Metal-Free Visible-Light Catalytic Deoxygenation of Azaaryl N-Oxides: Harnessing Photons for Efficient Greener Synthesis.

Regio- and chemo-selective functionalization of electron deficient azaarenes often required their transformations to corresponding N-oxides and subsequent removal of oxygen after functionalization to get back the desired substituted azaarenes. An efficient metal-free visible-light photo-redox catalytic deoxygenation of N-oxides of azaheterocyclic compounds has been developed using acridinium based organo-photocatalyst in blue LED light. High efficiency and mildness of this methodology has been demonstrated through higher deoxygenation yield of wide variety of azaheterocyclic N-oxides with reactive functional groups. Robustness of the photocatalytic reduction has been demonstrated through easy scaling-up of the reaction to gram level without much change in the reaction yield.

Organelle-Targeted Fluorescent Probes for Sulfane Sulfur Species.

Sulfane sulfurs, which include hydropersulfides (RSSH), hydrogen polysulfides (H2Sn, n > 1), and polysulfides (RSnR, n > 2), play important roles in cellular redox biology and are closely linked to hydrogen sulfide (H2S) signaling. While most studies on sulfane sulfur detection have focused on sulfane sulfurs in the whole cell, increasing the recognition of the effects of reactive sulfur species on the functions of various subcellular organelles has emerged. This has driven a need for organelle-targeted detection methods. However, the detection of sulfane sulfurs, particularly of RSSH and H2Sn, in biological systems is still a challenge due to their low endogenous concentrations and instabilities. In this review, we summarize the development and design of organelle-targeted fluorescent sulfane sulfur probes, examine their organelle-targeting strategies and choices of fluorophores (e.g., ratiometric, near-infrared, etc.), and discuss their mechanisms and ability to detect endogenous and exogenous sulfane sulfur species. We also present the advantages and limitations of the probes and propose directions for future work on this topic.

Single-Component Photo-Responsive Template for the Controlled Release of NO and H2S2.

Redox signaling molecules include a number of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS). These molecules work collectively in the regulation of many physiological processes. Understanding the crosstalk mechanisms in these signaling molecules is important but challenging. The development of donor compounds of ROS/RNS/RSS will aid the advances in this field. While many donors that can release one ROS/RNS/RSS have been developed, dual donors that can release two signaling species and facilitate their crosstalk studies are still very rare. Those limited examples lack the ability to precisely control the timing of two releases. In this work, a 2-methoxy-6-naphthacyl-derived tertiary SNO compound, Naph-SNO, was designed and evaluated as the dual donor for NO and H2S2. The 2-methoxy-6-naphthacyl structure was demonstrated to be a novel photoremovable protecting group that could directly uncage C-S bonds. Under the irradiation of lights with different wavelengths (visible or UV), Naph-SNO could release NO and H2S2 in a stepwise manner, or simultaneously (i.e., likely producing the crosstalk product HSNO/HSSNO). In addition, the release of payloads from the donor also produced an end product with blue fluorescence. Therefore, the release process could be easily monitored in "real time." This controllable photo-triggered release strategy has the potential to be used in the design of other RNS/RSS dual donors.

Cu(II)-Based Coordination Polymer as a Pristine Form Usable Electrocatalyst for Oxygen Reduction Reaction: Experimental Evaluation and Theoretical Insights into Biomimetic Mechanistic Aspects.

As the postsynthesis-processed metal-organic material-based catalysts for energy applications add additional cost to the whole process, the importance of developing synthesized usable pristine catalysts is quite evident. The present work reports a new Cu-based coordination polymer (Cu-CP) catalyst to be used in its pristine form for oxygen reduction reaction (ORR) application. The catalyst was characterized using single-crystal X-ray diffraction, field emission scanning electron microscopy, and X-ray photoemission spectroscopy. The Cu-CP exhibits admirable electrocatalytic ORR activity with an onset potential of 0.84 V versus RHE and a half wave potential of 0.69 V versus RHE. As revealed by the density functional theory-based computational mechanistic investigation of the electrocatalytic ORR process, the electrochemically reduced Cu(I) center binds to the molecular O2 through an exergonic process (ΔG = -6.8 kcal/mol) and generates the Cu(II)-O2•- superoxo intermediate. Such superoxo intermediates are frequently encountered in the catalytic cycle of the Cu-containing metalloenzymes in their O2 reduction reaction. This intermediate undergoes coupled proton and electron transfer processes to give OH- in an alkaline medium involving H2O2 as the intermediate. The electrocatalytic performance of Cu-CP remained stable even up to 3000 cycles. Overall, the newly developed Cu-CP-based electrocatalyst holds promising potential for efficient biomimetic ORR reactivity, which opens new possibilities toward the development of robust coordination polymer-based electrocatalysts.

