α/ß-Stereo- and diastereoselective glycosylation with n-pentenyl glycoside donors, promoted by N-iodosuccinimide and catalyzed by chiral Brønsted acid.

A method involving stereoselective glycosylation catalyzed by (+)-isomenthol ester of pentacarbomethoxycyclopentadiene as a chiral Brønsted acid, with n-pentenyl glycosides in the presence of N-iodosuccinimide as the promoter is described; this method offered a chiral recognition of racemic substrates.

Transition Metal/Lewis Acid Catalyzed Reactions of Zerumbone for Diverse Molecular Motifs.

Zerumbone is a naturally occurring humulene type sesquiterpene, isolated from the rhizomes of Zingiber zerumbet (L.) Smith with excellent therapeutic potential and is recognized as a valuable synthon for the construction of diverse array of natural product motifs. In this review, we intended to highlight our achievements in utilizing abundant natural product zerumbone and its derivatives for the development of pharmacologically relevant molecular scaffolds. We provided an account of the transition-metal catalyzed 1,4-conjugate addition reactions of zerumbone and its derivatives along with palladium-catalyzed cross-couplings, transition metal-based Lewis acid promoted interrupted Nazarov cyclisation reaction with substituted indoles and transannular cyclizations, photo-induced transformations of zerumbone and its epoxide.

Dienaminodioate based multicomponent reactions with post-benzylic oxidative transformations mediated by DDQ.

Multicomponent reactions (MCRs) using dienaminodioate with post-benzylic oxidative transformation mediated by DDQ that afforded a diverse array of products are described. An unprecedented rearrangement of 1,2-dihydropyridines (1,2-DHPs), 3CR products, to 2-pyridones in good yields with a broad substrate scope by DDQ-mediated benzylic oxidation via a pyridinium intermediate is reported. Treatment of the pyridinium intermediate with tert-butyl isocyanide afforded isomerized 1,2-DHPs, analogous to Ritter amides. Further diversification using 3CR products bearing a benzylic group, predictably, promoted the synthesis of 2-pyridone with a benzylideneamine group and a benzo[d]oxazole appended biaryl group by DDQ. A formal 1,6-reduction product from 2-pyridone in the presence of NaBH4 is also observed.

Synthesis of ß-C-galactosyl ceramide and its new aza variant via the Horner-Wadsworth-Emmons reaction.

A simple strategy for the synthesis of ß-C-galactosyl ceramide and its new aza-variant analogue is described using the Horner-Wadsworth-Emmons reaction as the key step in combining the sugar and aglycone portions.

Synergistic activity of phenazines isolated from Pseudomonas aeruginosa in combination with azoles against Candida species.

Candidiasis infections are caused by yeasts from the genus Candida. The types of infection range from superficial to systemic. Treatment often requires antifungals such as the azoles; however, increased use of these drugs has led to the generation of yeasts with increased resistance to these drugs. Here, we describe the synergistic anticandidal activity of three phenazines-phenazine-1-ol, phenazine-1-carboxylic acid, and phenazine-1-carboxamide. These phenazines were purified from Pseudomonas aeruginosa in combination with three clinically used azoles-fluconazole, itraconazole, and clotrimazole. The synergistic anticandidal activities of phenazines and azoles were assessed using the checkerboard microdilution and time-kill methods. Study results show that the combined effects of phenazines and azoles were predominantly synergistic activity (fractional inhibitory concentration index <0.5). The time-kill study, which included a combination of the minimum inhibitory concentration of phenazines and azoles, showed growth of Candida species that was completely attenuated after 0-6 h of treatment. These results, which suggest that the activity of phenazines and azoles may be beneficial, have potential implications in delaying the development of resistance, as the anticandidal effect is achieved with lower concentrations of both agents (phenazines and azoles). The cytotoxicity of phenazines was also tested against a normal human cell line (foreskin normal fibroblast). No cytotoxicity was recorded at concentrations up to 200 µg/ml. The in vitro synergistic activity of phenazines and azoles against Candida species is reported here for the first time.

