Search

This article provides a comprehensive review of recent advancements in the synthesis of tetrahydroindole compounds, which are important for natural alkaloids and synthetic medications. The authors discuss various methods for synthesizing these compounds, including intramolecular cyclization reactions and intermolecular condensations. They highlight the advantages of these methods, such as high yields, shorter reaction times, and low cost of reagents. The authors also identify areas for further development, particularly in the functionalization of the indole benzene ring. [Extracted from the article]

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. Several classes of hypoglycemic drugs are used to treat it, but various side effects limit their clinical use. Consequently, the search for new anti-diabetic agents remains an urgent task for modern pharmacology. In this investigation, we examined the hypoglycemic effects of bornyl-containing benzyloxyphenylpropanoic acid derivatives (QS-528 and QS-619) in a diet-induced model of T2DM. Animals were given the tested compounds per os at a dose of 30 mg/kg for 4 weeks. At the end of the experiment, compound QS-619 demonstrated a hypoglycemic effect, while QS-528 showed hepatoprotection. In addition, we performed a number of in vitro and in vivo experiments to study the presumed mechanism of action of the tested agents. Compound QS-619 was determined to activate the free fatty acid receptor-1 (FFAR1) similarly to the reference agonist GW9508 and its structural analogue QS-528. Both agents also increased insulin and glucose-dependent insulinotropic polypeptide concentrations in CD-1 mice. Our results indicate that QS-619 and QS-528 are probably full FFAR1 agonists. [ABSTRACT FROM AUTHOR]

This study was conducted to evaluate the effects of long-term administration of a new herbal composition of leuzea and cranberry meal extracts at a dose of 70:500 mg/kg in healthy and pathological mice. After 4 weeks of daily composition administration to healthy CD-1 mice and C57BL/6 mice with diet-induced metabolic syndrome, oral glucose tolerance test (OGTT), serum biochemical examination and histology of internal organs were performed. Additionally, histological examination of white and brown adipose tissue was performed to evaluate the ability of the composition to prevent abdominal obesity in C57BL/6Ay (agouti yellow) mice. The results showed that the composition increased tissue sensitivity to glucose in healthy CD-1 mice; at the same time, it did not worsen the course of pathological processes in pathological mice. In both cases, the application of the developed composition was safe and contributed to the restoration of metabolic parameters. [ABSTRACT FROM AUTHOR]

The composition of an ethanol extract from the roots of Rumex tianschanicus Losinsk of the Trans-Ili Alatau wild flora was studied in order to determine its antiulcer activity. The phytochemical composition of the anthraquinone–flavonoid complex from (AFC) R. tianschanicus revealed the presence of numerous polyphenolic compounds, the most abundant of which are anthraquinones (1.77%), flavonoids (6.95%), and tannins (13.39%). The use of column chromatography (CC) and thin-layer chromatography (TLC) in conjunction with UV, IR, NMR spectroscopy, and mass spectrometry data allowed the researchers to isolate and identify the major components of the anthraquinone–flavonoid complex's polyphenol fraction: physcion, chrysophanol, emodin, isorhamnetin, quercetin, and myricetin. The gastroprotective effect of the polyphenolic fraction of the anthraquinone–flavonoid complex (AFC) of R. tianschanicus roots was examined in an experimental model of rat gastric ulcer induced by indomethacin. The preventive and therapeutic effect of the anthraquinone–flavonoid complex at a dose of 100 mg/kg was analyzed using intragastric administration per day for 1 to 10 days, followed by a histological examination of stomach tissues. It has been demonstrated that prophylactic and prolonged use of the AFC R. tianschanicus in laboratory animals resulted in significantly less pronounced hemodynamic and desquamative changes in the epithelium of gastric tissues. The acquired results thus offer fresh insight into the anthraquinone and flavonoid metabolite component composition of R. tianschanicus roots, and they imply that the examined extract can be used to develop herbal medicines with antiulcer activity. [ABSTRACT FROM AUTHOR]

Free fatty acid receptor-1 (FFAR1) is one of the possible therapeutic targets in the search for new hepatoprotective drugs. FFAR1 agonists were found to have hypolipidemic, antifibrotic, anti-inflammatory, antiproliferative and antioxidant effects in addition to hypoglycemic action. In this work, we conducted a study of the hepatoprotective effect of the compound QS-528 (previously discovered as an agonist of FFAR1) at doses of 60, 90, 120 and 150 mg/kg on carbon tetrachloride (CCl4)-induced liver injury. At the end of the experiment, a biochemical blood assay demonstrated that the introduction of QS-528 dose-dependently reduces the levels of liver enzymes (AST, ALT and ALKP). Histological and morphometric studies of animals' livers treated with QS-528 at doses of 120 and 150 mg/kg showed a decrease in degenerative/necrotic changes in hepatocytes and an increase in the regenerative activity of the liver. In addition, no toxicity at a single oral dose of 1000 mg/kg and an increase in HepG2 cell viability in vitro were found. Thus, the compound QS-528 was found to exhibit a hepatoprotective effect against CCl4-induced toxic liver damage. [ABSTRACT FROM AUTHOR]

