Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

Cyclopentadienyl capped thorium(IV) porphyrinoid complex.

The reaction between Th(IV) dipyriamethyrin dichloride and sodium cyclopentadienyl (Cp) results in the formation of a cyclopentadienyl capped thorium dipyriamethyrin complex, which to our knowledge represents the first expanded porphyrin f-element Cp complex.

A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry.

Photoredox-transition metal dual catalysis provides a unique platform for constructing sp3-rich chemical matter. Here, we report a nickel-catalyzed cross-coupling of commercially available or easily prepared redox-active NHP azetidine-2-carboxylates with commercially available heteroaryl iodides to yield 2-heteroaryl azetidines. This "off-the-shelf" approach yielded products amenable to diversification giving access to novel saturated heterocyclic scaffolds useful for medicinal chemistry programs. An alternative mechanism for Hantzsch ester within nickel-catalyzed cross-coupling of heteroaryl halides and α-amino radicals is also presented.

Using Spectator Ligands to Enhance Nanocrystal-to-Molecule Electron Transfer.

Semiconductor nanocrystals (NCs) have emerged as promising photocatalysts. However, NCs are often functionalized with complex ligand shells that contain not only charge acceptors but also other "spectator ligands" that control NC solubility and affinity for target reactants. Here, we show that spectator ligands are not passive observers of photoinduced charge transfer but rather play an active role in this process. We find the rate of electron transfer from quantum-confined PbS NCs to perylenediimide acceptors can be varied by over a factor of 4 simply by coordinating cinnamate ligands with distinct dipole moments to NC surfaces. Theoretical calculations indicate this rate variation stems from both ligand-induced changes in the free energy for charge transfer and electrostatic interactions that alter perylenediimide electron acceptor orientation on NC surfaces. Our work shows NC-to-molecule charge transfer can be fine-tuned through ligand shell design, giving researchers an additional handle for enhancing NC photocatalysis.

Robotic-Assisted Versus Conventional Posterior Lumbar Fusion-An Analysis of 90-Day Complications and Readmissions.

OBJECTIVE: To evaluate medical and surgical complication rates between robotic-assisted versus conventional elective posterior lumbar fusions. METHODS: The Symphony Integrated DataVerse was queried using International Classification of Diseases, 10th Edition, Clinical Modification procedure codes to identify patients undergoing elective posterior lumbar fusions for degenerative spine pathologies between 2015 and 2018. International Classification of Diseases, 10th Edition, Clinical Modification procedure codes (8E0W4CZ, 8E0W0CZ, 8E0W3CZ) were used to identify patients undergoing a robotic-assisted spinal fusion. Outcome measures were 90-day medical and surgical complications, 1-year pseudarthrosis, and 1-year revision surgery rates. Multivariate logistic regression analyses were used to assess whether undergoing a robotic-assisted fusion (vs. conventional fusion) was associated with differences in wound complications, medical complications, pseudarthrosis, revision surgery, and readmissions within 90 days of surgery. RESULTS: A total of 39,387 patients undergoing elective posterior lumbar fusions were included in the cohort-of whom 245 (0.62%) patients underwent a robotic-assisted fusion. Multivariate analysis showed that robotic-assisted fusion (vs. conventional fusion) was not associated with significant differences in 90-day rates of wound complications (P = 0.299), urinary tract infections (P = 0.648), acute myocardial infarctions (P = 0.209), acute renal failure (P = 0.461), pneumonia (P = 0.214), stroke (P = 0.917), deep venous thrombosis (P = 0.562), pulmonary embolism (P = 0.401), and readmissions (P = 0.985). In addition, there were no significant differences in the 1-year rates of revision fusions (P = 0.316) and pseudarthrosis (P = 0.695). CONCLUSIONS: Patients who underwent a robotic-assisted fusion had similar rates of surgical and medical complications compared with those who underwent a conventional fusion. Further studies are warranted to better understand the future role of robots in spine surgery.

Magnetic-Field-Induced Modulation of Charge-Recombination Dynamics in a Rosarin-Fullerene Complex.