NIR-Responsive Lysosomotropic Phototrigger: An "AIE + ESIPT" Active Naphthalene-Based Single-Component Photoresponsive Nanocarrier with Two-Photon Uncaging and Real-Time Monitoring Ability.

In recent times, organelle-targeted drug delivery systems have gained tremendous attention due to the site-specific delivery of active drug molecules, resulting in enhanced bioefficacy. In this context, a phototriggered drug delivery system (DDS) for releasing an active molecule is superior, as it provides spatial and temporal control over the release. So far, a near-infrared (NIR) light-responsive organelle-targeted DDS has not yet been developed. Hence, we introduced a two-photon NIR light-responsive lysosome-targeted "AIE + ESIPT" active single-component DDS based on the naphthalene chromophore. The two-photon absorption cross section of our DDS is 142 GM at 850 nm. The DDS was converted into pure organic nanoparticles for biological applications. Our nano-DDS is capable of selective targeting, AIE luminogenic imaging, and drug release within the lysosome. In vitro studies using cancerous cell lines showed that our single-component photoresponsive nanocarrier exhibited enhanced cytotoxicity and real-time monitoring ability of drug release.

A Carbohydrate-based Synthetic Approach to Diverse Structurally and Stereochemically Complex Chiral Polyheterocycles.

Chiral polyheterocycles are one of the most frequently encountered scaffolds in natural products and in current drugs repertoire. A carbohydrate-based diversity oriented synthetic (DOS) approach has been employed for gaining access to many structurally diverse and stereochemically complex rigid polyheterocyclic molecules with multiple chiral hydroxyl groups to enhance aqueous solubility. Inexpensive chiral pool of D-Glucose has been judiciously exploited to get access of complex chiral polyheterocyclic structures using inexpensive, common achiral reagents and domino-Knoevenagel hetero-Diels-Alder (DKHDA) reaction as one of the key synthetic tools. Stereochemistry of newly generated stereocenters of polycyclic structures are unambiguously determined through NMR and X-ray crystallographic study. A chemoinformatic comparison (PCA and PMI) with 40 branded blockbuster drugs showed that newly generated polyheterocycles have good three-dimensional scaffold diversity and most of these pass the Lipinski filter of drug-likeness.

Ground-State Proton-Transfer (GSPT)-Assisted Enhanced Two-Photon Uncaging from a Binol-based AIE-Fluorogenic Phototrigger.

We demonstrated for the first time without any chemical modification the two-photon absorption (TPA) cross-section can be enhanced and red-shifted to the near-infrared (NIR) region by the ground-state proton-transfer (GSPT) process. Using GSPT, we developed a simple binol-based aggregation-induced emission (AIE)-fluorogenic phototrigger having a large two-photon uncaging cross-section in the "phototherapeutic window". As a proof of concept, we showed our phototrigger for the release of two different anticancer drugs in the NIR region.

Targeting the Trypanothione Reductase of Tissue-Residing Leishmania in Hosts' Reticuloendothelial System: A Flexible Water-Soluble Ferrocenylquinoline-Based Preclinical Drug Candidate.

