Intramolecular, Interrupted Homo-Nazarov Cascade Biscyclizations to Angular (Hetero)Aryl-Fused Polycycles.

Herein, a SnCl4 -catalyzed intramolecular, interrupted homo-Nazarov cascade biscyclization to access angular (hetero)aryl-fused polycycles is reported. Subsequent decarboxylation of the readily enolizable products afforded the angular products in up to 71 % yield over two steps, with the trans-diastereomers as the major products. The cyclopropyl homo-Nazarov cyclization precursors were formed using a scalable and modular synthetic route that, ultimately, offers access to 6,6,6-, 6,6,5-, 6,5,6-, 6,6,5,6-, and 6,6,6,5-fused angular polycyclic products. To showcase the rigor and utility of the method, an 8-step total synthesis of (±)-1-oxoferruginol, an antibacterial aromatic abietane diterpenoid, was disclosed.

Elucidation of a Sequential Iminium Ion Cascade Reaction Triggered by a Silica Gel-Promoted Aza-Peterson Reaction.

In a recent methodological study investigating the synthesis of N-alkoxyazomethine ylides, an unexpected aminal byproduct was generated during our attempt to isolate O-benzyl-N-((trimethylsilyl)methyl)hydroxylamine. After a strategic investigation, silica gel was discovered to be the cause of the byproduct formation. Through the mechanistic insight from control and trapping experiments, we propose the formation of a methaniminium ion via a novel aza-Peterson reaction, which ultimately triggers a sequential iminium ion cascade sequence. Herein, we discuss the elucidation of this cascade reaction mechanism and the constraints for the byproduct formation.

Ligand deconstruction: Why some fragment binding positions are conserved and others are not.

Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots--regions of the protein where interactions with a ligand contribute substantial binding free energy--the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

Discovery of 8-Hydroxyquinoline as a Histamine Receptor 2 Blocker Scaffold.

Histamine receptor 2 (HRH2) activation in the stomach results in gastric acid secretion, and HRH2 blockers are used for the treatment of peptidic ulcers and acid reflux. Over-the-counter HRH2 blockers carry a five-membered aromatic heterocycle, with two of them additionally carrying a tertiary amine that decomposes to N-nitrosodimethylamine, a human carcinogen. To discover a novel HRH2 blocker scaffold to serve in the development of next-generation HRH2 blockers, we developed an HRH2-based sensor in yeast by linking human HRH2 activation to cell luminescence. We used the HRH2-based sensor to screen a 403-member anti-infection chemical library and identified three HRH2 blockers, chlorquinaldol, chloroxine, and broxyquinoline, all sharing an 8-hydroxyquinoline scaffold, which is not found among known HRH2 antagonists. Critically, we validate their HRH2-blocking ability in mammalian cells. Molecular docking suggests that the HRH2 blockers bind the histamine binding pocket and structure-activity data point toward these blockers acting as competitive antagonists. Chloroxine and broxyquinoline are antimicrobials that can be found in the gastrointestinal tract at concentrations that would block HRH2, thus likely modulating gastric acid secretion. Taken together, this work demonstrates the utility of GPCR-based sensors for rapid drug discovery applications, identifies a novel HRH2 blocker scaffold, and provides further evidence that antimicrobials not only target the human microbiota but also the human host.

An efficient route to xanthine based A(2A) adenosine receptor antagonists and functional derivatives.

A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and carboxaldehydes. Yields are good and the process applicable to a range of substrates including a family of A(2A) adenosine receptor antagonists. A new route to the KW-6002 family of antagonists is presented including a pro-drug variant, and application to related image contrast agents developed.

A Review on Functional Electrical Stimulation Cycle Ergometer Exercise for Spinal Cord Injured Patients.

The purpose of this collective review on functional electrical stimulation (FES) cycle ergometer training is to describe the pathologic effects of spinal cord injury (SCI) and the structure and function of the FES cycle ergometers, which reverse the devastating systemic and life-threatening effects of SCI. The pathophysiologic consequences of SCI include diminished cardiopulmonary and circulatory function as well as lower extremity muscle atrophy and bone mass reduction. Clinical studies have demonstrated that the two FES cycle ergometers offer promise in reversing these devastating consequences of SCI, which can shorten patients' lives. On the basis of this collective review, it is recommended that all patients with SCI have the benefits of this potentially life-sustaining clinical modality.

A Review on Functional Electrical Stimulation in Tetraplegic Patients to Restore Hand Function.

