Synthesis of O6-alkylated preQ1 derivatives

A naturally occurring riboswitch can utilize 7-aminomethyl-O6-methyl-7-deazaguanine (m6preQ1) as cofactor for methyl group transfer resulting in cytosine methylation. This recently discovered riboswitch-ribozyme activity opens new avenues for the development of RNA labeling tools based on tailored O6-alkylated preQ1 derivatives. Here, we report a robust synthesis for this class of pyrrolo[2,3-d]pyrimidines starting from readily accessible N2-pivaloyl-protected 6-chloro-7-cyano-7-deazaguanine. Substitution of the 6-chloro atom with the alcoholate of interest proceeds straightforward. The transformation of the 7-cyano substituent into the required aminomethyl group turned out to be challenging and was solved by a hydration reaction sequence on a well-soluble dimethoxytritylated precursor via in situ oxime formation. The synthetic path now provides a solid foundation to access O6-alkylated 7-aminomethyl-7-deazaguanines for the development of RNA labeling tools based on the preQ1 class-I riboswitch scaffold.

Continuous-flow hydrogenation over resin supported palladium catalyst for the synthesis of industrially relevant chemicals

Herein, the catalytic performance of palladium nanoparticles grafted on the polymeric TSNH2 (Tentagel-S-NH2) resin was investigated for continuous-flow liquid-phase hydrogenation of two industrially relevant chemicals: 2-methyl-3-butyn-2-ol and nitrocyclohexane. We investigated the effect of process parameters such as temperature and pressure on PdTSNH2 activity and selectivity. Depending on the reaction conditions, well-dispersed PdNPs with average size of about 2 nm have shown very high flexibility in terms selectivity toward the desired products: 2-methyl-3-buten-2-ol or 2-methyl-2-butanol in the case of 2-methyl-3-butyn-2-ol hydrogenation and cyclohexanone oxime or cyclohexylamine as the main product in the case of nitrocyclohexane conversion. The optimal reaction conditions for 2-methyl-3-buten-2-ol formation were estimated at 25 °C and 5 bar, and in the case of cyclohexanone oxime formation at 40 °C and 10 bar. We demonstrated the general trend in the catalytic performance of 2.2 wt% Pd grafted on Tentagel-S-NH2. Independently of the hydrogenated substrate, the increase in conversion leads to decreased selectivity to 2-methyl-3-buten-2-ol and cyclohexanone oxime at the expense of increasing the selectivity to 2-methyl-2-butanol or cyclohexylamine. Graphic abstract

Chemoenzymatic one-pot reaction from carboxylic acid to nitrile via oxime

We report a new chemoenzymatic cascade starting with aldehyde synthesis by carboxylic acid reductase (CAR) followed by chemical in situ oxime formation. The final step to the nitrile is catalyzed...

A fast and versatile cross-linking strategy via o-phthalaldehyde condensation for mechanically strengthened and functional hydrogels

Fast and catalyst-free cross-linking strategy is of great significance for construction of covalently cross-linked hydrogels. Here, we report the condensation reaction between o-phthalaldehyde (OPA) and N-nucleophiles (primary amine, hydrazide and aminooxy) for hydrogel formation for the first time. When four-arm poly(ethylene glycol) (4aPEG) capped with OPA was mixed with various N-nucleophile-terminated 4aPEG as building blocks, hydrogels were formed with superfast gelation rate, higher mechanical strength and markedly lower critical gelation concentrations, compared to benzaldehyde-based counterparts. Small molecule model reactions indicate the key to these cross-links is the fast formation of heterocycle phthalimidine product or isoindole (bis)hemiaminal intermediates, depending on the N-nucleophiles. The second-order rate constant for the formation of phthalimidine linkage (4.3 M−1 s−1) is over 3000 times and 200 times higher than those for acylhydrazone and oxime formation from benzaldehyde, respectively, and comparable to many cycloaddition click reactions. Based on the versatile OPA chemistry, various hydrogels can be readily prepared from naturally derived polysaccharides, proteins or synthetic polymers without complicated chemical modification. Moreover, biofunctionality is facilely imparted to the hydrogels by introducing amine-bearing peptides via the reaction between OPA and amino group.