Since inception, the magic bullets developed against leishmaniasis traveled a certain path and then dropped down due to either toxicity or the emergence of resistance. The route of administration is also an important concern. We developed a series of water-soluble ferrocenylquinoline derivatives, targeting Leishmania donovani, among which CQFC1 showed the highest efficacy even in comparison to other drugs, in use or used, both in oral and intramuscular routes. It did not induce any toxicity to splenocytes and on hematopoiesis, induced protective cytokines, and did not hamper the drug-metabolizing enzymes in hosts. It acts through the reduction and the inhibition of parasites' survival enzyme trypanothione reductase of replicating amastigotes in hosts' reticuloendothelial tissues. Unlike conventional drugs, this molecule did not induce the resistance-conferring genes in laboratory-maintained resistant L. donovani lines. Experimentally, this easily bioavailable preclinical drug candidate overcame all of the limitations causing the discontinuation of the other conventional antileishmanial drugs.

A two-photon responsive naphthyl tagged p-hydroxyphenacyl based drug delivery system: uncaging of anti-cancer drug in the phototherapeutic window with real-time monitoring.

We report a two-photon responsive drug delivery system (DDS), namely, p-hydroxyphenacyl-naphthalene-chlorambucil (pHP-Naph-Cbl), having a two-photon absorption (TPA) cross-section of ≥20 GM in the phototherapeutic window (700 nm). Our DDS exhibited both AIE and ESIPT phenomena, which were utilized for the real-time monitoring of anti-cancer drug release.

Ni(ii)-Catalyzed vinylic C-H functionalization of 2-acetamido-3-arylacrylates to access isotetronic acids.

A ligand-free Ni(ii)-catalyzed cascade annulation reaction for the synthesis of 4-aryl-substituted isotetronic acids from 2-acetamido-3-arylacrylates via vinylic C-H functionalization is reported. The reaction proceeds through heteroatom guided electrophilic insertion of nickel to the vinylic double bond followed by annulation with dibromomethane. This unconventional route features cascade steps, sole product formation, multiple functional group tolerance, low cost of catalysts and reagents, and readily available starting materials. Using this method, various aryl-substituted isotetronic acids have been synthesized which are biologically relevant. The annulation of 2-acetamido-3-arylacrylates has also been assessed with 1,2-dichloroethane, which resulted in the rearranged annulated products of 5-methyl substituted isotetronic acids.

Stepwise dual stimuli triggered dual drug release by a single naphthalene based two-photon chromophore to reverse MDR for alkylating agents with dual surveillance in uncaging steps.

In this work, we depleted glutathione (GSH) by releasing SO2 with internal stimulus GSH itself, and also selectively marked the cancer cells followed by release of anticancer drug using another orthogonal stimulus i.e., two-photon (TP) NIR light by a single naphthalene based chromophore (TP absorbance 77 GM and uncaging cross-section 21 GM). We demonstrated the improved therapeutic efficacy of chlorambucil by the stepwise dual stimuli approach and dual surveillance of both the drug uncaging process in real-time using in vitro studies.

Formation or Cleavage of Rings via Sulfide-Mediated Reduction Offers Background-Free Detection of Sulfide.

A set of three highly selective probes for sulfide detection has been developed. Two novel mechanistic strategies for the detection, including (a) transformation of a pro-fluorophore into an active fluorophore and (b) destruction of a fused ring to activate a fluorophore, have been explored. The structural features of the probes including azido groups ("active" and "latent") and leaving groups (with or without being attached to the fluorophore) have been investigated. During the course of the mechanistic studies, the single-crystal structures of all the probes and the products were obtained. One of the probes proved to be superior in terms of its ability to detect sulfide in pure water via an in situ formation of a fluorophore from a nonfluorescent precursor. These cheap and easy-to-prepare probes offer practical applications of sulfide recognition in environmental water samples and in the ovaries of fruit flies. A detection and quantification method using one of these probes and analysis with a smartphone enabled nonspecialists to detect sulfide reliably.

A Minimalist Approach for Distinguishing Individual Lanthanide Ions Using Multivariate Pattern Analysis.

To discriminate among the 14 trivalent lanthanide ions, curcumin, a naturally occurring, nontoxic, off-the-shelf, commercially available compound containing a single fluorophore, was chosen as a probe in the water media at pH 6.8 and pH 8.2. By measuring the emission and absorption spectra of the probe, under the different pH conditions, and by performing linear discriminant analysis on the data, 14 Ln3+ ions were discriminated. Additionally, an easy tool for the nonspecialists was developed with easily available household substances, using a smartphone app, which added an extra advantage to this single probe. This probe possesses advantageous features in terms of low-cost and instant on-site detection of the lanthanide ions.