Several novel 9-N-n-alkyl derivatives of berberine (C5, C7, C10, C12) were synthesized. They were analyzed in vitro and in vivo for their hypoglycemic activity. In vitro studies showed that the derivatives with shorter alkyl substitutes at concentrations ranging from 2.5 to 10 μM were able to stimulate glucose consumption by HepG2 cells more prominently than the derivatives with longer substitutes (C10 and C12). All compounds demonstrated a better effect compared to berberine. Their impact on cells' viability also depended on the alkyl substitutes length, but in this case, C10 and C12 derivatives demonstrated the best results. A similar correlation was also found in the OGTT, where the C5 derivative demonstrated a pronounced hypoglycemic effect at a dose of 15 mg/kg and C12 was less effective. This compound was further investigated in C57BL/6Ay mice for four weeks and was administered at a dose of 15 mg/kg. Pronounced effect of C12 on carbohydrate metabolism in mice was discovered: there was a decrease in fasting glucose levels and an increase in glucose tolerance in OGTT on the 14th and 28th days of the experiment. However, at the end of the experiment, signs of hepatosis exacerbation and an increase in the content of hepatic aminotransferases in blood were found. [ABSTRACT FROM AUTHOR]

Novel 9-N-alkyltetrahydroberberine derivatives were synthesized, among which, based on the results of OGTT, one compound containing the longest aliphatic substituent was selected for study in mice C57BL/6Ay, which demonstrate obesity, impaired glucose tolerance, and concomitant liver non-alcoholic fatty disease. Administration of this substance at a dose of 15 mg/kg for four weeks improved the insulin sensitivity of mice, which resulted in a decrease in fasting glucose levels and improved the tolerance of mice to OGTT glucose loading. A decrease in the level of lactate in the blood and a decrease in the amount of glucokinase in the liver were also found. The introduction of compound 3c did not have a toxic effect on animals based on biochemical data, histological analysis, and measurements of general parameters such as body weight and feed intake. Thus, the 9-N-heptyltetrahydroberberine derivative showed prominent hypoglycemic effects, which makes it promising to obtain and study other derivatives with longer substituents. [ABSTRACT FROM AUTHOR]

In terms of prevalence, thyroid pathology, associated both with a violation of the gland function and changes in its structure, occupies one of the main places in clinical endocrinology. The problem of developing low-toxic and highly effective herbal preparations for the correction of thyroid hypofunction and its complications is urgent. Salidroside is a glucoside of tyrosol, found mostly in the roots of Rhodiola spp., and has various positive biological activities. The purpose of this study was to study the antihypothyroid potential of salidrosid-containing extract from R. semenovii roots, which was evaluated on a mercazolyl hypothyroidism model. We showed that extract containing salidroside is a safe and effective means of hypothyroidism correction, significantly reducing (p ≤ 0.001) the level of thyroid-stimulating hormone and increasing the level of thyroid hormones. The combined use of R. semenovii extract with potassium iodide enhances the therapeutic effect of the extract by 1.3-times. [ABSTRACT FROM AUTHOR]

Benzimidazole is an important heterocycle that is widely researched and utilized by the pharmaceutical industry and is one of the five most commonly used five-membered aromatic heterocyclic compounds approved by the US Food and Drug Administration. In view of their wide-ranging bioactivities, systems containing benzimidazole as one of the moieties occupy a special place among other benzimidazole derivatives. Since 2010, many improved synthetic strategies have been developed for the construction of hetaryl- and arylbenzimidazole molecular scaffolds under environmentally benign conditions. This review emphasizes the recent trends and modifications frequently used in the synthesis of derivatives of benzimidazole such as the Phillips–Ladenburg and Weidenhagen reactions, as well as entirely new methods of synthesis, involving oxidative cyclization, cross-coupling, ring distortion strategy, and rearrangements carried out under environmentally benign conditions. 1 Introduction 2 From 1,2-Diaminobenzenes with Various One-Carbon Unit Suppliers 2.1 Phillips–Ladenburg Reaction 2.1.1 With (Het)arenecarboxylic Acids 2.2.2 With (Het)arenecarboxylic Acid Derivatives 2.2 Weidenhagen Reaction 2.2.1 With (Het)arenecarbaldehydes or (Het)aryl Methyl Ketones 2.2.2 With Primary Alcohols 2.2.3 With Primary Alkylamines 2.2.4 With 2-Methylazaarenes 2.2.5 With Other One-Carbon Fragment Suppliers 3 From 2-Haloacetanilides and Amines 4 From Amidines 5 From Tetrahydroquinazolines 6 Mamedov Rearrangement 7 Conclusions and Outlook [ABSTRACT FROM AUTHOR]