Charge-recombination processes are critical for photovoltaic applications and should be suppressed for efficient charge transport. Here, we report that an applied magnetic field (0-1 T) can be used control the charge-recombination dynamics in an expanded rosarin-C60 complex. In the low magnetic field regime (<100 mT), the charge-recombination rate slows down due to hyperfine coupling, as inferred from transient absorption spectroscopic analyses. In contrast, in the high field regime, i.e., over 500 mT, the charge-recombination rate recovers and increases because the Δg mechanism facilitates spin conversion to a triplet charge-separated state (S to T0 ) that undergoes rapid charge-recombination to a localized rosarin triplet state. Therefore, we highlight the charge-recombination rate and the localized triplet state population can be modulated by the magnetic field in charge donor/acceptor non-covalent complexes.

Deferasirox (ExJade): An FDA-Approved AIEgen Platform with Unique Photophysical Properties.

Deferasirox, ExJade, is an FDA-approved iron chelator used for the treatment of iron overload. In this work, we report several fluorescent deferasirox derivatives that display unique photophysical properties, i.e., aggregation-induced emission (AIE), excited state intramolecular proton transfer, charge transfer, and through-bond and through-space conjugation characteristics in aqueous media. Functionalization of the phenol units on the deferasirox scaffold afforded the fluorescent responsive pro-chelator ExPhos, which enabled the detection of the disease-based biomarker alkaline phosphatase (ALP). The diagnostic potential of these deferasirox derivatives was supported by bacterial biofilm studies.

Indicator displacement assays (IDAs): the past, present and future.

Indicator displacement assays (IDAs) offer a unique and innovative approach to molecular sensing. IDAs can facilitate the detection of a range of biologically/environmentally important species, provide a method for the detection of complex analytes or for the determination and discrimination of unknown sample mixtures. These attributes often cannot be achieved by traditional molecular sensors i.e. reaction-based sensors/chemosensors. The IDA pioneers Inouye, Shinkai, and Anslyn inspired researchers worldwide to develop various extensions of this idea. Since their early work, the field of indicator displacement assays has expanded to include: enantioselective indicator displacement assays (eIDAs), fluorescent indicator displacement assays (FIDAs), reaction-based indicator displacement assays (RIAs), DimerDye disassembly assays (DDAs), intramolecular indicator displacement assays (IIDAs), allosteric indicator displacement assay (AIDAs), mechanically controlled indicator displacement assays (MC-IDAs), and quencher displacement assays (QDAs). The simplicity of these IDAs, coupled with low cost, high sensitivity, and ability to carry out high-throughput automation analysis (i.e., sensing arrays) has led to their ubiquitous use in molecular sensing, alongside the other common approaches such as reaction-based sensors and chemosensors. In this review, we highlight the various design strategies that have been used to develop an IDA, including the design strategies for the newly reported extensions to these systems. To achieve this, we have divided this review into sections based on the target analyte, the importance of each analyte and then the reported IDA system is discussed. In addition, each section includes details on the benefit of the IDAs and perceived limitations for each system. We conclude this Tutorial Review by highlighting the current challenges associated with the development of new IDAs and suggest potential future avenues of research.

Condition-Dependent Coordination and Peroxidase Activity of Hemin-Aß Complexes.

The peroxidase activity of hemin-peptide complexes remains a potential factor in oxidative damage relevant to neurodegeneration. Here, we present the effect of temperature, ionic strength, and pH relevant to pathophysiological conditions on the dynamic equilibrium between high-spin and low-spin hemin-Aß40 constructs. This influence on peroxidase activity was also demonstrated using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and dopamine (DA) oxidation rate analyses with increasing ratios of Aß16 and Aß40 (up to 100 equivalents). Interaction and reactivity studies of aggregated Aß40-hemin revealed enhanced peroxidase activity versus hemin alone. Comparison of the results obtained using Aß16 and Aß40 amyloid beta peptides revealed marked differences and provide insight into the potential effects of hemin-Aß on neurological disease progression.

Amethyrin-type expanded porphyrins that display anti-aromatic character upon protonation.

The use of protonation to switch nonaromatic expanded porphyrins to their corresponding anti-aromatic forms has not been widely explored. Here, we show that free-base pyriamethyrin and dipyriamethyrin display nonaromatic character, as inferred from NMR spectroscopic analyses, their optical properties, and theoretical calculations. Addition of two protons extends the π - conjugation of these amethyrin analogues and yields formally anti-aromatic systems.

Protein Encapsulation: A Nanocarrier Approach to the Fluorescence Imaging of an Enzyme-Based Biomarker.

