Nitroso-azomethine(ene) reaction enabled annulations of nitrosoarenes, azomethines and alkenes.

An unprecedented example of a nitroso-azomethine(ene) reaction is reported. Nitroso-azomethine(ene) reaction-mediated unprecedented annulation of nitrosoarenes, azomethines, and alkenes to furnish arylquinolines via arene functionalization of nitrosoarene has been developed. DFT studies provided mechanistic insights into the newly developed nitroso-azomethine(ene) reaction.

Iminium and azonium-activated metal and oxidant-free C-H functionalization of aliphatic amines.

A wide variety of synthetic methods have been developed for the synthesis of functionalized aliphatic amines because of their broad utility in both synthetic and medicinal chemistry. The synthesis of functionalized aliphatic amines via direct C-H functionalization of readily available aliphatic amines, the majority of which rely on the use of metallic reagents/catalysts and hazardous oxidants, is advantageous in comparison to the classical multistep approaches. However, the scope to carry out such direct C-H functionalization of aliphatic amines under metal and oxidant-free conditions is being continuously explored. As a result, the examples of C-H functionalization of aliphatic amines employing iminium/azonium ions, which are formed via classical condensation of amines and carbonyl/nitroso compounds, are on the rise. This article summarizes the recent developments in the iminium and azonium-activated metal and oxidant-free C-H functionalization of aliphatic amines with the main focus on the intermolecular reactions of iminium/azonium ions, enamines, and zwitterions with suitable nucleophiles, electrophiles and dipolarophiles.

Oxidation of biological molecules with age and induced oxidative stress in different growth phases of Saccharomyces cerevisiae.

One of the mechanistic approaches for explaining ageing is the oxidative stress theory of ageing. Saccharomyces cerevisiae has been used as a model to study ageing due to many factors. We have attempted to investigate if the differential ability to withstand oxidative stress can be correlated with their lifespans. In all the four strains studied (AP22, 699, 8C, and SP4), there was no age-associated increases in lipid peroxidation levels measured as thiobarbituric acid reactive substances (TBARS). Under induced oxidative stress conditions, there was an increased TBARS level in both the ages assessed with a quantum-fold increase in the stationary phase cells of AP22. In contrast, the late stationary phase cells of 8C exhibited the least susceptibility to induced oxidative stress. The level of TBARS in both exponential and late stationary phase cells of 699 was overall more than that in the other three strains. Protein carbonylation increased with age in 8C and 699. Induced stress increased carbonylation in the exponential cells of SP4 and 699 and the stationary phase cells of all four strains. Protein carbonylation data indicate that the AP22 cells exhibit decreased protein carbonylation vis-à-vis the other strains. Induced stress data showed that while the exponential cells of 699 are susceptible, the late stationary phase cells of 699 are most resistant. Western blotting analysis using anti-HNE antibodies showed two proteins of molecular mass ~ 56 and ~ 84 kDa that were selectively modified with age in all the strains. Under induced stress conditions, an additional protein of ~ 69 kDa was oxidized. Our investigation shows that the difference in lifespan between the four strains of S. cerevisiae may be regulated by oxidative stress. Knowledge of the identity of the oxidized proteins will significantly facilitate a better understanding of the effect of oxidative stress conditions on the cells of S. cerevisiae.

Ring Opening of Pyrrolinium Ions Enabled Regioselective Synthesis of 4-Alkyl N-Arylpyrazoles.

An unprecedented method for the regioselective synthesis of 1,3-diaryl 4-alkyl pyrazoles has been reported. A wide variety of 1,3-diaryl 4-alkyl pyrazoles were synthesized as a single regioisomer via a ring-opening cyclization reaction of unsaturated pyrrolinium ions in the presence of arylhydrazines. This method avoids using additional alkylation steps and hazardous oxidants that generally are essential for the synthesis of 4-alkyl N-arylpyrazoles.

Proline selective labeling via on-site construction of naphthoxazole (NapOx).

Chemoselective construction of naphthoxazoles (NapOx) via a three-component annulation reaction enables proline selective labeling of peptides in solution or in solid-phase synthesis. The fluorogenic peptides possess low cytotoxicity, efficient cell membrane permeability and excellent bioimaging potential for biomedical applications.

Computational Investigation of Multifaceted Cationic Rearrangement and Stereo- and Regioselectivity in the Formation of Dysideanone's Analogues.

Mechanistic studies of regiodivergent arylations of cycloalkanols to furnish enantioenriched dysideanone's analogues are performed by employing density functional theory (DFT) calculations (B3LYP-D3(SMD)/6-311++G**//B3LYP-D3/6-31+G** level of theory). On the basis of our calculations, remote γ'-C-H arylation is preferred for unsubstituted carbinol 1, an outcome from combined factors like carbocationic stability, less steric hindrance during C-C coupling, and facile dearomatization. Meanwhile, in the presence of dimethyl substituent 1Me, regioselective γ-arylation is favored by 3.4 kcal/mol, and both findings are in agreement with the reported experimental observations. Most importantly, we concur that the barrier associated with the formation of carbocation 6 and its substituted analogues correlates with the C-H arylation outcomes. Furthermore, the ß-arylation route remains unlikely for all the reaction pathways explored in this study.

