Nucleophilic Ring Opening of Donor-Acceptor Cyclopropanes through Umpolung Reactivity of Organochlorophosphines: Phosphine Oxide-Functionalized Boron-Pendanted Compounds.

We present a novel set of frustrated Lewis pair (FLP) systems that exhibit a remarkable ability to promote the ring opening of donor-acceptor cyclopropanes (DACs). This FLP-promoted protocol offers umpolung reactivity of RRPCl/CN (R, R = aryl, alkyl) toward DACs via nucleophilic ring-opening reactions to provide phosphinated boron-pendanted diester compounds. This novel approach exhibits the dual role of BF·OEt as an activator and a reactant.

Small molecule innate immune modulators in cancer therapy.

Immunotherapy has proved to be a breakthrough in cancer treatment. So far, a bulk of the approved/late-stage cancer immunotherapy are antibody-based. Although these antibody-based drugs have demonstrated great promise, a majority of them are limited due to their access to extracellular targets, lack of oral bioavailability, tumor microenvironment penetration, induction of antibody dependent cytotoxicity etc.

Metal-Free Switchable Chemo- and Regioselective Alkylation of Oxindoles Using Secondary Alcohols.

In this study, we have disclosed N-alkylation and C-alkylation reactions of 2-oxindoles with secondary alcohols. Interestingly, these chemoselective reactions are tunable by changing the reaction conditions. Utilization of protic solvent and Brønsted acid catalyst afforded C-alkylation, whereas, aprotic solvent and Lewis acid catalyst afforded N-alkylation of 2-oxindoles in good to excellent yields.

Synthetic F labeled biomolecules that are selective and promising for PET imaging: major advances and applications.

The concept of positron emission tomography (PET) based imaging was developed more than 40 years ago. It has been a widely adopted technique for detecting and staging numerous diseases in clinical settings, particularly cancer, neuro- and cardio-diseases. Here, we reviewed the evolution of PET and its advantages over other imaging modalities in clinical settings.

Synthesis of trifluoroethoxy/aryloxy cinnolines, cinnolinones and indazoles from -alkynylanilines metal-free diazotization reagent.

A facile and user-friendly protocol for the synthesis of trifluoroethoxy/aryloxy cinnolines, cinnolinones and indazoles from -alkynylaniline in good-to-excellent yields has been developed using a metal-free diazotization reagent (a combination of BF·OEt and TBN). The methodology has been further extended to construct bis-cinnolinones and for the chemoselective synthesis of -propargylated cinnolinones.

Copper-Catalyzed Chemoselective O-Arylation of Oxindoles: Access to Cyclic Aryl Carboxyimidates.

We have developed a highly efficient base- and additive-free chemoselective CuO-catalyzed strategy for the O-arylation of 2-oxindoles to synthesize 2-phenoxy-3-indole and 2-phenoxy-1-indole derivatives in the presence of diaryl iodonium salts. This method offers a variety of O-arylated oxindoles in good to excellent yields under relatively milder reaction conditions. Furthermore, this methodology was extended for the O-arylation of 2-pyridinone and isoindoline-1-one derivatives as well.

Tunable Regio- and Stereoselective Synthesis of -Acrylonitrile Indoles and 3-Cyanoquinolines from 2-Alkynylanilines and Alkynylnitriles.

The merger of two bifunctional moieties, 2-alkynylaniline and alkynylnitriles, in the presence of ZnBr offers the tunable synthesis of two biologically important motifs: acrylonitrile indoles and 3-cyanoquinolines. The group present on the terminal alkyne of 2-alkynylaniline regulates the reaction pathways, intra- versus intermolecular, which thereby adds stereoselectivity and regioselectivity in this protocol. The conversion of an acrylonitrile indole ring to quinoline is an intriguing synthetic utility of this methodology.

Synthesis of Indole-Fused Dihydrothiopyrano Scaffolds (3 + 3)-Annulations of Donor-Acceptor Cyclopropanes with Indoline-2-Thiones.

A new methodology for the synthesis of -haloindole-fused dihydrothiopyrano derivatives (3 + 3)-annulation of donor-acceptor cyclopropanes (DACs) with indoline-2-thiones in the presence of Sc(OTf) as a Lewis acid catalyst has been developed. This protocol provides a variety of indole-fused dihydrothiopyrano molecules in good to excellent yields, which architecturally resemble other indole-fused tricyclic molecules having potential medicinal value. In addition, we have described a detailed reaction mechanism and transformation of the furnished product into -fused thiazino indole molecule.

AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model.

Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) from ATP and GTP. 2'3'-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2'3'-cGAMP.

Immunomodulatory effect of mycobacterial outer membrane vesicles coated nanoparticles.

Tuberculosis (TB) is one of the most widely prevalent infectious diseases that cause significant mortality. Bacillus Calmette-Guérin (BCG), the current TB vaccine used in clinics, shows variable efficacy and has safety concerns for immunocompromised patients. There is a need to develop new and more effective TB vaccines.

Ionic Liquid-Mediated One-Pot 3-Acylimino-3-1,2-dithiole Synthesis from Thiocarboxylic Acids and Alkynylnitriles via In Situ Generation of Disulfide Intermediates.

A practical and straightforward strategy for the synthesis of 3-acylimino-3-1,2-dithiol derivatives via a metal-free annulation reaction of alkynylnitriles with thiocarboxylic acids mediated by ionic liquids [BMIM]Br has been reported. This operationally simple protocol offers an easy and rapid access to a library of dithiol derivatives in moderate to good yields. The mechanistic studies show a benzoyldithio anion addition to alkynylnitriles followed by an annulation reaction through the involvement of a disulfide moiety as the key intermediate.

A metal-free BF·OEt mediated chemoselective protocol for the synthesis of propargylic cyclic imines.

A chemoselective and metal/additive-free protocol for the synthesis of propargylic cyclic imine derivatives (3 + 2)-cycloaddition of donor-acceptor cyclopropanes and alkynylnitriles in the presence of BF·OEt has been established. The newly developed methodology provided access to a variety of propargylic cyclic imines in good to excellent yields. In addition, the synthesis of propargylic amines and the corresponding very stable enol derivatives from the title compound is also explored.

Cationic inhalable particles for enhanced drug delivery to M. tuberculosis infected macrophages.

Inhalable microparticle-based drug delivery platforms are being investigated extensively for Tuberculosis (TB) treatment as they offer efficient deposition in lungs and improved pharmacokinetics of the encapsulated cargo. However, the effect of physical parameters of microcarriers on interaction with Mycobacterium tuberculosis (Mtb) infected mammalian cells is underexplored. In this study, we report that Mtb-infected macrophages are highly phagocytic and microparticle surface charge plays a major role in particle internalization by infected cells.

Leishmania survives by exporting miR-146a from infected to resident cells to subjugate inflammation.

, the causative agent of visceral leishmaniasis, infects and resides within tissue macrophage cells. It is not clear how the parasite infected cells crosstalk with the noninfected cells to regulate the infection process. During infection, adopts a dual strategy for its survival by regulating the intercellular transport of host miRNAs to restrict inflammation.

Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy.

Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes).

Transition-Metal-Free HFIP-Mediated Organo Chalcogenylation of Arenes/Indoles with Thio-/Selenocyanates.

We have developed a protocol for the synthesis of diaryl thio-/selenoethers by the reaction of aryl chalcogenocyanates with electron rich arenes/hetero arenes HFIP promoted C-H activation. The reaction produces chalcogenides in good to excellent yields under mild conditions without the need of a transition metal as a catalyst. The HFIP-mediated reactions tolerated a wide range of functional groups and set the stage for the synthesis of diversely decorated chalcogenides.

Combatting intracellular pathogens using bacteriophage delivery.

Intracellular pathogens reside in specialised compartments within the host cells restricting the access of antibiotics. Insufficient intracellular delivery of antibiotics along with several other resistance mechanisms weaken the efficacy of current therapies. An alternative to antibiotic therapy could be bacteriophage (phage) therapy.

A periodic development of BPA and BSH based derivatives in boron neutron capture therapy (BNCT).

Boron neutron capture therapy (BNCT) is a particular type of radiotherapy that requires a selective and high concentration of boron accumulation in neoplastic cells. To distinguish the distribution of boron compounds between tumour and normal cells, multiple research groups have been involved and successively innovated a wide variety of boron-based compounds. Despite the development of numerous boron compounds, only boronophenylalanine (BPA) and sodium mercaptoundecahydro-closo-dodecaborate (BSH) have emerged as effective in clinical trials.

A novel microRNA boosts hyper-β-oxidation of fatty acids in liver by impeding CEP350-mediated sequestration of PPARα and thus restricts chronic hepatitis C.

Imbalance in lipid metabolism induces steatosis in liver during Chronic hepatitis C (CHC). Contribution of microRNAs in regulating lipid homoeostasis and liver disease progression is well established using small RNA-transcriptome data. Owing to the complexity in the development of liver diseases, the existence and functional importance of yet undiscovered regulatory miRNAs in disease pathogenesis was explored in this study using the unmapped sequences of the transcriptome data of HCV-HCC liver tissues following miRDeep2.

