Withania somnifera (L.) Dunal (Ashwagandha); current understanding and future prospect as a potential drug candidate.

Cancer and Neurodegenerative diseases are one of the most dreadful diseases to cure and chemotherapy has found a prime place in cancerous treatments while as different strategies have been tested in neurodegenerative diseases as well. However, due to adverse shortcomings like the resistance of cancerous cells and inefficiency in neurodegenerative disease, plant sources have always found a prime importance in medicinal use for decades, Withania somnifera (L.) Dunal (W. somnifera) is a well-known plant with medicinal use reported for centuries. It is commonly known as winter cherry or ashwagandha and is a prime source of pharmaceutically active compounds withanolides. In recent years research is being carried in understanding the extensive role of W. somnifera in cancer and neurological disorders. W. somnifera has been reported to be beneficial in DNA repair mechanisms; it is known for its cellular repairing properties and helps to prevent the apoptosis of normal cells. This review summarizes the potential properties and medicinal benefits of W. somnifera especially in cancer and neurodegenerative diseases. Available data suggest that W. somnifera is effective in controlling disease progressions and could be a potential therapeutic target benefiting human health status. The current review also discusses the traditional medicinal applications of W. somnifera, the experimental evidence supporting its therapeutical potential as well as obstacles that necessitate being overcome for W. somnifera to be evaluated as a curative agent in humans.

Correction: Diastereoselective synthesis of glycopyrans 1,2-annulated with dioxazinanes from 1,2-anhydrosugars and N-substituted nitrones.

Correction for 'Diastereoselective synthesis of glycopyrans 1,2-annulated with dioxazinanes from 1,2-anhydrosugars and N-substituted nitrones' by Ajaz Ahmed et al., Org. Biomol. Chem., 2022, 20, 1436-1443, DOI: 10.1039/d1ob02310a.

Diastereoselective synthesis of glycopyrans 1,2-annulated with dioxazinanes from 1,2-anhydrosugars and N-substituted nitrones.

1,2-Annulated pyranose sugars fused with six membered rings have emerged as an important class of carbohydrates with wide biological and synthetic utility. We now describe zinc chloride catalyzed one pot diastereoselective synthesis of sugar fused dioxazinanes from 1,2-anhydro sugars and N-substituted aromatic nitrones. Various aromatic nitrones with different substituents undergo the reaction smoothly. The developed strategy works well with both ester and ether protection on the sugar and proceeds under mild reaction conditions. The mechanism seems to involve activation of the anhydrosugar by ZnCl2 for nucleophilic attack by the nitrone followed by cyclization.

Construction of Fused Oxabicyclic Scaffolds from Glycals and Styrenes via One-Pot Domino Transformations.

Triflic acid catalyzed cascade stereoselective reaction of glycals with styrenes delivers complex oxabicyclic scaffolds such as cis-oxadecalins or cis-cyclopentanofurans simply by tweaking the solvent. In the presence of participating solvents like benzene/toluene, cascade Ferrier C-glycosylation and double Friedel-Crafts reaction leads to densely chiral benzo-fused oxadecalins, whereas in DCM, an unprecedented ring-opening, ring-closing sequence generated cis-cyclopentanofurans. An attempt has been made to explain the above cascade sequences via intermediate trapping, kinetic experiments, and Baldwin's rules.

One-Pot Regioselective and Stereoselective Synthesis of C-Glycosyl Amides from Glycals Using Vinyl Azides as Glycosyl Acceptors.

The reaction of glycals containing good leaving groups with aromatic vinyl azides to give α- C-glycosyl amides in good yields is described. Various vinyl azides with different groups undergo the reaction smoothly. In these reactions, an iminodiazonium intermediate is generated by the attack of the vinyl azide onto the glycal under Lewis acid conditions. This undergoes Schmidt-type denitrogenative 1,2-migration to form a nitrilium ion, which, upon hydrolysis, gives the desired C-glycosyl amide.

Regiospecific Synthesis of Ring A Fused Withaferin A Isoxazoline Analogues: Induction of Premature Senescence by W-2b in Proliferating Cancer Cells.