Here, we report a new pentafluoropropanamido rhodamine fluorescent probe (ACS-HNE) that allows for the selective detection of neutrophil elastase (NE). ACS-HNE displayed high sensitivity, with a low limit of detection (<5.3 nM), and excellent selectivity toward elastase over other relevant biological analytes and enzymes. The comparatively poor solubility and cell permeability of neat ACS-HNE was improved by creating an ACS-HNE-albumin complex; this approach allowed for improvements in the in situ visualization of elastase activity in RAW 264.7 cells relative to ACS-HNE alone. The present study thus serves to demonstrate a simple universal strategy that may be used to overcome cell impermeability and solubility limitations, and to prepare probes suitable for the cellular imaging of enzymatic activity in vitro.

Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents.

Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc.

Boronate ester cross-linked PVA hydrogels for the capture and H2O2-mediated release of active fluorophores.

A new set of PVA hydrogels were formed using the boronate ester fluorescent probe PF1 and the novel boronate fluorescent probe PT1 as the covalent crosslinkers. Treatment with aqueous H2O2 allowed triggered release of the fluorescent dye accompanied by complete dissolution of the hydrogel.

Long-term Comparison of Retrograde and Antegrade Femoral Nailing.

Antegrade or retrograde nailing for femoral shaft fractures remains the gold standard, but long-term data on functional outcomes after intramedullary nailing are lacking. In a retrospective review of prospectively collected patient registry data, patients with an isolated femoral shaft fracture treated with antegrade or retrograde femoral nailing from 1997 to 2012 were interviewed and their medical records analyzed. Functional reported outcome data were obtained via the visual analog scale (VAS) for pain and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 5 to 17 years postoperatively. Antegrade and retrograde intramedullary nailing of diaphyseal femur shaft fractures demonstrated a mean WOMAC of 23.5%±23.6% (range, 0%-82.3%) and 29.7%±24.0% (range, 0%-88%), respectively (P=.23). The mean VAS scores of the antegrade vs retrograde intramedullary nailing groups were 2.5±2.6 (range, 0-8) and 3.4±2.8 (range, 0-10), respectively (P=.11). Location of pain differed between groups as well, with the antegrade group noting an increased rate of hip pain (25.6% vs 7.0%, P=.01), but a nonsignificant difference in the rate of thigh pain (27.9% vs 15.5%, P=.15) and knee pain (18.6% vs 26.7%, P=.49) as compared with the retrograde group. Diaphyseal femur fractures are successfully treated with either antegrade or retrograde intramedullary nails without significantly differing long-term functional outcomes, which correlates with other reported findings in the literature at short-term follow-up. [Orthopedics. 2020;43(4):e278-e282.].

Metal-based imaging agents: progress towards interrogating neurodegenerative disease.

Central nervous system (CNS) neurodegeneration is defined by a complex series of pathological processes that ultimately lead to death. The precise etiology of these disorders remains unknown. Recent efforts show that a mechanistic understanding of the malfunctions underpinning disease progression will prove requisite in developing new treatments and cures. Transition metals and lanthanide ions display unique characteristics (i.e., magnetism, radioactivity, and luminescence), often with biological relevance, allowing for direct application in CNS focused imaging modalities. These techniques include positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and luminescent-based imaging (LumI). In this Tutorial Review, we have aimed to highlight the various metal-based imaging techniques developed in the effort to understand the pathophysiological processes associated with neurodegeneration. Each section has been divided so as to include an introduction to the particular imaging technique in question. This is then followed by a summary of key demonstrations that have enabled visualization of a specific neuropathological biomarker. These strategies have either exploited the high binding affinity of a receptor for its corresponding biomarker or a specific molecular transformation caused by a target species, all of which produce a concomitant change in diagnostic signal. Advantages and disadvantages of each method with perspectives on the utility of molecular imaging agents for understanding the complexities of neurodegenerative disease are discussed.

Synthesis and Characterization of a Binuclear Copper(II)-dipyriamethyrin Complex: [Cu2(dipyriamethyrin)(µ2-1,1-acetato)2].

The reaction between dipyriamethyrin and copper(II) acetate [Cu(OAc)2] afforded what is, to our knowledge, the first transition metal-dipyriamethyrin complex. Molecular and electronic characterization of this binuclear Cu(II) complex via EPR, UV-vis, and single crystal X-ray diffraction analysis revealed marked differences between the present constructs and previously reported binuclear copper(II) hexaphyrin species. UV-vis titration analyses provided evidence for a homotropic positive allosteric effect, wherein the binuclear species is formed without significant intermediacy of a monomeric complex.