The exosome encapsulated microRNAs as circulating diagnostic marker for hepatocellular carcinoma with low alpha-fetoprotein.

Diagnosis of hepatocellular carcinoma (HCC) remains challenging to clinicians, particularly in a patient with low alpha-fetoprotein. Here, in silico, ex vivo and in vitro data were combined to identify liver-specific exosomal miRNAs as an early diagnostic marker for HCC. Transcriptome profiling for mRNA and small RNA in same HCV-HCC and normal liver tissues followed by cross-validation of 41 deregulated miRNAs (log FoldChange > 1.

MicroRNA exporter HuR clears the internalized pathogens by promoting pro-inflammatory response in infected macrophages.

HuR is a miRNA derepressor protein that can act as miRNA sponge for specific miRNAs to negate their action on target mRNAs. Here we have identified how HuR, by inducing extracellular vesicles-mediated export of miRNAs, ensures robust derepression of miRNA-repressed cytokines essential for strong pro-inflammatory response in activated mammalian macrophages. Leishmania donovani, the causative agent of visceral leishmaniasis, on the contrary alters immune response of the host macrophage by a variety of complex mechanisms to promote anti-inflammatory response essential for the survival of the parasite.

Synthesis of 3-(2-thiopyridyl)indoles via the ruthenium catalyzed [2 + 2 + 2] cycloaddition of diynes and 3-thiocyanatoindoles.

A highly efficient protocol for the synthesis of 3-(2-thiopyridyl)indoles via the ruthenium(ii) catalyzed [2 + 2 + 2] cycloaddition reaction of α,ω-diynes with 3-thiocyanatoindoles under mild reaction conditions has been developed. A variety of 3-(2-thiopyridyl)indole derivatives were prepared by the reaction of the aforesaid substrates in the presence of a readily available chloro(pentamethylcyclopentadienyl)(cyclooctadiyne)ruthenium(ii) catalyst in ethanol with good to excellent yields. This atom economical methodology provides us efficient access to 3-(2-thiopyridyl)indole skeletons with close structural similarity to other pyridyl indole thioethers that have potential medicinal value.

Atom-Economic Route to Cyanoarenes and 2,2'-Dicyanobiarenes via Iron-Catalyzed Chemoselective [2 + 2 + 2] Cycloaddition Reactions of Diynes and Tetraynes with Alkynylnitriles.

An efficient protocol for the synthesis of cyanoarenes has been developed via an iron-catalyzed chemoselective [2 + 2 + 2] cycloaddition reaction of diynes with alkynylnitriles under mild reaction conditions with good to excellent yields. The reaction is catalyzed by the combination of FeCl·4HO as a metal source, 2-(2,6-diisopropylphenyl)iminomethylpyridine (dipimp) as a ligand, and Zn as a reducing agent in DME solvent. The protocol was further extended to the synthesis of 2,2'-dicyanobiarene skeletons from the reaction of tetraynes with alkynylnitriles.

Spatiotemporal Uncoupling of MicroRNA-Mediated Translational Repression and Target RNA Degradation Controls MicroRNP Recycling in Mammalian Cells.

MicroRNA (miRNA)-mediated repression controls expression of more than half of protein-coding genes in metazoan animals. Translation repression is associated with target mRNA degradation initiated by decapping and deadenylation of the repressed mRNAs. Earlier evidence suggests the endoplasmic reticulum (ER) as the site where microRNPs (miRNPs) interact with their targets before translation repression sets in, but the subcellular location of subsequent degradation of miRNA-repressed messages is largely unidentified.

A Metal and Base-Free Chemoselective Primary Amination of Boronic Acids Using Cyanamidyl/Arylcyanamidyl Radical as Aminating Species: Synthesis and Mechanistic Studies by Density Functional Theory.

An efficient, metal and base-free, chemoselective synthesis of aryl-, heteroaryl-, and alkyl primary amines from the corresponding boronic acids has been achieved at ambient temperature mediated by [bis(trifluoroacetoxy)iodo]benzene (PIFA) and N-bromosuccinimide (NBS) using cyanamidyl/arylcyanamidyl radicals as the aminating species. The primary amine compounds were initially obtained as their corresponding ammonium trifluoroacetate salts which, on treatment with aq NaOH, provide the free amines. Finally, the primary amines were isolated through column chromatography over silica-gel using hexane-EtOAc solvent system as the eluent.