Protein-Based Electronic Skin Akin to Biological Tissues.

Human skin provides an interface that transduces external stimuli into electrical signals for communication with the brain. There has been considerable effort to produce soft, flexible, and stretchable electronic skin (E-skin) devices. However, common polymers cannot imitate human skin perfectly due to their poor biocompatibility, biofunctionality, and permeability to many chemicals and biomolecules. Herein, we report on highly flexible, stretchable, conformal, molecule-permeable, and skin-adhering E-skins that combine a metallic nanowire (NW) network and silk protein hydrogel. The silk protein hydrogels offer high stretchability and stability under hydration through the addition of Ca2+ ions and glycerol. The NW electrodes exhibit stable operation when subjected to large deformations and hydration. Meanwhile, the hydrogel window provides water and biomolecules to the electrodes (communication between the environment and the electrode). These favorable characteristics allow the E-skin to be capable of sensing strain, electrochemical, and electrophysiological signals.

A Curious Case of Ankylosing Spondylosis and Motor Neuron Disease: A Mere Coincidence or Correlation?

Ankylosing spondylitis (AS) is a chronic (progressive) painful inflammatory rheumatic disease with genetic predisposition. Genetic susceptibility and common expression cause susceptibility to other inflammatory diseases such as psoriasis, ulcerative colitis, and Crohn's disease. However, cases of motor neuron disease (MND) in patients of biologically treated patients of AS have been rarely reported. AS does not follow the same course in everyone; even among affected members of one family, the outcome varies. Here, we present a case of an unusual AS without expression of human leukocyte antigen-B27 genetic marker who subsequently develops amyotrophic lateral sclerosis the most common form of MND. This mere correlation of one noncurable disease with one potentially treatable chronic rheumatological condition adds our knowledge to existing literature.

Ground state charge transfer complex formation of some metalloporphyrins with aromatic solvents: Further theoretical and experimental investigations.

In our earlier work (Chem. Phys. Letts. 592 (2014) 149-154), a new broad band was observed in the near infrared region (700-900nm) of the steady state absorption spectra of some metalloporphyrins (zinc tetraphenylporphyrin, zinc octaethylporphyrin and magnesium octaethylporphyrin) in aromatic solvents (chlorobenzene, 1,2-dichlorobenzene, benzonitrile, benzene and toluene) at high concentrations (~10-4molL-1). The band was ascribed to be due to ground state charge transfer complexation between solute and solvent molecules. In the present work, density functional theory calculations are carried out to study the possibility of such ground state charge transfer complex formation between zinc tetraphenylporphyrin and four aromatic solvents viz., benzene, toluene, chlorobenzene and benzonitrile with 1:1 and 2:1 solvent-solute stoichiometries. Also, we determined the association constants for the ground state charge transfer complex formation of zinc tetraphenylporphyrin and zinc octaethylporphyrin with two aromatic solvents (benzene and benzonitrile) by Benesi-Hildebrand method.

Humidity sensing using THz metamaterial with silk protein fibroin.

In this study, we developed hybrid humidity sensing methods by incorporating silk fibroin protein onto metamaterials, operating in the terahertz (THz) frequencies; the resonant frequency shifted but saturated at a specific thickness due to the limited sensing volume of the metamaterial. From the saturated value, we extracted the dielectric constant for the silk films. We also observed additional resonance shifts when we applied humid air to silk-coated metamaterials, due to the increased water molecule numbers on the film. Frequency shifts depend linearly on relative humidity. Also, in situ THz spectroscopy measurements reveal that the time response is instantaneous within our detection limit, especially upon exposure to humid air, whereas the small slowly decaying component appeared when we applied dry air. The time taken by the slow component in the drying process was 10-50 s, depending on film thickness. This could optimize humidity sensors as a fast and efficient detection tool to measure air humidity.

