMS). The obtained data were analyzed on MetaboScape(R) platform (Bruker Daltonics). Specifically, t-test applied to LC-HRMS data revealed several ions presenting at least 3-fold higher intensities in MetS with respect to the control samples (p < 0.05). Data analysis and complementary experiments yielded the identification of the following metabolites: Indole-3-acetic acid, Indole-3-acetic acid-O-glucuronide, N-(indol-3-ylacetyl) glutamine, Indole-3-carbaldehyde and hydroxyhexanoycarnitine. Additionally, Indole-3-carboxylic acid was annotated with 2.13-fold higher abundance in MetS patients. To assess the contribution of individual metabolites in the difference between two groups of subjects, partial least square discriminant analysis was performed for LC-HRMS data and the obtained values of variable importance in projection (VIP), confirmed the association of six above mentioned compounds with MetS. Overall, this study provides direct evidence on the disturbed catabolism of tryptophan in metabolic syndrome.

Photoredox-Catalyzed Intermolecular Hydroalkylative Dearomatization of Electron-Deficient Indole Derivatives.[Pubmed:33295778]

Org Lett. 2020 Dec 9.

Dearomatization of Indole derivatives offers a straightforward approach to access diverse indolines. To date, the corresponding dearomative transformations involving electron-deficient Indoles are limited. Herein, we report a one-electron strategy for dearomatization of electron-deficient Indoles via a photoredox-catalyzed hydroalkylation employing commercially available glycine derivatives as the hydrofunctionalization reagents. Followed by DBU-mediated lactamization, structurally appealing lactam-fused indolines are obtained in good to excellent yields with exclusive selectivity.

Enantioselective Aza-Friedel-Crafts Reaction of Indoles and Pyrroles Catalyzed by Chiral C1-Symmetric Bis(phosphoric Acid).[Pubmed:33295179]

Org Lett. 2020 Dec 9.

A hydrogen bonding network in chiral Bronsted acid catalysts is important for the construction of a chiral cavity and the enhancement of catalytic activity. In this regard, we developed a highly enantioselective aza-Friedel-Crafts reaction of Indoles and pyrroles with acyclic alpha-ketimino esters in the presence of a chiral C1-symmetric BINOL-derived bis(phosphoric acid) catalyst. The desired alkylation products with chiral quaternary carbon centers were obtained in high yields with high enantioselectivities on up to a 1.2-g scale with 0.2 mol % catalyst loading. Interestingly, the absolute configurations of the products from Indoles and pyrroles were opposite even with the use of the same chiral catalyst. Moreover, preliminary mechanistic considerations disclosed that a unique hydrogen bonding network with or without pi-pi interactions among the catalyst and substrates might partially play a pivotal role.

LDOC1 as Negative Prognostic Marker for Vulvar Cancer Patients.[Pubmed:33291445]

Int J Mol Sci. 2020 Dec 5;21(23). pii: ijms21239287.

So far, studies about targeted therapies and predictive biomarkers for vulva carcinomas are rare. The leucine zipper downregulated in cancer 1 gene (LDOC1) has been identified in various carcinomas as a tumor-relevant protein influencing patients' survival and prognosis. Due to the lack of information about LDOC1 and its exact functionality, this study focuses on the expression of LDOC1 in vulvar carcinoma cells and its surrounding immune cells as well as its correlation to clinicopathological characteristics and prognosis. Additionally, a possible regulation of LDOC1 in vulvar cancer cell lines via the NF-kappaB signaling pathway was analyzed. Vulvar carcinoma sections of 157 patients were immunohistochemically stained and examined regarding LDOC1 expression by using the immunoreactive score (IRS). To characterize LDOC1-positively stained immune cell subpopulations, immunofluorescence double staining was performed. The effect of the NF-kappaB inhibitor C-DIM 12 (3,3'-[(4-chlorophenyl)methylene]bis[1 H-Indole]) on vulvar cancer cell lines A431 and SW 954 was measured according to MTT and BrdU assays. Baseline expression levels of LDOC1 in the vulvar cancer cell lines A431 and SW 954 was analyzed by real-time PCR. LDOC1 was expressed by about 90% of the cancer cells in the cytoplasm and about half of the cells in the nucleus. Cytoplasmatic expression of LDOC1 was associated with decreased ten-year overall survival of the patient, whereas nuclear staining showed a negative association with disease-free survival. Infiltrating immune cells were mainly macrophages followed by regulatory T cells. Incubation with C-DIM 12 decreased the cell viability and proliferation of vulvar cancer cell line A431, but not of cell line SW 954. LDOC1 expression on mRNA level was twice as high in the cell line A431 compared to the cell line SW 954. Overexpression of LDOC1 was associated with unfavorable overall and disease-free survival. Tumor growth could be inhibited by C-DIM 12 in vitro if the expressed LDOC1 level was high enough.

