Chiral Thianthrenes.

The absolute configuration and stability of two thianthrene chiral sulfoxides has been determined by means of X-ray single-crystal structure determinations. The analyses and configurations allow verification that the diastereomeric sulfoxides are stable in solution and are not interconverting, which has been suggested in some studies of sulfoxides. The two thianthrene sulfoxides have slightly different Rf values, which allowed their separation using flash chromatography on silica. The spots run back-to-back, which posed a challenge for their separation. The pure, separated compounds in solution remain as separate, single spots on a Thin Layer Chromatography (TLC) plate.

Sequential Nucleophilic Aromatic Substitution Reactions of Activated Halogens.

Building blocks have been identified that can be functionalised by sequential nucleophilic aromatic substitution. Some examples are reported that involve the formation of cyclic benzodioxin and phenoxathiine derivatives from 4,5-difluoro-1,2-dinitrobenzene, racemic quinoxaline thioethers, and sulfones from 2,3-dichloroquinoxaline and (2-aminophenylethane)-2,5-dithiophenyl-4-nitrobenzene from 1-(2-aminophenylethane)-2-fluoro-4,5-dinitrobenzene. Four X-ray single-crystal structure determinations are reported, two of which show short intermolecular N-O…N "π hole" contacts.

Porous and Close Packed Supramolecular Assemblies from 2,4-Difluoronitrobenzene with Three Different Linkers and an n-Butylamine Cap.

A porous structure formed from sheets with cavities and two close packed structures were crystallised from building blocks prepared from 2,4-difluoronitrobenzene, a diamine linker and n-butylamine. The porous structure crystallised from a flexible building block prepared using 1,4-diaminobutane as linker. The close packed structures were prepared using either piperazine or 1,4-bis(aminomethyl)benzene as a linker and have less conformational freedom.

Recurrent Glioblastoma Treated with Recombinant Poliovirus.

BACKGROUND: The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. METHODS: We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue-culture infectious doses (TCID50), first in a dose-escalation phase and then in a dose-expansion phase. RESULTS: From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×107 TCID50) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (1010 TCID50) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months. CONCLUSIONS: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).

Understanding the remarkable difference in liquid crystal behaviour between secondary and tertiary amides: the synthesis and characterisation of new benzanilide-based liquid crystal dimers.

A number of liquid crystal dimers have been synthesised and characterised containing secondary or tertiary (N-methyl) benzanilide-based mesogenic groups. The secondary amides all form nematic phases, and we present the first example of an amide to show the twist-bend nematic (NTB) phase. Only two of the corresponding N-methylated dimers formed a nematic phase and with greatly reduced nematic-isotropic transition temperatures. Characterisation using 2D ROESY NMR experiments, DFT geometry optimisation and X-ray diffraction reveal that there is a change in the preferred conformation of the benzanilide core on methylation, from Z to E. The rotational barrier around the N-C(O) bond has been measured using variable temperature 1H NMR spectroscopy. This dramatic change in shape accounts for the remarkable difference in liquid crystalline behaviour between these secondary and tertiary amide-based materials.

Sudden Unexpected Death in a Child From Acute Myeloid Leukemia.

ABSTRACT: Acute myeloid leukemia can rarely cause sudden, unexpected death in children. Presentation may be non-specific and death may occur in children with no prior medical history. Herein we present the case of a previously healthy 2-year and 2 month-old White girl, who on autopsy, was found to have acute myeloid leukemia with KMT2A rearrangement extensively involving all major thoracic and abdominal organs. This case is presented to the forensic community to discuss the presentation and findings in sudden death caused by acute leukemia. The case highlights when acute leukemia should enter the differential as a potential cause of death, as well as potential resources available in the postmortem workup of acute leukemias.

Crystalline Forms of Trazodone Dihydrates.