Benzimidazoles and benzimidazolones can be efficiently synthesized via acid‐catalyzed rearrangements of 3‐aroylquinoxalin‐2‐ones with various nucleophiles. The detailed mechanisms of typical rearrangements of 3‐benzoylquinoxalin‐2‐one (1 Q) with 1,2‐benzendiamine (1 a, Type I) and with methyl 3‐aminocrotonate (1 b, Type II) in acetic acid solution are explored by extensive DFT calculations. Acetic acid acts as proton source and efficient proton shuttle during the catalysis. The former rearrangement is initiated by site‐selective N⋅⋅⋅C condensation at protonated benzoyl site of 1 Q, while the latter is initiated by two competing C⋅⋅⋅C nucleophilic additions at protonated imine and benzoyl sites of 1 Q that eventually leads to two isomeric products. Both rearrangements proceed via intramolecular SN(ANRORC) mechanism (sequential Addition of Nucleophile, Ring‐Opening and Ring‐Closing) involving spiro‐quinoxalinone intermediates, but with fundamentally different RORC steps via ring‐opening anilide cation and isocyanate cation species, respectively. A simple energetic rule is suggested to determine the type of rearrangement by counting the conjugated π‐electrons within the spiro‐forming ring that may stabilize the ring‐opening anilide cation species, which may enable further rational design of novel spiro‐quinoxalinone based rearrangements. [ABSTRACT FROM AUTHOR]

The new α,α′‐diimine ligands with benzimidazole moiety were synthesized based on the rearrangement of 3‐aroylquinoxalin‐2(1H)‐ones when exposed to 4,5‐diamino‐2,1,3‐benzoxadiazole, 4,5‐diamino‐2,1,3‐benzothiadiazole and 5,6‐diaminoquinoxaline. Among them, we report the first examples of the new heterocyclic system namely benzo[4′,5′]imidazo[1′,2′:1,2]quinolino[3,4‐b and 4,3‐b][1,2,5]oxadiazolo[3,4‐f]quinoxalines, which exhibits an interesting electrochemical behavior. All compounds were fully characterized by IR, 1H and 13C NMR spectroscopies, and mass spectrometry. [ABSTRACT FROM AUTHOR]

Facile and efficient methods for the synthesis of 3‐benzylquinoxalin‐2(1H)‐ones and thiazolo[3,4‐a]quinoxalin‐4(5H)‐ones by the reaction of the readily available 3‐(α‐chlorobenzyl)quinoxalin‐2(1H)‐ones and thiourea have been developed, with multiple roles of the latter. Possible mechanisms are discussed. These two‐step sequences can be performed in a one‐pot manner to produce the desired products in moderate to high yields. [ABSTRACT FROM AUTHOR]

In pediatric low‐grade gliomas not amenable to complete resection, various chemotherapy regimens are the mainstream of treatment. An excellent overall survival of these patients makes justification of the intensification of chemotherapy difficult and calls for the development of new strategies. Bevacizumab, a humanized monoclonal antibody directed against Vascular endothelial growth factor (VEGF), has been successfully used in combination with irinotecan in a number of adult and pediatric studies and reports. Fifteen patients at median age of 7 years old (range 3 months to 15 years) were treated with bevacizumab in combination with conventional low‐toxicity chemotherapy. The majority had chiasmatic/hypothalamic and midline tumors, seven had confirmed BRAF pathway alterations including neurofibromatosis type 1 (2). Fourteen patients had more than one progression and three had radiotherapy. No deaths were documented, PFS at 11 and 15 months was 71.5% ± 13.9% and 44.7% ± 17.6% respectively. At the end of follow‐up 40% of patients has radiologically stable disease, three patients progressed shortly after completion of bevacizumab and two showed mixed response with progression of cystic component. Rapid visual improvement was seen in 6/8 patients, resolution of endocrine symptoms in 2/4 and motor function improvement in 4/6. No relation between histology or BRAF status and treatment response was observed. Treatment‐limiting toxicities included grade 4 proteinuria (2) and hypertension (2) managed with cessation (1) and pausing of therapy plus antihypertensives (1). In conclusion, bevacizumab is well tolerated and appears most effective for rapid tumor control to preserve vision and improve morbidity. This study demonstrates that anti‐VEGF humanized monoclonal antibody bevacizumab is well tolerated and can be effectively used in pediatric patients with unresectable or progressive low‐grade glioma in combination with a number of conventional chemotherapies. Addition of bevacizumab to chemotherapy does not increase toxicity and allows for rapid control of clinical symptoms. However, optimal duration of therapy is yet to be determined in future studies. [ABSTRACT FROM AUTHOR]