Induction of premature senescence represents a novel functional strategy to curb the uncontrolled proliferation of malignant cancer cells. This study unveils the regiospecific synthesis of novel isoxazoline derivatives condensed to ring A of medicinal plant product Withaferin-A. Intriguingly, the cis fused products with ß-oriented hydrogen exhibited excellent cytotoxic activities against proliferating human breast cancer MCF7 and colorectal cancer HCT-116 cells. The most potent derivative W-2b triggered premature senescence along with increase in senescence-associated ß-galactosidase activity, G2/M cell cycle arrest, and induction of senescence-specific marker p21Waf1/Cip1 at its sub-toxic concentration. W-2b conferred a robust increase in phosphorylation of mammalian checkpoint kinase-2 (Chk2) in cancer cells in a dose-dependent manner. Silencing of endogenous Chk2 by siRNA divulged that the amplification of p21 expression and senescence by W-2b was Chk2-dependent. Chk2 activation (either by ectopic overexpression or through treatment with W-2b) suppressed NM23-H1 signaling axis involved in cancer cell proliferation. Finally, W-2b showed excellent in vivo efficacy with 83.8% inhibition of tumor growth at a dose of 25 mg/kg, b.w. in mouse mammary carcinoma model. Our study claims that W-2b could be a potential candidate to limit aberrant cellular proliferation rendering promising improvement in the treatment regime in cancer patients.

Design and synthesis of indolopyridone hybrids as new antituberculosis agents.

Tuberculosis continues to be the most dangerous infectious disease globally and need for development of new therapies is of utmost importance. In this study we describe the rationale design for synthesis using molecular hybridization and subsequent in-vitro antimycobacterial activity of various indolo-pyridone hybrid molecules against Mycobacterium tuberculosis H37Rv. A total of 16 indolo-pyridone hybrid molecules were synthesized with 85-90% yields and characterized by various spectroscopic techniques. Four compounds were ineffective with MIC >256 µg/ml (highest concentration tested), six exhibited poor activity with MIC > 100 µg/ml, four showed moderate activity with MIC > 50 µg/ml and two had notable anti-TB activity with MIC values 32 µg/ml. Interestingly the last two compounds were observed equally effective against drug susceptible and various drug resistant strains including multidrug-resistant (MDR) strains, thereby clearly demonstrating their potential against MDR-TB. Our results showed that un-substituted aryl rings posses better antituberculosis activity than those having any kind of substitution and derivatives with small sized electron withdrawing groups in aryl ring exhibited activity while bigger groups lead to considerable loss in activity. The results of this study open up a new door for further SAR guided synthesis on one hand and on the other hand provide a promising opportunity that may lead to the discovery of a new class of antituberculosis agents.

Pd-Catalyzed Regio- and Stereoselective C-Nucleoside Synthesis from Unactivated Uracils and Pyranoid Glycals.

Pd-catalyzed regio- and stereoselective C-nucleoside synthesis from pyranoid glycals and unactivated N,N-dialkyluracils is described. Depending upon the reaction conditions, either ß-hydride or ß-heteroatom eliminated C-nucleosides were obtained exclusively. Different glycals with various protecting groups reacted smoothly. Mechanistically, uracil first undergoes electrophilic palladation regioselectively at the C-5 position to generate the active organopalladium species, which then attacks the glycal in a regio- and stereoselective mode to generate C-nucleosides. The method obviates the use of heavy metals such as mercury or preactivation of protected uracils, making it an attractive strategy for C-nucleoside synthesis.

Diastereoselective sp2-sp3 coupling of sugar enol ethers with unactivated cycloalkenes: new entries to C-branched sugars.

Sugar enol ethers undergo efficient coupling at C-2 with unactivated cycloalkenes under a low Pd loading affording allylic substitution products. High diastereoselectivity was observed at the allylic centre with sterically hindered substrates. Generation of a π-allyl complex by the Pd(ii) catalyst via cleavage of the allylic C-H bond of the cycloalkene may be responsible for the formation of sp2-sp3 coupling products.