Dihydrotanshinone, a Natural Diterpenoid, Preserves Blood-Retinal Barrier Integrity via P2X7 Receptor.[Pubmed:33291318]

Int J Mol Sci. 2020 Dec 6;21(23). pii: ijms21239305.

Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead to the over-expression of pro-inflammatory markers. In order to identify novel P2X7R antagonists, we carried out virtual screening on a focused compound dataset, including Indole derivatives and natural compounds such as caffeic acid phenethyl ester derivatives, flavonoids, and diterpenoids. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring and structural fingerprint clustering of docking poses from virtual screening highlighted that the diterpenoid dihydrotanshinone (DHTS) clustered with the well-known P2X7R antagonist JNJ47965567. A human-based in vitro BRB model made of retinal pericytes, astrocytes, and endothelial cells was used to assess the potential protective effect of DHTS against HG and 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate (BzATP), a P2X7R agonist, insult. We found that HG/BzATP exposure generated BRB breakdown by enhancing barrier permeability (trans-endothelial electrical resistance (TEER)) and reducing the levels of ZO-1 and VE-cadherin junction proteins as well as of the Cx-43 mRNA expression levels. Furthermore, HG levels and P2X7R agonist treatment led to increased expression of pro-inflammatory mediators (TLR-4, IL-1beta, IL-6, TNF-alpha, and IL-8) and other molecular markers (P2X7R, VEGF-A, and ICAM-1), along with enhanced production of reactive oxygen species. Treatment with DHTS preserved the BRB integrity from HG/BzATP damage. The protective effects of DHTS were also compared to the validated P2X7R antagonist, JNJ47965567. In conclusion, we provided new findings pointing out the therapeutic potential of DHTS, which is an inhibitor of P2X7R, in terms of preventing and/or counteracting the BRB dysfunctions elicited by HG conditions.

Physiological impacts of zero valent iron, Fe3O4 and Fe2O3 nanoparticles in rice plants and their potential as Fe fertilizers.[Pubmed:33290949]

Environ Pollut. 2020 Dec 1;269:116134.

Fe-based nanoparticles (Fe-based NPs) have great potential as a substitute for traditional Fe-fertilizer; however, their environmental risk and impact on plant growth are not fully understood. In this study, we compared the physiological impacts of three different Fe-based NP formulations: zero-valent iron (ZVI), Fe3O4 and Fe2O3 NPs, on hydroponic rice after root exposure for 2 weeks. Fe-normal (Fe(+)) and Fe-deficiency (Fe(-)) conditions were compared. Results showed that low dose (50 mg L(-1)) of ZVI and Fe3O4 NPs improved the rice growth under Fe(-) condition, while Fe2O3 NPs did not improve plant growth and caused phytotoxicity at high concentration (500 mg L(-1)). Under Fe(+) conditions, none of the Fe-based NPs exhibited positive effects on the rice plants with plant growth actually being inhibited at 500 mg L(-1) evidenced by reduced root volume and leaf biomass and enhanced oxidative stress in plant. Under Fe(-) condition, low dose (50 mg L(-1)) of ZVI NPs and Fe3O4 NPs increased the chlorophyll content by 30.7% and 26.9%, respectively. They also alleviated plant stress demonstrated by the reduced oxidative stress and decreased concentrations of stress related phytohormones such as gibberellin and Indole-3-acetic acid. Low dose of ZVI and Fe3O4 NPs treatments resulted in higher Fe accumulation in plants compared to Fe2O3 NPs treatment, by down-regulating the expression of IRT1 and YSL15. This study provides significant insights into the physiological impacts of Fe-based NPs in rice plants and their potential application in agriculture. ZVI and Fe3O4 NPs can be used as Fe-fertilizers to improve rice growth under Fe-deficient condition, which exist in many rice-growing regions of the world. However, dose should be carefully chosen as high dose (500 mg L(-1) in this study) of the Fe-based NPs can impair rice growth.

Assembly of Indole Cores through a Palladium-Catalyzed Metathesis of Ar-X sigma-Bonds.[Pubmed:33290655]

Org Lett. 2020 Dec 8.

We describe the development of a new method for construction of highly substituted Indole scaffolds through the strategic utilizing of the metathesis of Ar-X sigma-bonds based on the dynamic nature of palladium-based oxidative addition/reductive elimination. A suitable and simple catalytic system has provided an appropriate platform for a productive ligand exchange and consecutive carbopalladation/C-H activation/amination of phosphine ligands with alkynes and aromatic/aliphatic amines for construction of structurally diverse Indoles.

Rhodium-Catalyzed Chemodivergent Regio- and Enantioselective Allylic Alkylation of Indoles.[Pubmed:33289185]

Chemistry. 2020 Dec 2.