In this study, treatment of anhydrous trazodone powder with ammonium carbamate in warm water crystallised two new polymorphs or dihydrates of trazodone after 5 h, whose structures were determined by X-ray single crystal diffraction. Each dihydrate contains infinite zigzag hydrogen-bonded chains of water molecules, which are stabilised by the N4 acceptor atom of the piperazine ring and the pendant carbonyl O1 atom of the triazole ring, as well as other water molecules. The strong dipole moment expected for the O1 atom makes it a good hydrogen bond acceptor for stabilising the chains of water molecules. Each molecule of trazodone has a similar conformation in both hydrates, except for the propyl chains, which adopt different conformations: anti-gauche in the ß hydrate (triazole N-C-C-C and C-C-C-piperazine N) and anti-anti in the γ hydrate. Both piperazine rings adopt chair conformations, and the exocyclic N-C bonds are in equatorial orientations. The Hirshfeld surfaces and two-dimensional fingerprint plots for the polymorphs were calculated using CrystalExplorer17, which indicated contacts significantly shorter than the sum of the van der Waals radii in the vicinity of the piperazine N4 and triazole O1 atoms corresponding to the strong hydrogen bonds accepted by these atoms.

Cyclophosphamide-induced cystitis results in NLRP3-mediated inflammation in the hippocampus and symptoms of depression in rats.

Recent breakthroughs demonstrate that peripheral diseases can trigger inflammation in the brain, causing psychosocial maladies, including depression. While few direct studies have been made, anecdotal reports associate urological disorders with mental dysfunction. Thus, we investigated if insults targeted at the bladder might elicit behavioral alterations. Moreover, the mechanism of neuroinflammation elicited by other peripheral diseases involves the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is present in microglia in the brain and cleaves and activates proinflammatory cytokines such as IL-1ß. Thus, we further explored the importance of NLRP3 in behavioral and neuroinflammatory changes. Here, we used the well-studied cyclophosphamide (CP)-treated rat model. Importantly, CP and its metabolites do not cross the blood-brain barrier or trigger inflammation in the gut, so that any neuroinflammation is likely secondary to bladder injury. We found that CP triggered an increase in inflammasome activity (caspase-1 activity) in the hippocampus but not in the pons. Evans blue extravasation demonstrated breakdown of the blood-brain barrier in the hippocampal region and activated microglia were present in the fascia dentata. Both changes were dependent on NLRP3 activation and prevented with 2-mercaptoethane sulfonate sodium (Mesna), which masks the effects of the CP metabolite acrolein in the urine. Finally, CP-treated rats displayed depressive symptoms that were prevented by NLRP3 inhibition or treatment with Mesna or an antidepressant. Thus, we conclude that CP-induced cystitis causes NLRP3-dependent hippocampal inflammation leading to depression symptoms in rats. This study proposes the first-ever causative explanation of the previously anecdotal link between benign bladder disorders and mood disorders.

Creutzfeldt-Jakob Disease Mimicking Neurosyphilis: A Complex Presentation, Histopathological Findings, and Special Precautions for Autopsy.

Creutzfeldt-Jakob disease (CJD) is a complex and rapidly fatal prion infection of the central nervous system with characteristic clinical and pathological findings. Herein, we present the case of an 80-year-old man with a 2-month history of rapid cognitive decline and ataxic gait. He was found to have a positive rapid plasma reagin and fluorescent treponemal antibody absorption (FTA-ABS) upon clinical testing and was presumed to have neurosyphilis. His neurological status precipitously declined during his hospitalization and he died. A complete autopsy was performed, which revealed diffuse spongiform change throughout the cerebrum. Brain tissue was sent to the National Prion Disease Surveillance Center, where immunostaining for prion protein (3F4) showed granular deposits, confirming the diagnosis of CJD. There have been rare cases reported in which CJD was clinically suspected but neurosyphilis was confirmed at autopsy. To our knowledge, this is the first case to be published in which the clinical findings strongly favored neurosyphilis, but spongiform encephalopathy was identified at autopsy. We review the clinical, radiographic, electrophysiological, laboratory, and histopathological features of both diseases and discuss the overlapping findings and inherent diagnostic difficulties. We also review the recommended protocols for safely handling suspected prion-infected autopsy tissue. A heightened awareness of the features of CJD and other prion diseases is needed among forensic pathologists, neuropathologists, and general autopsy pathologists to understand how to safely handle the tissue to get definite diagnoses for the decedent's family members and clinical care team.

Sudden Unexpected Death in a Child From an Anaplastic Ependymoma.