Metallotexaphyrins as MRI-Active Catalytic Antioxidants for Neurodegenerative Disease: A Study on Alzheimer's Disease.

The complex etiology of neurodegeneration continues to stifle efforts to develop effective therapeutics. New agents elucidating key pathways causing neurodegeneration might serve to increase our understanding and potentially lead to improved treatments. Here, we demonstrate that a water-soluble manganese(II) texaphyrin (MMn) is a suitable magnetic resonance imaging (MRI) contrast agent for detecting larger amyloid beta constructs. The imaging potential of MMn was inferred on the basis of in vitro studies and in vivo detection in Alzheimer's disease C. elegans models via MRI and ICP-MS. In vitro antioxidant- and cellular-based assays provide support for the notion that this porphyrin analog shows promise as a therapeutic agent able to mitigate the oxidative and nitrative toxic effects considered causal in neurodegeneration. The present report marks the first elaboration of an MRI-active metalloantioxidant that confers diagnostic and therapeutic benefit in Alzheimer's disease models without conjugation of a radioisotope, targeting moiety, or therapeutic payload.

Outcomes and Review of Periprosthetic Tibial Fractures.

Periprosthetic fractures around total knee arthroplasties (TKA) are well documented in the literature. Fractures of the tibial side occur least frequently and often pose reconstructive challenges to the treating surgeon. As use of arthroplasty continues to rise, periprosthetic fractures of the tibia will likely become more prevalent. Periprosthetic fracture management is based on recommendations (Mayo classification) made 20 years ago. With newer design technology, the adjuvant use of locking plates in the presence of implant stable periprosthetic tibial fractures (Felix types IIA and IIIA) is unknown. The authors retrospectively reviewed 19 patients who sustained periprosthetic Felix type IIA or IIIA fractures that were treated with operative stabilization using plate and screw constructs. Union rate, time to union, incidence of need for revision on an acute or delayed basis, and restoration of ambulation were investigated. Fourteen patients were followed for the entire course of treatment. Preoperative range of motion was unable to be obtained due to the nature of the injuries. After primary surgical stabilization, 78.6% of the patients obtained successful union of their fracture at a mean of 25 months, but no arthroplasty component revision was necessary in any patient. Three (21.4%) patients required revision surgery, resulting in an overall union rate of 92.9%. Mean time to union in this cohort was 8.4±3.4 months, and the overall complication rate was 28.6%. Treatment of periprosthetic (TKA) tibial fractures carries a relatively high risk of complications and nonunion after primary stabilization, and patients should be counseled accordingly. [Orthopedics. 2020;43(3):182-186.].

Porphyrinoid f-Element Complexes.

Porphyrin and related pyrrole-containing macrocycles, collectively porphyrinoids, are versatile ligands that allow access to a multitude of coordination modes. Judicious modification of the porphyrin core as well as the pendant substituents has extended the coordination chemistry of porphyrinoids to include systems that are able to stabilize f-block element complexes with possible utility. This review focuses on our group's efforts to prepare expanded porphyrin and porphyrinogen ligands that can serve as tools to study and apply f-element metal coordination chemistry: it covers the background of the topic, selected syntheses, and application of these species in the chemical and medical sciences.

In-Plane Thorium(IV), Uranium(IV), and Neptunium(IV) Expanded Porphyrin Complexes.

Here we report the first series of in-plane thorium(IV), uranium(IV), and neptunium(IV) expanded porphyrin complexes. These actinide (An) complexes were synthesized using a hexa-aza porphyrin analogue, termed dipyriamethyrin, and the nonaqueous An(IV) precursors, ThCl4(DME)2, UCl4, and NpCl4(DME)2. The molecular and electronic structures of the ligand, each An(IV) complex, and a corresponding uranyl(VI) complex were characterized using nuclear magnetic resonance (NMR) and UV-vis spectroscopies as well as single-crystal X-ray diffraction analysis. Computational analyses of these complexes, coupled to their structural features, provide support for the conclusion that a greater degree of covalency in the ligand-cation orbital interactions arises as the early actinide series is traversed from Th(IV) to U(IV) and Np(IV). The axial ligands in the present An(IV) complexes proved labile, allowing for the electronic features of these complexes to be further modified.