Rational design of 2-benzylsulfinyl-benzoxazoles as potent and selective indoleamine 2,3-dioxygenase 1 inhibitors to combat inflammation.

Mimicking the transition state of tryptophan (Trp) and O in the enzymatic reaction is an effective approach to design indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. In this study, we firstly assembled a small library of 2-substituted benzo-fused five membered heterocycles and found 2-sulfinyl-benzoxazoles with interesting IDO1 inhibitory activities. Next the inhibitory activity toward IDO1 was gradually improved.

Bio-orthogonally activated tetraphenylene-tetrazine aggregation-induced emission fluorogenic probes.

Tetrazine-based bio-orthogonally activated fluorogenic probes have drawn great attention due to their excellent performance in bioimaging; however, most of them suffer from aggregation-caused quenching (ACQ) problems. Herein, we developed a set of novel tetrazine-modified tetraphenylenes (TPEs) as bio-orthogonally activated aggregation-induced emission (AIE) fluorogenic probes. Both the fluorescence and AIE features are quenched by tetrazine, which is mediated by the through-bond energy-transfer (TBET) mechanism, and are activated upon converting tetrazine to pyridazine the inverse electron-demand Diels-Alder (iEDDA) reaction.

Bioorthogonally applicable multicolor fluorogenic naphthalimide-tetrazine probes with aggregation-induced emission characters.

A series of naphthalimidetetrazines were developed as bioorthogonal fluorogenic probes, which could produce significant fluorescence enhancement, notable aggregation-induced emission (AIE) characters and multicolor emissions after bioorthogonal reaction with strained dienophiles. Manipulating the π-bridge in the fluorophore skeleton allows fine-tuning of the emission wavelength and influences the AIE-active properties. With these probes, we succeeded in no-wash fluorogenic protein labeling and mitochondria-selective bioorthogonal imaging in live cells.

Developing fluoromodule-based probes for in vivo monitoring the bacterial infections and antibiotic responses.

Recently, antibiotic resistant has become a serious public health concern, which warrants new generations of antibiotics to be developed. Pharmacodynamic evaluation is crucial in drug discovery processes. Despite numerous advanced imaging systems are available nowadays, technologies for the sensitive in vivo diagnosis of bacterial infections and direct visualization of drug efficacy are yet to be developed.

Design of Nitroso-Modified Naphthylene-Based Fluorophores as Photoactivatable Bioorthogonal Turn-On Probes.

We reported a series of nitroso-modified naphthylene-based fluorophores as novel bioorthogonal fluorescence turn-on probes. The cycloadducts from nitroso-diene Diels-Alder reaction could be either photochemically or spontaneously transformed into highly fluorescent rearrangement products with remarkable photophysical properties including significant fluorescence enhancement, large Stokes shift, high fluorescence quantum yield, superior photostability, and distinct solvatochromic effect. This strategy is suitable for selective labeling of diene-modified proteins and visualizing specific organelles in live mammalian cells under no-wash conditions.

Formation and Disproportionation of Xanthenols to Xanthenes and Xanthones and Their Use in Synthesis.

A facile and versatile strategy employing TiCl-mediated cyclization followed by a Cannizzaro reaction has been developed for the synthesis of various xanthene derivatives. The reaction proceeded smoothly to afford both xanthenes/xanthones or their sulfur derivatives and tolerated a wide range of electronically diverse substrates. Using this methodology, pranoprofen was synthesized in three steps in 59% overall yield from commercially available starting materials.

Design and synthesis of analogues of the sphingosine-1-phosphate receptor 1 agonist IMMH001 with improved phosphorylation rate in human blood.

IMMH001, which is a prodrug for sphingosine-1-phosphate receptor 1 (S1P) agonist, is converted to the active form, its monophosphate ester (S)-IMMH001-P, by sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) in vivo. In this study, we designed head-piece-modified analogues of IMMH001 based on structural information and prepared them with an efficient modular synthetic strategy. The analogues showed higher phosphorylation rates in human blood than the parent compound.