Development of an analytical method for determination of carbohydrates in food by gc - fid using chemical derivatization with anhydride acetic acid

The present research describes a simple and inexpensive derivatization method that uses acetylation to address the challenges associated with the quantification of the ten most common carbohydrates. The derivatization reaction has two periods : (1) The oxime formation of carbohydrates was carried out at 15 minutes, 500 µL of NH2OH 2.5% and 60 ºC and (2) acetylation of carbohydrates was carried out at 45 minutes, 600 µL of AAA and 80ºC. Most of the carbohydrates generate single peaks via chromatographic separation, except fructose, which generates a double peak. The procedure was successfully applied to analyze carbohydrates in some samples including honey, fresh milk, and polysaccharide hydrolyzate. The method validation results had the linear concentration range of carbohydrates at 50-4000 mg/g, the LODs at 20-50 µg/g, the relative standard deviations (% RSDs) of peak area under 5.0 % and the accuracy at 95–115% of recoveries. The method was applied to determine carbohydrate content in raw milk, honey, and hydrolysis polysaccharide extract. The results showed that the honey sample has fructose and glucose content of 65.8% and 33.4%, respectively, while sucrose makes up 0.74% of the total carbohydrate content. The raw milk sample has lactose content of 47.6% of the total carbohydrates. Some rare polysaccharides such as arabinose and xylose were found in the hydrolysis polysaccharide extract from the mushroom sample.

Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle

Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known for their antitumor properties. The protoflavone B-ring is a versatile moiety that might be explored for various pharmacological purposes, but the common cytotoxicity of these compounds is a limitation to such efforts. Protoapigenone was previously found to be active against the lytic cycle of Epstein–Barr virus (EBV). Further, the 5-hydroxyflavone moiety is a known pharmacophore against HIV-integrase. The aim of this work was to prepare a series of less cytotoxic protoflavone analogs and study their antiviral activity against HIV and EBV. Twenty-seven compounds, including 18 new derivatives, were prepared from apigenin through oxidative de-aromatization and subsequent continuous-flow hydrogenation, deuteration, and/or 4′-oxime formation. One compound was active against HIV at the micromolar range, and three compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these derivatives, protoapigenone 1′-O-isopropyl ether (6) was identified as a promising lead that had a 73-times selectivity of antiviral over cytotoxic activity, which exceeds the selectivity of protoapigenone by 2.4-times. Our results open new opportunities for designing novel potent and safe anti-EBV agents that are based on the natural protoflavone moiety.

Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl Ether Shows Improved Selectivity Against the Epstein-Barr Virus Lytic Cycle

Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known of their antitumor properties. The protoflavone B-ring is a versatile moiety that may be explored for other pharmacological purposes, but common cytotoxicity of these compounds is a limitation to such efforts. Protoapigenone was previously found to be active against the lytic cycle of Epstein-Barr virus (EBV). Further, the 5-hydroxyflavone moiety is a known pharmacophore against HIV-integrase. The aim of this work was to prepare a series of less cytotoxic protoflavone analogs, and to study their antiviral activity against HIV and EBV. Twenty-seven compounds including 18 new derivatives were prepared from apigenin through oxidative de-aromatization and subsequent continuous-flow hydrogenation, deuteration, and/or 4′-oxime formation. One compound was active against HIV at the micromolar range, and 3 compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these, protoapigenone 1′-O-isopropyl ether (6) was identified as a promising lead due to its 73-times selectivity of its antiviral over its cytotoxic effect, which exceeds that of protoapigenone by 2.4-times. Our results open new opportunities to design new, potent and safe anti-EBV agents based on the natural protoflavone moiety.

Biological Evaluation of Noscapine analogues as Potent and Microtubule-Targeted Anticancer Agents

In present investigation, an attempt was undertaken to modify the C-9 position of noscapine (Nos), an opium alkaloid to yield 9 -hydroxy methyl and 9 -carbaldehyde oxime analogues for augmenting anticancer potential. The synthesis of 9-hydroxy methyl analogue of Nos was carried out by Blanc reaction and 9-carbaldehyde oxime was engineered by oxime formation method and characterized using FT-IR, 1H NMR, 13C NMR, mass spectroscopy, and so on techniques. In silico docking techniques informed that 9-hydroxy methyl and 9-carbaldehyde oxime analogues of Nos had higher binding energy score as compared to Nos. The IC50 of Nos was estimated to be 46.8 µM signficantly (P < 0.05) higher than 8.2 µM of 9-carbaldehyde oxime and 4.6 µM of 9-hydroxy methyl analogue of Nos in U87, human glioblastoma cells. Moreover, there was significant (P < 0.05) difference between the IC50 of 9-carbaldehyde oxime and 9-hydroxy methyl analogue of Nos. Consistent to in vitro cytotoxicity data, 9-hydroxy methyl analogue of Nos induced significantly (P < 0.05) higher degree of apoptosis of 84.6% in U87 cells as compared to 78.5% and 64.3% demonstrated by 9-carbaldehyde oxime and Nos, respectively. Thus the higher therapeutic efficacy of 9-hydroxy methyl analogue of Nos may be credited to higher solubility and inhibitory constant (K).