Hydrazine functionalized probes for chromogenic and fluorescent ratiometric sensing of pH and F-: experimental and DFT studies.

Two novel hydrazine based sensors, BPPIH (N1,N3-bis(perfluorophenyl)isophthalohydrazide) and BPBIH (N1',N3'-bis(perfluorobenzylidene)isophthalohydrazide), are presented here. BPPIH is found to be a highly sensitive pH sensor in the pH range 5.0 to 10.0 in a DMSO-water solvent mixture with a pKa value of 9.22. Interesting optical responses have been observed for BPPIH in the above mentioned pH range. BPBIH on the other hand turns out to be a less effective pH sensor in the above mentioned pH range. The increase in fluorescence intensity at a lower pH for BPPIH was explained by using density functional theory. The ability of BPPIH to monitor the pH changes inside cancer cells is a useful application of the sensor as a functional material. In addition fluoride (F-) selectivity studies of these two chemosensors have been performed and show that between them, BPBIH shows greater selectivity towards F-. The interaction energy calculated from the DFT-D3 supports the experimental findings. The pH sensor (BPPIH) can be further interfaced with suitable circuitry interfaced with desired programming for ease of access and enhancement of practical applications.

Highly Selective Sub-ppm Naked-Eye Detection of Hydrazine with Conjugated-1,3-Diketo Probes: Imaging Hydrazine in Drosophila Larvae.

A pair of pyrene- and anthracene-based turn-on fluorescent probes (1 and 2, respectively) reported here can be easily synthesized in a single-step process and also exhibit outstanding sensing behavior toward hydrazine over various competing nucleophilic species and environmentally relevant ions. The probes display dramatic enhancements in the emission intensity with as high as 83- and 173-fold increases in the presence of hydrazine. Nitrogenous bases, thiols, and lanthanides do not interfere in the fluorometric detection. These probes enable the detection of hydrazine with the naked eye well below sub-ppm concentrations (ca. 30 ppb) with analytical detection limits of 5.4 ppb for 1 and 7.7 ppb for 2, which are far exceeded by the accepted lower limit for hydrazine (10 ppb) set by the US EPA. Simple paper strips based on these probes could be used for the detection of hydrazine even in the gas phase. Both of the probes could selectively detect hydrazine even in pond water samples efficiently. The probes were successfully applied to visualize, for the first time, accumulation of hydrazine in live fruit-fly larvae using epifluorescence microscopy. The novel and interesting detection mechanism, proposed on the basis of spectroscopic evidence and single crystal XRD results, indicates that the detection pathway proceeds via the initial step of a five-membered ring formation upon attack of the hydrazine, followed by a dehydration step for gaining aromaticity.

Potential of small-molecule fungal metabolites in antiviral chemotherapy.

Various viral diseases, such as acquired immunodeficiency syndrome, influenza, and hepatitis, have emerged as leading causes of human death worldwide. Scientific endeavor since invention of DNA-dependent RNA polymerase of pox virus in 1967 resulted in better understanding of virus replication and development of various novel therapeutic strategies. Despite considerable advancement in every facet of drug discovery process, development of commercially viable, safe, and effective drugs for these viruses still remains a big challenge. Decades of intense research yielded a handful of natural and synthetic therapeutic options. But emergence of new viruses and drug-resistant viral strains had made new drug development process a never-ending battle. Small-molecule fungal metabolites due to their vast diversity, stereochemical complexity, and preapproved biocompatibility always remain an attractive source for new drug discovery. Though, exploration of therapeutic importance of fungal metabolites has started early with discovery of penicillin, recent prediction asserted that only a small percentage (5-10%) of fungal species have been identified and much less have been scientifically investigated. Therefore, exploration of new fungal metabolites, their bioassay, and subsequent mechanistic study bears huge importance in new drug discovery endeavors. Though no fungal metabolites so far approved for antiviral treatment, many of these exhibited high potential against various viral diseases. This review comprehensively discussed about antiviral activities of fungal metabolites of diverse origin against some important viral diseases. This also highlighted the mechanistic details of inhibition of viral replication along with structure-activity relationship of some common and important classes of fungal metabolites.