Gasserian Ganglion Stimulation for Facial Pain.

Non-neuralgic trigeminal neuropathic pain can be challenging in terms of treatment as pharmacological interventions often tend to be ineffective. Within the pain-transmitting pathway, the Gasserian ganglion (GG) is a rather unique anatomical and physiological structure where the sensory (including pain) information from the entire half of the face undergoes primary processing in a very compact and clearly defined entity. Moreover, GG is positioned in a completely immobile intradural location (the Meckel's cave) and is insulated from the brain by a layer of dura.

Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates.

FTY720 and IMMH002, prodrugs for sphingosine-1-phosphate receptor 1 (S1P) agonists, show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats. In this study, FTY720 or IMMH002 analogues (-) were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms. Target compounds were synthesized a convergent route using the key and optically pure building block , which was first synthesized asymmetrically catalyzed amination.

S1P-selective agonist prodrug IMMH002 is phosphorylated in rats to form an S-configured enantiomer: Synthesis, verification, and biological activity of the in vivo active metabolite.

IMMH002 (1), a prodrug for a sphingosine-1-phosphate receptor 1 (S1P) agonist, is converted to the monophosphate ester, which has an immunomodulatory effect. Starting from prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after the chiral resolution of the key intermediate by chiral high-performance liquid chromatography and the absolute configuration was determined by circular dichroism.

A novel S1P1 modulator IMMH002 ameliorates psoriasis in multiple animal models.

Psoriasis is characterized by abnormal proliferation of keratinocytes, as well as infiltration of immune cells into the dermis and epidermis, causing itchy, scaly and erythematous plaques of skin. The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently. Here, we showed that IMMH002, a novel orally active S1P modulator, desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus.

Design, Synthesis, and Biological Evaluation of Amidobenzimidazole Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.

Stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor protein (STING receptor) that has been shown to be activated by binding to natural cyclic dinucleotide (CDN) ligands and plays a vital role in innate immune sensing of exogenous or endogenous DNA, which then induces type I interferons and other cytokines. In this paper, we described a series of amidobenzimidazole STING agonists with high potency for the STING receptor and presented the relevant structure-activity relationships (SARs). The relative potencies of compounds , , and were measured by a STING competition binding assay.

Asymmetric amination of α,α-dialkyl substituted aldehydes catalyzed by a simple chiral primary amino acid and its application to the preparation of a S1P agonist.

The chiral catalytic amination of an α,α-dialkyl substituted aldehyde usually proceeds with low enantioselectivity. We selected naphthyl-l-alanine as the catalyst and observed improved enantioselectivity for the amination. Using this method, racemic α-methyl-α-benzyloxypropanal was aminated to give chiral serine derivatives in 74% ee, which was further increased to >99% ee after recrystallization.

Sphingosine-1-Phosphate Receptor Subtype 1 (S1P1) Modulator IMMH001 Regulates Adjuvant- and Collagen-Induced Arthritis.

Sphingosine-1-phosphate receptor subtype 1 (S1P) is essential for lymphocyte egress from lymphoid organs into systemic circulation and provides a well-defined drug target for autoimmune disorders. IMMH001, also called SYL930, is a specific S1P/S1P/S1P modulator. Here, we investigated the potential therapeutic effect of IMMH001 on rheumatoid arthritis (RA).

Development of 4-oxime-1,8-naphthalimide as a bioorthogonal turn-on probe for fluorogenic protein labeling.

4-Oxime-1,8-naphthalimide was reported as a novel bioorthogonal turn-on probe based on 1,3-dipolar cycloaddition reactions between in situ generated nitrile oxide and alkenes/alkynes. The resulting isoxazole products displayed dramatically strong fluorescence enhancement upon photoirradiation through isoxazole-oxazole photoisomerization. This new methodology was successfully applied for in situ fluorogenic protein labeling.