Isolation, characterization and HPLC quantification of compounds from Aquilegia fragrans Benth: Their in vitro antibacterial activities against bovine mastitis pathogens.

ETHNO-PHARMACOLOGICAL RELEVANCE: The underground parts of Aquilegia fragrans are traditionally used for the treatment of wounds and various inflammatory diseases like bovine mastitis. However, there are no reports on the phytochemical characterization and antibacterial studies of A. fragrans. AIM OF THE STUDY: To isolate compounds from the methanol extract of the underground parts of A. fragrans and determine their antibacterial activity against the pathogens of bovine mastitis. The study was undertaken in order to scientifically validate the traditional use of A. fragrans. MATERIALS AND METHODS: Five compounds were isolated from the methanol extract of the underground parts of A. fragrans using silica gel column chromatography. Structural elucidation of the isolated compounds was done using spectral data analysis and comparison with literature. High performance liquid chromatography (HPLC) was used for the qualitative and quantitative determination of isolated compounds in the crude methanol extract. The methanol extract and isolated compounds were evaluated for antibacterial activities against mastitis pathogens using broth micro-dilution technique. RESULTS: The five isolated compounds were identified as (1) 2, 4-dihydroxyphenylacetic acid methyl ester (2) ß-sitosterol (3) Aquilegiolide (4) Glochidionolactone-A and (5) Magnoflorine. A quick and sensitive HPLC method was developed for the first time for qualitative and quantitative determination of four isolated marker compounds from A. fragrans. The crude methanol extract and compound 5 exhibited weak antibacterial activities that varied between the bacterial species (MIC=500-3000 µg/ml). CONCLUSIONS: The above results show that the crude methanol extract and isolated compounds from A. fragrans exhibit weak antibacterial activities. Further phytochemical and pharmacological studies are required for proper scientific validation of the folk use of this plant species in the treatment of various inflammatory diseases like bovine mastitis.

Benchmarking the clinical prosthetic dental literature on MEDLINE.

STATEMENT OF PROBLEM: The utility of evidence-based clinical prosthetic dental decision making is, in part, predicated on the availability of high-quality clinical trials and the use of current best evidence. With literature or outcomes continually evolving, it is difficult to know how much information is available, how fast it changes, or where it is located. PURPOSE: This study identified and quantified the availability of high-quality prosthetic dental clinical trials, determined the dynamics of literature increase, and identified the location of relevant literature published within a specific decade. MATERIAL AND METHODS: A search strategy based on the Medical Subject Headings (MeSH) vocabulary for prosthetic dentistry was developed to examine MEDLINE with use of the Ovid Web Gateway search engine between the years 1990-1999. Specific and sensitive methodologic search filters identified 4 categories of information: etiology, diagnosis, therapy, and prognosis. The identified studies were limited to human subjects and to articles written in English. The results were subdivided by year to identify trends and location of the literature. This evaluation did not include the following: (1) other databases or languages or (2) an evaluation of the validity or clinical applicability of the literature. The first factor would increase the estimated number of relevant articles, whereas the second factor would decrease it. RESULTS: Between 1990 and 1999, MEDLINE identified 10,258 articles published in English on human prosthodontic issues. When subdivided by clinical category, the number of articles per year (mean +/- SD) for specific and sensitive searches, respectively, was as follows: etiology, 10 +/- 6 and 95 +/- 27; diagnosis, 11 +/- 5 and 77 +/- 21; therapy, 6 +/- 2 and 153 +/- 52; and prognosis, 13 +/- 6 and 91 +/- 27. For sensitive searches, this amounted to approximately 416 articles per year. The time-course analysis indicated that the number of articles in each category increased by approximately 7% per year. The articles were published in more than 60 different journals: approximately 50% of the articles were published in 14 journals, whereas the remaining articles were published in 46 journals. CONCLUSION: There appears to be substantial clinical prosthetic dental literature upon which to base clinical decisions. With the sensitive search strategy used as an estimate, to stay current, one would need to read and absorb approximately 8 articles per week, 52 weeks per year, across 60 different journals. Increases in the volume of literature each year make access even more difficult. These trends suggest the need for computer-based clinical knowledge systems.