A metal-free one-pot cascade synthesis of highly functionalized biaryl-2-carbaldehydes.

A metal-free one-pot cascade annulation of acyclic substrates dienaminodioate, cinnamaldehydes and allyl amine was achieved for the synthesis of polyfunctional biaryl-2-carbaldehydes. The reaction proceeds at room temperature by a trifluoroacetic acid mediated Diels-Alder pathway. Synthetic applications of the resulting biaryl-2-carbaldehyde have been demonstrated by conversion into an array of diverse molecules with biological and materials chemistry relevance. The present work offers a complementary route to the existing metal mediated cross-coupling methods for the preparation of biaryls.

Peracetylation transforms natural products beyond mere derivatization.

Peracetylation of the methanolic extract of Benincasa hispida led to the isolation of a compound with a peracetylated hex-4-en-3-one backbone. Mechanistic insights revealed that the isolated compound is an outcome of the chemical transformation of a α-dicarbonyl compound.

Natural Prenylflavones from the Stem Bark of Artocarpus altilis: Promising Anticancer Agents for Oral Squamous Cell Carcinoma Targeting the Akt/mTOR/STAT-3 Signaling Pathway.

Artonin E (AA2) and artobiloxanthone (AA3) were extracted and purified from the acetone extract of the stem bark of Artocarpus altilis (Parkinson) Fosberg. Preliminary investigations of both candidates revealed promising cytotoxic effects in oral cancer cells. Moreover, these candidates modulated the expression of pivotal proteins linked to oral cancer progression, eliciting apoptosis through caspase-3 and caspase-9 activation. Additionally, our results showed that AA2 and AA3 suppressed several proteins linked with oral cancer, such as Bcl-2, COX-2, VEGF, and MMP-9, and modulated the cell signaling pathways, such as Akt/mTOR and STAT-3, offering valuable insights into the underlying mechanism of action of these compounds. These findings were robustly validated in silico using molecular docking and molecular dynamic simulations. To our knowledge, these findings have not been previously reported, and the continued exploration and development of these natural products may offer a potential avenue for the effective management of this malignancy.

Generation of reactive oxygen species (ROS) is a key factor for stimulation of macrophage proliferation by ceramide 1-phosphate.

We previously demonstrated that ceramide 1-phosphate (C1P) is mitogenic for fibroblasts and macrophages. However, the mechanisms involved in this action were only partially described. Here, we demonstrate that C1P stimulates reactive oxygen species (ROS) formation in primary bone marrow-derived macrophages, and that ROS are required for the mitogenic effect of C1P. ROS production was dependent upon prior activation of NADPH oxidase by C1P, which was determined by measuring phosphorylation of the p40phox subunit and translocation of p47phox from the cytosol to the plasma membrane. In addition, C1P activated cytosolic calcium-dependent phospholipase A(2) and protein kinase C-α, and NADPH oxidase activation was blocked by selective inhibitors of these enzymes. These inhibitors, and inhibitors of ROS production, blocked the mitogenic effect of C1P. By using BHNB-C1P (a photolabile caged-C1P analog), we demonstrate that all of these C1P actions are caused by intracellular C1P. It can be concluded that the enzyme responsible for C1P-stimulated ROS generation in bone marrow-derived macrophages is NADPH oxidase, and that this enzyme is downstream of PKC-α and cPLA(2)-α in this pathway.

Isolation of proline-based cyclic dipeptides from Bacillus sp. N strain associated with rhabditid [corrected] entomopathogenic nematode and its antimicrobial properties.