The control of C3/N1 chemo-selectivity with the same electrophiles is still challenging in the Indole alkylation. A Rh/bisoxazolinephosphine-catalyzed chemodivergent regio- and enantioselective allylic alkylation of unbiased Indoles has been developed. Chiral C3- and N1-allylIndoles can be selectively obtained in high branch/linear ratio and up to 99% ee by changing the counter anions of Rh, allylic carbonates, reaction temperatures and ligands.

Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel alpha-amylase inhibitors.[Pubmed:33288322]

Bioorg Chem. 2020 Nov 26:104507.

In a sustained search for novel alpha-amylase inhibitors for the treatment of type 2 diabetes mellitus (T2DM), we report herein the synthesis of a series of nineteen novel rhodanine-fused spiro[pyrrolidine-2,3'-oxIndoles]. They were obtained by one-pot three component [3 + 2] cycloaddition of stabilized azomethine ylides, generated in situ by condensation of glycine methyl ester and the cyclic ketones 1H-Indole-2,3-dione (isatin), with (Z)-5-arylidine-2-thioxothiazolidin-4-ones. The highlight of this protocol is the efficient high-yield construction of structurally diverse rhodanine-fused spiro[pyrrolidine-2,3'-oxIndoles] scaffolds, including four contiguous stereocenters, along with excellent regio- and diastereoselectivities. The stereochemistry of all compounds was confirmed by NMR and corroborated by an X-ray diffraction study performed on one derivative. All cycloadducts were evaluated in vitro for their alpha-amylase inhibitory activity and showed good alpha-amylase inhibition with IC50 values ranging between 1.49 +/- 0.10 and 3.06 +/- 0.17 microM, with respect to the control drug acarbose (IC50 = 1.56 microM). Structural activity relationships (SARs) were also established for all synthesized compounds and the binding interactions of the most active spiropyrrolidine derivatives were modelledby means of molecular insilico docking studies. The most potent compounds 5 g, 5 k, 5 s and 5 l were further screened in vivo for their hypoglycemic activity in alloxan-induced diabetic rats, showing a reduction of the blood glucose level. Therefore, these spiropyrrolidine derivatives may be considered as promising candidates for the development of new classes of antidiabetic drugs.

Identification of key metabolites based on non-targeted metabolomics and chemometrics analyses provides insights into bitterness in Kucha [Camellia kucha (Chang et Wang) Chang].[Pubmed:33288175]

Food Res Int. 2020 Dec;138(Pt B):109789.

Camellia kucha (Chang et Wang) Chang is a special tea in China, which is extremely bitter but beneficial for human health. However, there are no systematic studies on Kucha metabolites, especially those associated with bitterness. In this study, a non-targeted metabolomics approach based on UHPLC-LTQ-Orbitrap-MS was applied to comprehensively profile the characteristic metabolites of two Kucha cultivars by comparison with three common tea cultivars. A total of 90 differential metabolites were identified. Among them, eight key metabolites (theacrine, 2,4-dimethyl-1H-Indole, EGCG, dihydrokaempferol, panasenoside, 3-cresotinic acid, 3-methylglutaconic acid, and L-histidine) were more abundant in Kucha than in the controls, most of which were positively correlated with bitterness. Furthermore, quantitative analysis of some important catechins and alkaloids by HPLC implied absolutely higher concentrations of EGCG and theacrine in Kucha, which was similar to the metabolomics results. These results will be contribute to future research on the bitter and nutritional properties of Kucha.

Lycium barbarum polysaccharide attenuates myocardial injury in high-fat diet-fed mice through manipulating the gut microbiome and fecal metabolome.[Pubmed:33288164]

Food Res Int. 2020 Dec;138(Pt B):109778.

High-fat diets (HFDs) can induce health problems including gut microbiota dysbiosis and cardiac dysfunction. In this study, we modulated the gut microbiota in mice to investigate whether Lycium barbarum polysaccharide (LBP), a potential prebiotic fiber, could alleviate HFD-induced myocardial injury. Mice fed a HFD were given LBP (HFPD group) by gavage once/day for 2 months. Left ventricular function and serum trimethylamine N-oxide were significantly improved in HFPD mice compared with HFD mice. HFD increased the abundances of Bifidobacterium, Lactobacillus, and Romboutsia, while LBP increased the abundances of Gordonibacter, Parabacteroides, and Anaerostipes. Fecal metabolic profiling revealed significant increases in metabolites involved in nicotinate, nicotinamide and purine metabolism pathways, as well as Indole derivatives of tryptophan metabolites in the HFPD group. LBP reduced intestinal permeability and inflammatory cytokine levels, maintained a healthy intestinal microenvironment, and alleviated myocardial injury. Modulating the gut microbiota is a potential treatment for cardiovascular diseases.