Lewis acid catalyzed reactivity switch: pseudo three-component annulation of nitrosoarenes and (epoxy)styrenes.

A Lewis acid catalyzed annulation reaction via arene functionalization of nitrosoarenes and C-C cleavage of (epoxy)styrene to provide arylquinolines is reported. The Lewis acid catalyst altered the annulation pattern providing arylquinolines instead of oxazolidines. The reaction with styrene resulted in a mixture of 2,4-diarylquinoline and 4-arylquinoline, while only 3-arylquinoline was formed from the reaction of epoxystyrene.

Diastereoselective and Reversed Regioselective Annulations of N-Alkyl Anilines to Julolidines and Lilolidines.

A three-component annulation reaction of N-alkyl anilines, cyclic 1,3-dicarbonyl compounds, and aryl aldehydes to julolidines and lilolidines is reported. The 6π-electrocyclization enabled the annulation to proceed with reversed regioselectivity as compared with the annulation that occurs in the Povarov reaction. Both cyclic and acyclic N-alkyl anilines participated in the reaction to provide a wide range of julolidines and lilolidines as the single regio- and diastereoisomers in good to excellent yields.

Protein extraction from Saccharomyces cerevisiae at different growth phases.

Saccharomyces cerevisiae is an established model organism with a well characterized genome. However, this model presents a unique problem due to a very resistant cell wall which develops in the late stationary phase resulting in sub-optimal extraction of proteins from such cells using majority of the cell lysis protocols. In this study, several methods from the literature with modifications thereof for lysis of S. cerevisiae cells were analyzed for their suitability for redox proteomics and biological activity studies of both exponential and late stationary phase cultures. The protocols applied are glass bead lysis, sonication, their combinations, alkali extraction, hot-SDS extraction methods and their modifications. The glass bead lysis method showed low yield but could be convenient in cases where in vitro processing steps post extraction is required or if only hydrophilic proteins are of interest. Hot-SDS and alkali extraction protocols yielded higher amount of proteins and these methods are potentially suitable for Western blotting and redox proteomic studies but allow no post-processing treatment(s) on the extracts which may be required for aging- and oxidative stress-related or other studies.

Acid mediated coupling of aliphatic amines and nitrosoarenes to indoles.

Traditionally, amines react with nitrosoarenes to provide the corresponding imines or azo compounds. Herein, we report an acid mediated annulation reaction of aliphatic amines and nitrosoarenes to provide indole derivatives. The elusive direct annulation of aliphatic amines and nitrosoarenes via simultaneous C-C and C-N bond formation was achieved under metal free conditions. This conceptually novel method for indole synthesis does not require pre-functionalization steps for the new C-C and C-N bond formation. The method has been applied for an elegant synthesis of nor-neocryptolepine and neocryptolepine.

Role of Catalase in Oxidative Stress- and Age-Associated Degenerative Diseases.

Reactive species produced in the cell during normal cellular metabolism can chemically react with cellular biomolecules such as nucleic acids, proteins, and lipids, thereby causing their oxidative modifications leading to alterations in their compositions and potential damage to their cellular activities. Fortunately, cells have evolved several antioxidant defense mechanisms (as metabolites, vitamins, and enzymes) to neutralize or mitigate the harmful effect of reactive species and/or their byproducts. Any perturbation in the balance in the level of antioxidants and the reactive species results in a physiological condition called "oxidative stress." A catalase is one of the crucial antioxidant enzymes that mitigates oxidative stress to a considerable extent by destroying cellular hydrogen peroxide to produce water and oxygen. Deficiency or malfunction of catalase is postulated to be related to the pathogenesis of many age-associated degenerative diseases like diabetes mellitus, hypertension, anemia, vitiligo, Alzheimer's disease, Parkinson's disease, bipolar disorder, cancer, and schizophrenia. Therefore, efforts are being undertaken in many laboratories to explore its use as a potential drug for the treatment of such diseases. This paper describes the direct and indirect involvement of deficiency and/or modification of catalase in the pathogenesis of some important diseases such as diabetes mellitus, Alzheimer's disease, Parkinson's disease, vitiligo, and acatalasemia. Details on the efforts exploring the potential treatment of these diseases using a catalase as a protein therapeutic agent have also been described.

Metal free biomimetic deaminative direct C-C coupling of unprotected primary amines with active methylene compounds.

An unprecedented direct C-C coupling reaction of unprotected primary amines with active methylene compounds is reported. The reaction involves a biomimetic deamination of amines which was achieved under conditions free of metallic reagents and strong oxidizing agents. A wide range of primary amines was reacted with different active methylene compounds to provide structurally diverse trisubstituted alkenes and dihydropyridines. A kinetic study revealed an activation barrier of 10.1 kcal mol-1 for the conversion of a key intermediate of the reaction.