Entomopathogenic nematodes (EPN) are well-known as biological control agents and are found to have associated bacteria which can produce a wide range of bioactive secondary metabolites. We report herewith isolation of six proline containing cyclic dipeptides cyclo(D-Pro-L-Leu), cyclo(L-Pro-L-Met), cyclo(D-Pro-L-Phe), cyclo(L-Pro-L-Phe), cyclo(L-Pro-L-Tyr) and cyclo(L-Pro-D-Tyr) from ethyl acetate extract of the Luria Broth (LB) cell free culture filtrate of Bacillus sp. strain N associated with a new EPN Rhabditis sp. from sweet potato weevil grubs collected from Central Tuber Crops Research Institute farm. Antimicrobial studies of these 2,5-diketopiperazines (DKPs) against both medicinally and agriculturally important bacterium and fungi showed potent inhibitory values in the range of µg/mL. Cyclic dipeptides showed significantly higher activity than the commercial fungicide bavistin against agriculturally important fungi, viz., Fusarium oxysporum, Rhizoctonia solani, and Pencillium expansum. The highest activity of 2 µg/mL by cyclo(L-Pro-L-Phe) was recorded against P. expansum, a plant pathogen responsible for causing post harvest decay of stored apples and oranges. To our knowledge, this is the first report on the isolation of these DKPs from Rhabditis EPN bacterial strain Bacillus sp.

Artifacts from the methanolic extract of Solanum nigrum Linn.

Two new lactones, γ-butyrolactone and δ-valerolactone were isolated from the methanolic extract of Solanum nigrum. Structure elucidation was carried out by exhaustive 2D NMR analysis. The structures of the lactones depict the outcome of their isolation as a situation that involve the formation of artifacts.

A potent bioactive fraction against colon cancer from Plectranthus vettiveroides.

Aim: This study was designed to investigate the anticancer efficacy of the organic leaf extracts of the plant, Plectranthus vettiveroides (P. vettiveroides), and to analyze the molecular mechanism of the anticancer activity. Methods: The leaf extracts were prepared by polarity-graded serial extraction of the dried leaf powder. The cytotoxic effect of the extracts was analyzed by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The most active ethyl acetate extract was subjected to bioactivity-guided fractionation by column chromatography, which yielded a cytotoxic fraction designated as the P. vettiveroides fraction (PVF). The anticancer property of PVF was confirmed further by clonogenic assay. The mechanism of PVF-induced cell death was analyzed by flow cytometry and fluorescence microscopy. Additionally, the effects of PVF on apoptotic and cell survival pathways were analyzed using western immunoblot analysis. Results: A bioactive fraction PVF, was isolated from the ethyl acetate leaf extract. PVF showed significant anticancer activity against colon cancer cells, whilst normal cells were comparatively less affected. PVF induced strong apoptotic stimuli in colorectal carcinoma cell line HCT116, involving both extrinsic and intrinsic pathways. Investigation into the molecular mechanism of anticancer activity of PVF in HCT116 cells revealed that the fraction activates the pro-apoptotic pathway via tumor suppressor protein 53 (p53) and inhibits the anti-apoptotic pathway by regulating phosphatidylinositol 3-kinase (PI3K) signaling. Conclusions: The findings of this study demonstrate, with mechanism-based evidence, the chemotherapeutic potential of a bioactive fraction PVF, derived from the leaves of the medicinal plant P. vettiveroides against colon cancer.

Isolation of two new stereochemical variants of streptophenazine by cocultivation of Streptomyces NIIST-D31, Streptomyces NIIST-D47, and Streptomyces NIIST-D63 strains in 3C2 combinations.