One-Pot Synthesis of O-Heterocycles or Aryl Ketones Using an InCl/EtSiH System by Switching the Solvent.

An efficient one-pot synthesis of O-heterocycles or aryl ketones has been achieved using EtSiH in the presence of InCl via a sequential ionic hydrogenation reaction by switching the solvent. This methodology can be used to construct C-O bonds and to prepare conjugate reduction products, including chromans, tetrahydrofurans, tetrahydropyrans, dihydroisobenzofurans, dihydrochalcones, and 1,4-diones in a facile manner. In addition, a novel plausible mechanism involving a conjugate reduction and a tandem reductive cyclization was verified by experimental investigations.

Occipital Nerve Stimulation.

Although the first publications on clinical use of peripheral nerve stimulation for the treatment of chronic pain came out in the mid-1960s, it took 10 years before this approach was used to stimulate the occipital nerves. The future for occipital nerve stimulation is likely to bring new indications, devices, stimulation paradigms, and a decrease in invasiveness. As experience increases, one may expect that occipital nerve stimulation will eventually gain regulatory approval for more indications, most likely for occipital neuralgia, migraines and cluster headaches.

Autophagy alleviates the decrease in proliferation of amyloid β1‑42‑treated bone marrow mesenchymal stem cells via the AKT/mTOR signaling pathway.

Alzheimer's disease (AD) and osteoporosis (OP) are 2 common progressive age‑associated diseases, primarily affecting the elderly worldwide. Accumulating evidence has demonstrated that patients with AD are more likely to suffer from bone mass loss and even OP, but whether it is a pathological feature of AD or secondary to motor dysfunction remains poorly understood. The present study aimed to investigate whether amyloid‑β1‑42 (Aβ1‑42), the typical pathological product of AD, exhibited a negative effect on the proliferation of bone marrow mesenchymal stem cells (BMSCs) and the role of autophagy.

A Computational Approach to the Study of the Binding Mode of S1PR Agonists Based on the Active-Like Receptor Model.

Sphingosine-1-phosphate receptor 1 (S1PR), a member of the G protein-coupled receptor (GPCR) family, is an attractive protein target for the treatment of autoimmune diseases, and a diverse array of S1PR agonists have been developed. Rational drug design based on S1PR remains challenging due to the limited information available on the binding mode between S1PR and its agonists. In this work, the active-like state of S1PR was modeled via Gaussian accelerated molecular dynamics (GaMD) based on its inactive form, which was further validated by docking studies with two representative S1PR agonists.

and Activities of the Riminophenazine TBI-166 against .

The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog, TBI-166, was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort.

Identification and Structure-Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P).

Agonism of S1P receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P modulators. In this paper we described a series of oxadiazole-based S1P direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P receptor and favorable selectivity against S1P receptor. In addition, two representative agents named 16-3b and 16-3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered.

Quantitative Evaluation of Target Efficacy of Anti-tumor Agents an Immunofluorescence and EdU Labeling Strategy.

Current methods used to evaluate target efficacy of selected compound include western blot to semi-quantitatively analyze protein expression. However, problems arise as it is difficult to compare target efficacy of anti-tumor agents with the same mode of action. It is therefore desirable to develop a protocol that can quantitatively display target efficacy while also providing other useful information.

Axial and oblique C2 pedicle diameters and feasibility of C2 pedicle screw placement: Technical note.

Background: For C2 pedicle screw placement/instrumentation, it is critical to adequately measure the axial and oblique C2 pedicle diameters utilizing the intraoperative O-arm.

Methods: Thirty-three patients who underwent C2 pedicle screw placement (2013-2016) utilizing the O-arm with tri-planar reconstruction. As O-arm software does not allow calibrated measurements with the application's measurement tool, we directly measured axial and oblique widths of the C2 pedicles on the screen with a regular ruler (e.