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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Author Correction: Evaluation of uttroside B, a saponin from Solanum nigrum Linn, as a promising chemotherapeutic agent against hepatocellular carcinoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Putative Biomimetic Route to 8-Oxabicyclo[3.2.1]octane Motif from a Humulene Sesquiterpenoid Zerumbone.

An approach to expand the diversity of terpenes to novel polycyclic skeletons with contiguous stereogenic centers is described. An unprecedented 8-oxabicyclo[3.2.1]octane motif was obtained in quantitative yield by photoirradiation of zerumbone in the presence of a catalytic amount of Lewis acid. The vital role of light in the isomerization of double bonds in zerumbone, which ensued cyclization via tertiary carbocation intermediate, emulates a biosynthetic route. Synthetic diversification of the phototransformed product afforded epoxy derivatives with up to seven contiguous stereogenic centers and eight-member ring fused tricyclic motifs. The present work sheds light on the possible role of UV irradiation in the biosynthesis of oxo-bridged tricyclic structures from polyene terpenes.

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.

New 1,2-Dihydropyridine-Based Fluorophores and Their Applications as Fluorescent Probes.

New 1,2-dihydropyridine (1,2-DHP)-based fluorophores 1a-1h were designed and synthesized by a one-pot four-component condensation reaction using dienaminodioate, aldehydes, and an in situ-generated hydrazone mediated by trifluoroacetic acid. The photophysical properties of 1,2-DHPs were studied in detail, and a few of them exhibited selective mitochondrial staining ability in HeLa cell lines (cervical cancer cells). A detailed photophysical investigation led to the design of 1,2-DHP 1h as an optimal fluorophore suitable for its potential application as a small molecule probe in the aqueous medium. Also, 1,2-DHP 1h exhibited sixfold enhanced emission intensity than its phosphorylated analogue 1h' in the long wavelength region (λem ≈ 600 nm), which makes 1,2-DHP 1h' meet the requirement as a bioprobe for protein tyrosine phosphatases, shown in L6 muscle cell lysate.

Metal-Free Diaryl Etherification of Tertiary Amines by Ortho-C(sp2)-H Functionalization for Synthesis of Dibenzoxazepines and -ones.

A phenyliodine(III) diacetate mediated umpolung reactivity of the tertiary amines with suitably substituted o-hydroxybenzyl and phenyl groups is exploited to facilitate o-C(sp2)-H functionalization to afford diaryl ethers. The presence of an o-CHO and secondary amine functionalities in the resulting diaryl ether, generated in situ, were utilized for synthesis of dibenzoxazepines and dibenzoxazepinones. Mild conditions and relative broad substrate scope, and potential for further diversification of the diaryl ethers are highlights of this methodology.

Metal-Free Multiple Carbon-Carbon and Carbon-Hydrogen Bond Activations via Charge-Switching Mechanism in Unstrained Diindolylmethanes.

A transformation of the unstrained phenol substituted 3,3'-diindolylmethanes (DIPMs) to 2,3'-diindolylketones (DIKs) by double C-C single bond cleavage with associated rearrangements, triggered by phenyliodine(III) diacetate (PIDA), is reported. Density functional theory studies reveal a mechanism involving multiple "charge-switching" steps by synergistic involvement of the two indole units with overall low activation energy. The indole 'charge-switching' mechanism in DIPMs was further extended toward synthesis of a natural product motif cyclohepta[b]indole from biaryl appended DIBM.

First report on isolation of 2,3,4-trihydroxy-5-methylacetophenone from palmyra palm (Borassus flabellifer Linn.) syrup, its antioxidant and antimicrobial properties.

The first report on isolation and characterization of 2,3,4-trihydroxy-5-methylacetophenone (1), nicotinamide (2), and uracil (3) from palmyra palm syrup is described. Total phenolic content (TPC) and Total flavonoid content (TFC) of palm syrup were 244.70±5.77(mggallic acid/kg of syrup) and 658.45±27.86(mg quercetin/kg of syrup), respectively. Compound 1 exhibited DPPH radical scavenging activity with an IC50 value of 20.02±0.14µM which was better than ascorbic acid (IC50=22.59±0.30µM). Compound 1 also showed broad spectrum antibacterial activity against Escherichia coli, Mycobacterium smegmatis, Staphylococcus aureus and Staphylococcus simulans.