Cocultivation of combinations of Streptomyces species isolated from the same soil was explored to isolate novel secondary metabolites. Recently, we reported the isolation of a novel vicinal diepoxide of alloaureothin along with three carboxamides, 4-aminobenzoic acid, and 1,6-dimethoxyphenazine from the individual culture of Streptomyces luteireticuli NIIST-D31. Herein, cocultivation of NIIST-D31 with Streptomyces luteoverticillatus NIIST-D47 afforded two new stereochemical variants of streptophenazine (S1 and S2), and 1-N-methylalbonoursin, where the individual culture of NIIST-D47 primarily produced carbazomycins A, D, and E. The new streptophenazines and 1-N-methylalbonoursin were also observed during cocultivation of NIIST-D31 with Streptomyces thioluteus NIIST-D63, where the individual culture of NIIST-D63 strain afforded for the first time 2,2'-bipyridines (caerulomycinamide and dipyrimicin B), picolinamide, 2,3-dimethoxybenzamide, 2-hydroxy-3-methoxybenzamide, and 6-amino-2-pyridone along with known natural products aureothin and 1,6-dimethoxyphenazine. Finally, cocultivation of NIIST-D47 and NIIST-D63 strains produced carbazomycins B and C, alloaureothin, cyclo-(Leu-Pro), investiamide, and 4-aminobenzoic acid. Some of the compounds observed in the individual cultures were also produced in cocultivations. Improvement in the yield of secondary metabolites during cocultivation compared to individual culturing is well-known, which is noted here for vicinal diepoxide of alloaureothin. The production of new streptophenazines by cocultivation combinations with NIIST-D31 suggests that NIIST-D47 and NIIST-D63 may function as inducers in activating cryptic secondary metabolite-biosynthetic gene clusters. Cytotoxicity of the new streptophenazines in cancerous (MCF7 and MDA-MB-231) or non-cancerous (WI-38) cells were tested, however, they exhibited no significant activity.

In vitro antibacterial effects of combination of ciprofloxacin with compounds isolated from Streptomyces luteireticuli NIIST-D75.

Three phenazines, 1-methoxyphenazine (1), methyl-6-methoxyphenazine-1-carboxylate (2), 1,6-dimethoxyphenazine (4), and a 2,3-dimethoxy benzamide (3) were isolated from the Streptomyces luteireticuli NIIST-D75, and the antibacterial effects of compounds 1-3, each in combination with ciprofloxacin, were investigated. The in vitro antibacterial activity was assessed by microdilution, checkerboard, and time-kill assay against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhi. According to the checkerboard assay results, each combination of compounds 1, 2 and 3 with ciprofloxacin resulted in a significantly lower minimum inhibitory concentrations (MICs) of 0.02-1.37 µg ml-1, suggesting synergistic combinations by fractional inhibitory concentration index, and displayed bactericidal activity in time-kill kinetics within 48 h. SEM analysis was carried out to determine the changes in morphology in S. aureus and E. coli during treatment with individual combination of ciprofloxacin and compounds (1-3), which revealed drastic changes in the cells such as dent formation, biofilm disruption, cell bursting, and doughnut-like formation, change in surface morphology in S. aureus, and cell elongation, cell burst with ruptured cell, and change in surface morphology in E. coli. Hep G2 cell viability was not affected by the compounds (1-3) that were tested for cytotoxicity up to 250 µM.

A pentacarbomethoxycyclopentadiene (PCCP) organic Brønsted acid catalyzed stereoselective glycosidation of N-pentenyl orthoesters (NPOE) of d-glucose and d-galactose, in conjunction with N-iodosuccinimide.

Herein, we report our preliminary results in utilizing the organic Brønsted acid, pentacarbomethoxycyclopentadiene (PCCP), for catalysing the glycosidation with n-pentenyl orthoesters (NPOE) of d-glucose and d-galactose in the presence of N-iodosuccinimide (NIS). Benzoyl and benzyl protection in d-glucosyl NPOEs led to 1,2-trans glycosides, while acetyl protection in NPOE led to a mixture of 1,2-cis and trans glycosides with >75% cis selectivity, and d-galactosyl NPOEs led to 1,2-orthoesters. Substrate scope was demonstrated with acceptors of natural product relevance. This article highlights the prospect of utilizing the organic Brønsted acid, PCCP, for stereoselective glycosidation.

Cu(I)-azidopyrrolo[3,2-d]pyrimidine Catalyzed Glaser-Hay Reaction under Mild Conditions.