Regio- and Enantioselective (Het)arylation of ß-Alkenyl Pyrroline to α-Aryl-ß-alkenyl Pyrrolidines.

Regio- and enantioselective direct arylation of ß-alkenyl pyrroline is reported. A wide range of electron-rich arenes and heteroarenes reacted under mild conditions with different ß-alkenyl pyrrolines to provide structurally diverse α-aryl-ß-alkenyl pyrrolidines with very good yields and excellent regioselectivity. Enantioselective reaction in the presence of Lewis acids and chiral phosphoric acids provided the desired arylated product with 73% enantiomeric excess.

Direct (het)arylation of tetrahydroisoquinolines via a metal and oxidant free C(sp3)-H functionalization enabled three component reaction.

An unprecedented method for the direct arylation and heteroarylation of tetrahydroisoquinolines under metal and oxidant free conditions is reported. The arylation reactions occurred via a C(sp3)-H functionalization enabled three component condensation of tetrahydroisoquinolines, 9-fluorenone imine, and arenes without involving a pre-functionalization/pre-derivatization step. A wide range of arenes and heteroarenes participated in the reaction to provide structurally diverse arylated tetrahydroisoquinolines with good to excellent yields.

Metal free direct C(sp2)-H arylaminations using nitrosoarenes to 2-hydroxy-di(het)aryl amines as multifunctional Aß-aggregation modulators.

An unprecedented metal free arylamination reaction involving nitrosoarenes as the electrophilic aminating agents is reported. The direct arylamination of a broad range of substrates, such as naphthols, hydroxyquinolines, hydroxyquinones, coumarins and 1,3-cyclohexadienones was achieved under operationally simple and mild conditions without the aid of additional reagents/steps for N-O bond reduction. Interestingly, novel 2-hydroxydiaryl amines were found to act as Aß-aggregation inhibitors.

Nature-inspired development of unnatural meroterpenoids as the non-toxic anti-colon cancer agents.

Structural analogues of anti-cancer natural product, dysideanone, were synthesized starting from Wieland-Miescher ketone derivative. In vitro studies have been conducted to evaluate the anti-cancer potential of these unnatural meroterpenoids against colon cancer. Synthesized carbotetracycles were found to be more active as compared to their acyclic carbinol-derivatives. Unnatural carbotetracycles 4b-e, 4h, 4i and 12 were found to be highly effective against the human colon adenocarcinoma cells with IC50 concentrations of 7.5-20 µM. In this series, the carbotetracyclic catechol 4e (IC50 = 7.5 µM) and quinone 12 (IC50 = 8 µM) were found to be the most potent compounds having the IC50 of less than 10 µM with no cytotoxic effect on the normal cells. Downregulation of Cox-2 and survivin and cell cycle arrest eventually leading to apoptosis were found to be the underlying mechanism of the anti-cancer effect of these unnatural meroterpenoids.

Metal Free C-H Functionalization Enabled Diastereoselective Multicomponent Reaction of N-Heterocycles to Fused Heteropolycycles.

A novel C-H functionalization enabled multicomponent reaction involving N-heterocycles, dinucleophile, and dipolarophile has been developed. Direct α- and more challenging ß-C(sp3)-H functionalization of aliphatic N-heterocycles was achieved without the use of metallic reagents and oxidants under either conventional or microwave aided heating conditions. In a single operation, up to five carbon-carbon and carbon-heteroatom bonds are formed in a highly diastereoselective manner, providing the expeditious access to the complex heteropolycycles.

Metal-Free Thermal Activation of Molecular Oxygen Enabled Direct α-CH2-Oxygenation of Free Amines.

Direct oxidation of α-CH2 group of free amines is hard to achieve due to the higher reactivity of amine moiety. Therefore, oxidation of amines involves the use of sophisticated metallic reagents/catalyst in the presence or absence of hazardous oxidants under sensitive reaction conditions. A novel method for direct C-H oxygenation of aliphatic amines through a metal-free activation of molecular oxygen has been developed. Both activated and unactivated free amines were oxygenated efficiently to provide a wide variety of amides (primary, secondary) and lactams under operationally simple conditions without the aid of metallic reagents and toxic oxidants. The method has been applied to the synthesis of highly functionalized amide-containing medicinal drugs, such as O-Me-alibendol and -buclosamide.

Regiodivergent Remote Arylation of Cycloalkanols to Dysideanone's Fused Carbotetracycles and Its Bridged Isomers.

Regiodivergent γ and γ' arylations across an all-carbon quaternary center of cycloalkanols to access enantioenriched fused and bridged carbotetracycles are reported. The conformation of the carbocation guided either sequential stereospecific ß-C-Me/γ-C-H-shifts or ß-C-Me/γ'-C-H-shifts, providing fused carbotetracyclic analogs of dysideanone or bridged tetracycles, respectively. The reaction is highly stereoselective in building three contiguous stereocenters, where one, two, or three could be all-carbon quaternary centers. Interestingly, mechanistic studies revealed a crucial role of a methyl substituent in controlling regioselectivity.