The purpose of this collective review is to describe a new form of functional electrical stimulation called neuroprosthesis. This unique technology has been devised to produce lateral pinch and palmar grasp in persons with C5 and C6 motor level spinal cord injuries. This neuroprosthesis includes external as well as implanted components. First, a receiver is surgically implanted into the patient's chest above a pectoralis major muscle. The receiver stimulator is then connected to 8 surgically implanted epimysial or intramuscular electrodes. Restoration of upper extremity function can greatly improve the lives of people affected with tetraplegia. When contralateral shoulder movements trigger an external transmitting coil, it sends a radio wave impulse to the stimulator inducing contraction of the muscles. Many tetraplegics are regaining hand function using implanted functional electrical stimulation. One major limitation is that the key muscles to be stimulated may have lower motor neuron damage, but this obstacle has been successfully overcome using surgical modifications of the biomechanics of the hand.

A Review on Functional Electrical Stimulation of Bladder and Bowel in Spinal Cord Injury.

The purpose of this collective review is to examine the use of functional electrical stimulation for incontinence. The Finetech-Brindley bladder system enhances voiding through stimulation via electrodes implanted around the ventral sacral roots. Detrusor hyperreflexia is eliminated through complete dorsal rhizotomy, which results in loss of reflex defecation and reflex erection/reflex lubrication. Consequently, a new system is being devised in which functional electrical stimulation for incontinence in spinal cord injury can be achieved without dorsal rhizotomy.

A Review on Functional Electrical Stimulation for a Dropped Foot.

The purpose of this collective review is to study the techniques, usage, methods, and clinical results of functional electrical stimulation applied to the peroneal nerve in the treatment of dropped foot. When stimulation is applied through surface electrodes, clinical reports have documented the therapeutic and orthotic benefits of functional electrical stimulation. Clinical trials are now being undertaken in which implantable electrodes are being used to stimulate the peroneal nerve in patients with dropped foot.

Functional electrical stimulation for a dropped foot.

The purpose of this collective review is to study the techniques, usage, methods, and clinical results of functional electrical stimulation applied to the peroneal nerve in the treatment of dropped foot. When stimulation is applied through surface electrodes, clinical reports have documented the therapeutic and orthotic benefits of functional electrical stimulation. Clinical trials are now being undertaken in which implantable electrodes are being used to stimulate the peroneal nerve in patients with dropped foot.

Functional electrical stimulation cycle ergometer exercise for spinal cord injured patients.

The purpose of this collective review on functional electrical stimulation (FES) cycle ergometer training is to describe the pathologic effects of spinal cord injury (SCI) and the structure and function of the FES cycle ergometers, which reverse the devastating systemic and life-threatening effects of SCI. The pathophysiologic consequences of SCI include diminished cardiopulmonary and circulatory function as well as lower extremity muscle atrophy and bone mass reduction. Clinical studies have demonstrated that the two FES cycle ergometers offer promise in reversing these devastating consequences of SCI, which can shorten patients' lives. On the basis of this collective review, it is recommended that all patients with SCI have the benefits of this potentially life-sustaining clinical modality.

Functional electrical stimulation in tetraplegic patients to restore hand function.

The purpose of this collective review is to describe a new form of functional electrical stimulation called neuroprosthesis. This unique technology has been devised to produce lateral pinch and palmar grasp in persons with C5 and C6 motor level spinal cord injuries. This neuroprosthesis includes external as well as implanted components. First, a receiver is surgically implanted into the patient's chest above a pectoralis major muscle. The receiver stimulator is then connected to 8 surgically implanted epimysial or intramuscular electrodes. Restoration of upper extremity function can greatly improve the lives of people affected with tetraplegia. When contralateral shoulder movements trigger an external transmitting coil, it sends a radio wave impulse to the stimulator inducing contraction of the muscles. Many tetraplegics are regaining hand function using implanted functional electrical stimulation. One major limitation is that the key muscles to be stimulated may have lower motor neuron damage, but this obstacle has been successfully overcome using surgical modifications of the biomechanics of the hand.

Functional electrical stimulation of bladder and bowel in spinal cord injury.

The purpose of this collective review is to examine the use of functional electrical stimulation for incontinence. The Finetech-Brindley bladder system enhances voiding through stimulation via electrodes implanted around the ventral sacral roots. Detrusor hyperreflexia is eliminated through complete dorsal rhizotomy, which results in loss of reflex defecation and reflex erection/reflex lubrication. Consequently, a new system is being devised in which functional electrical stimulation for incontinence in spinal cord injury can be achieved without dorsal rhizotomy.

Functional electrical stimulation for ejaculation.

The purpose of this collective review is to discuss the technique and effectiveness of rectal probe electroejaculation in conjunction with various assistive reproductive modalities. The electroejaculation probe is positioned inside the anal ring with the electrodes placed against the prostate gland and seminal vesicles, after which electrostimulation is begun. Rectal probe electroejaculation must be always employed in a hospital setting to detect and prevent autonomic dysreflexia. This technology is considered the best approach in patients with spinal cord injury levels below T10 or in other patients in which penile vibratory stimulation fails.