The limitation of the CuAAC "click" reaction with a 2-azidopyridine substrate, owing to its equilibrium with a tetrazole isomer, is exploited herein for its utility in the Glaser-Hay reaction. A catalytic combination of a 2-azidopyridine analogue, 4-azido-5H-pyrrolo[3,2-d]pyrimidine, and CuI afforded homocoupled products of terminal alkynes, without any trace of triazole product, under mild conditions with a broad substrate scope. Emphasis on carbohydrate-based substrates appended to a propargylic group led to 1,3-diynes in good to excellent yields.

Design, synthesis, and preliminary immunopotentiating activity of new analogues of nojirimycin.

Three new classes of nojirimycin analogues viz. N-alkyl with C1-substituent (4-phenylbutyl), N-substituted 1-deoxynojirimycin and its congener δ-lactam, and a 4-phenylbutyl-ß-C-glycoside were designed and synthesized for immunological studies. The resulting diverse compound library exhibited proliferation of B Cells and T cells induced by LPS and Con A, respectively. The majority of the analogues augmented the secretion of IL-12 in dendritic cells and TNF-α secretion in murine peritoneal macrophages compared to LPS (10 µg/ml). A deoxynojirimycin-triazole conjugate of phytosphingosine analogue was superior in the responses mentioned above and exhibited nitric oxide response equal to LPS. In comparison to findings on its congeners with immunosuppressive action, early immunological tests show that the novel nojirimycin analogues have immunopotentiating effect. Hence, nojirimycin analogues offer tremendous potential in tuning the immunomodulatory activity of iminosugars by subtle to substantial structural variations.

A novel aureothin diepoxide derivative from Streptomyces sp. NIIST-D31 strain.

A novel vicinal diepoxide of alloaureothin was isolated from Streptomyces sp. NIIST-D31 strain along with three carboxamides, p-aminobenzoic acid and 1,6-dimethoxyphenazine. Exhaustive 2D NMR analysis and analysis of experimental, theoretical CD spectra aided in establishing the structure of compound 1. Compound 1 inhibits adipogenesis and accumulation of lipid droplets during the differentiation of 3T3-L1 cells.

Augmented Efficacy of Uttroside B over Sorafenib in a Murine Model of Human Hepatocellular Carcinoma.

We previously reported the remarkable potency of uttroside B (Utt-B), saponin-isolated and characterized in our lab from Solanum nigrum Linn, against HCC. Recently, the U.S. FDA approved Utt-B as an 'orphan drug' against HCC. The current study validates the superior anti-HCC efficacy of Utt-B over sorafenib, the first-line treatment option against HCC. The therapeutic efficacies of Utt-B vs. sorafenib against HCC were compared in vitro, using various liver cancer cell lines and in vivo, utilizing NOD.CB17-Prkdcscid/J mice bearing human HCC xenografts. Our data indicate that Utt-B holds an augmented anti-HCC efficacy over sorafenib. Our previous report demonstrated the pharmacological safety of Utt-B in Chang Liver, the normal immortalized hepatocytes, and in the acute and chronic toxicity murine models even at elevated Utt-B concentrations. Here, we show that higher concentrations of sorafenib induce severe toxicity, in Chang Liver, as well as in acute and chronic in vivo models, indicating that, apart from the superior therapeutic benefit over sorafenib, Utt-B is a pharmacologically safer molecule, and the drug-induced undesirable effects can, thus, be substantially alleviated in the context of HCC chemotherapy. Clinical studies in HCC patients utilizing Utt-B, is a contiguous key step to promote this drug to the clinic.

Tandem Photoisomerization and Transannular Cyclizations of Zerumbone Epoxide: A Model for Diversity-Oriented Synthesis Using Abundant Natural Products.

Photoirradiation of (6E,9E)-zerumbone-2,3-epoxide afforded a diverse range of transannular cyclized products in the presence of a catalytic amount of Sc(OTf)3. At the behest of the geometrical isomers produced by photoirradiation, the diversity encompasses an unprecedented eudesmane core and oxo-bridged hydroxy-olefin skeletons. Structure elucidation and the stereochemical outcome of the products are described via extensive NMR analysis. The present study serves as a model for tandem photoisomerization and transannular cyclization of natural products with enone/dienone functionality.