We report on the photophysical properties, conjugation, conformational behavior, intra- and intermolecular hydrogen bonds (HBs) of a series of novel fluorophores, consisting of 3-arylquinoxaline and benzimidazole moieties linked by a single CC bond. Computations employing density functional theory (DFT) reveal that conjugation between these moieties stabilizes syn-conformers with two HB centers located on the same side of the molecule. Anti-conformers form stronger intermolecular HBs with DMSO and DMF than syn-conformers, and this influences the energy gap between syn- and anti-forms, especially upon excitation of the molecules to the S1 state. Substituents introduced in various positions of the molecules modify their conformational behavior, and mutual disposition of excited singlet states relative to the ground states. Various substitution patterns produce very different effects on relative quantum yield of luminescence: from a moderate increase in polar DMSO and DMF relative to 1,2-dichloroethane solutions to complete quenching of emission which is observable in polar media. The observed behavior is understood with the aid of DFT and time-dependent DFT calculations. The tuneability of the spectroscopic range of the luminescence and especially of its sensitivity to environmental effects allows rational design of the novel fluorophores of this family for various applications. [ABSTRACT FROM AUTHOR]

Background: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown.Methods: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database.Results: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes.Conclusions: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. [ABSTRACT FROM AUTHOR]

The reaction of 3-benzoylquinoxalin-2(1H)-ones with enamines (generated in situ from ammonium acetate and the corresponding methylaryl(hetaryl)ketones) proceeds smoothly to give the corresponding substituted 1-(pyrrolyl)benzimidazolone derivatives in moderate yields through the novel rearrangement of 3-benzoylquinoxalin-2(1H)-ones involving a dual cleavage of the C3=N4 and C2-C3 bonds under mild conditions. [ABSTRACT FROM AUTHOR]

The reaction of 3-ethoxycarbonylmethylene-3,4-dihydroquinoxalin-2(1 H)-one 5 with the Vilsmeier reagent, the treatment of 3-(3,4-dihydroquinoxalin-2(1 H)-on-3-yl)-1,2-dihydro-1,5-benzodiazepin-2(1 H)-one hydrochloride 7 with 10% and 3-benzimidazoylquinoxaline-2(1 H)-one 3 with both 1,2-phenylenediamine dihydrochloride, and the reactions of 1,2-phenylenediamine have been reinvestigated, and the structures of these reaction products have been revised. The aforementioned reactions have been shown to proceed with the formation of 1- N, N-dimethylaminomethylene-2-oxo-1,2-dihydrofuro[2,3- b]quinoxaline 10 in the first case, the formation of 3-[2-(benzimidazol-2-on-1-yl)vinyl]-1 H-quinoxalin-2-one 12 in the second case, and the formation of 2,3-bis-(1 H-benzimidazol-2-yl)quinoxaline 17 in the third case and not the formation of 3-( N, N-dimethylaminocarbonyl)furo[2,3- b]quinoxaline hydrochloride 6, the free base of 3-(3,4-dihydroquinoxalin-2(1 H)-on-3-yl)-1,2-dihydro-1,5-benzodiazepin-2(1 H)-one 7, that is, compound 11 and benzodiazepine derivative 4, as has been described earlier. In the third case, the formation of 2,3-bis-(1 H-benzimidazol-2-yl)quinoxaline 17 occurs according to the novel quinoxalin-2(1 H)-one benzimidazole discovered by us. The potential mechanisms for the investigated reactions are discussed. [ABSTRACT FROM AUTHOR]

A synthetically useful protocol has been developed for the preparation of highly functionalized N-pyrrolylbenzimidazol-2-ones. The reaction of variously substituted 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with commercially available enamines in acetic acid results in a rapid rearrangement and formation of N-pyrrolylbenzimidazol-2-ones in modest to excellent yields. The key step of the rearrangement involves the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with enamines. In this case, the atom of carbon which is displaced from the pyrazine ring of quinoxalin-2(1H)-one becomes the fourth carbon atom of the newly formed pyrrole ring. The method is applicable for the aza analogues of quinoxalin-2(1H)-ones. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase ( TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes. [ABSTRACT FROM AUTHOR]