Glycyrrhizin, the active compound of the TCM drug Gan Cao stimulates actin remodelling and defence in grapevine.[Pubmed:33288019]

Plant Sci. 2021 Jan;302:110712.

Actin remodelling by a membrane-associated oxidative process can sense perturbations of membrane integrity and activate defence. In the current work, we show that glycyrrhizin, a muscle relaxant used in Traditional Chinese Medicine, can activate oxidative burst and actin remodelling in tobacco BY-2 cells, which could be suppressed by diphenylene iodonium, an inhibitor of NADPH oxidases. Glycyrrhizin caused a dose-dependent delay of proliferation, and induced cell death, which was suppressed by addition of Indole-acetic acid, a natural auxin that can mitigate RboH dependent actin remodelling. To test, whether the actin remodelling induced by glycyrrhizin was followed by activation of defence, several events of basal immunity were probed. We found that glycyrrhizin induced a transient extracellular alkalinisation, indicative of calcium influx. Furthermore, transcripts of phytoalexins genes, were activated in cells of the grapevine Vitis rupestris, and this induction was followed by accumulation of the glycosylated stilbene alpha-piceid. We also observed that glycyrrhizin was able to induce actin bundling in leaves of a transgenic grape, especially in guard cells. We discuss these data in frame of a model, where glycyrrhizin, through stimulation of RboH, can cause actin remodelling, followed by defence responses, such as calcium influx, induction of phytoalexins transcripts, and accumulation of stilbene glycosides.

Identification and characterization of CTP:phosphocholine cytidylyltransferase CpCCT1 in the resurrection plant Craterostigma plantagineum.[Pubmed:33288011]

Plant Sci. 2021 Jan;302:110698.

Phosphatidylcholine is a major phospholipid which is shown to be involved in stress adaptation. Phosphatidylcholine increased during dehydration in Craterostigma plantagineum, and therefore we characterized CTP:phosphocholine cytidylyltransferase (CpCCT1), a key regulatory enzyme for phosphatidylcholine synthesis in plants. The CpCCT1 gene from the resurrection plant C. plantagineum was cloned and the amino acid sequence was compared with homologs from other species including yeast and rat. CCT proteins have conserved catalytic and membrane-binding domains while the N-terminal and C-terminal domains have diverged. The tissue specific expression analysis indicated that CpCCT1 is expressed in all tested tissues and it is induced by dehydration and in response to 0.5 M NaCl solutions. In plants exposed to low temperature in the dark, the CpCCT1 transcript increased after 4 h at 4 degrees C. CpCCT1 expression also increased during mannitol and sorbitol treatments in a concentration dependent manner. Phytohormones such as abscisic acid and Indole-3-acetic acid also trigged transcript accumulation. Comparisons of transcript and protein accumulations for different treatments (except for dehydration) suggest transcriptional and translational control mechanisms. Analysis of promoter activity and polysome occupancy suggest that CpCCT1 gene expression is mainly under translational regulation during dehydration.

Applying an association weight matrix in weighted genomic prediction of boar taint compounds.[Pubmed:33285013]

J Anim Breed Genet. 2020 Dec 7.

Biological information regarding markers and gene association may be used to attribute different weights for single nucleotide polymorphism (SNP) in genome-wide selection. Therefore, we aimed to evaluate the predictive ability and the bias of genomic prediction using models that allow SNP weighting in the genomic relationship matrix (G) building, with and without incorporating biological information to obtain the weights. Firstly, we performed a genome-wide association studies (GWAS) in data set containing single- (SL) or a multi-line (ML) pig population for androstenone, skatole and Indole levels. Secondly, 1%, 2%, 5%, 10%, 30% and 50% of the markers explaining the highest proportions of the genetic variance for each trait were selected to build gene networks through the association weight matrix (AWM) approach. The number of edges in the network was computed and used to derive weights for G (AWM-WssGBLUP). The single-step GBLUP (ssGBLUP) and weighted ssGBLUP (WssGBLUP) were used as standard scenarios. All scenarios presented predictive abilities different from zero; however, the great overlap in their confidences interval suggests no differences among scenarios. Most of scenarios of based on AWM provide overestimations for skatole in both SL and ML populations. On the other hand, the skatole and Indole prediction were no biased in the ssGBLUP (S1) in both SL and ML populations. Most of scenarios based on AWM provide no biased predictions for Indole in both SL and ML populations. In summary, using biological information through AWM matrix and gene networks to derive weights for genomic prediction resulted in no increase in predictive ability for boar taint compounds. In addition, this approach increased the number of analyses steps. Thus, we can conclude that ssGBLUP is most appropriate for the analysis of boar taint compounds in comparison with the weighted strategies used in the present work.