Primary central nervous system tumors are an extremely rare cause of sudden, unexpected death in children as most patients develop symptoms because of increased intracranial pressure and seek medical attention. Rarely, a forensic pathologist may encounter a primary intracranial neoplasm in a pediatric decedent that was not suspected before death. Herein, we present a case of a supratentorial neuroepithelial tumor found at autopsy in a 3-year-old African American boy without any reported significant medical history. The tumor had significant mass effect and caused cerebral edema, which ultimately resulted in transtentorial herniation and death. The gross, histopathological, immunohistochemical, and ultrastructural findings were most consistent with an anaplastic ependymoma.

3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation.

Hydroxylation and fluorination of proline alters the pyrrolidine ring pucker and the trans:cis amide bond ratio in a stereochemistry-dependent fashion, affecting molecular recognition of proline-containing molecules by biological systems. While hydroxyprolines and fluoroprolines are common motifs in medicinal and biological chemistry, the synthesis and molecular properties of prolines containing both modifications, i.e., fluoro-hydroxyprolines, have not been described. Here we present a practical and facile synthesis of all four diastereoisomers of 3-fluoro-4-hydroxyprolines (F-Hyps), starting from readily available 4-oxo-l-proline derivatives. Small-molecule X-ray crystallography, NMR spectroscopy, and quantum mechanical calculations are consistent with fluorination at C3 having negligible effects on the hydrogen bond donor capacity of the C4 hydroxyl, but inverting the natural preference of Hyp from C4-exo to C4-endo pucker. In spite of this, F-Hyps still bind to the von Hippel-Lindau (VHL) E3 ligase, which naturally recognizes C4-exo Hyp in a stereoselective fashion. Co-crystal structures and electrostatic potential calculations support and rationalize the observed preferential recognition for (3 R,4 S)-F-Hyp over the corresponding (3 S,4 S) epimer by VHL. We show that (3 R,4 S)-F-Hyp provides bioisosteric Hyp substitution in both hypoxia-inducible factor 1 alpha (HIF-1α) substrate peptides and peptidomimetic ligands that form part of PROTAC (proteolysis targeting chimera) conjugates for targeted protein degradation. Despite a weakened affinity, Hyp substitution with (3 S,4 S)-F-Hyp within the PROTAC MZ1 led to Brd4-selective cellular degradation at concentrations >100-fold lower than the binary Kd for VHL. We anticipate that the disclosed chemistry of 3-fluoro-4-hydroxyprolines and their application as VHL ligands for targeted protein degradation will be of wide interest to medicinal organic chemists, chemical biologists, and drug discoverers alike.

Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands.

(-)-Kainic acid potently increases stretch-induced afferent firing in muscle spindles, probably acting through a hitherto uncloned phospholipase D (PLD)-coupled mGlu receptor. Structural modification of (-)-kainic acid was undertaken to explore the C-4 substituent effect on the pharmacology related to muscle spindle firing. Three analogues 1a-c were synthesised by highly stereoselective additions of a CF3, a hydride and an alkynyl group to the Re face of the key pyrrolidin-4-one intermediate 5a followed by further structural modifications. Only the 4-(1,2,3-triazolyl)-kainate derivative 1c retained the kainate-like agonism, increasing firing in a dose-dependent manner. Further modification of 1c by introduction of a PEG-biotin chain on the 1,2,3-triazole fragment afforded compound 14 which retained robust agonism at 1 µM and appears to be suitable for future use in pull-down assays and far western blotting for PLD-mGluR isolation.

Crystal structure of tetra-guanidinium [hexa-hydrogen hexa-arsenato(V)tetra-vanadate(V)] tetra-hydrate.

The complete polyoxidometallate anion in the title compound, (CH6N3)4[H6V4As6O30]·4H2O, is generated by crystallographic inversion symmetry. The polyhedral building units are distorted VO6 octa-hedra and AsO3OH tetra-hedra. The VO6 units feature a short formal V=O double bond and are linked by a common edge. Two such V2O6 double octahedral units are linked by four isolated AsO3OH tetra-hedra to complete the anion, which features two inter-nal O-H⋯O hydrogen bonds. In the crystal, O-H⋯O hydrogen bonds between the polyoxidometallate anions generate (01-1) sheets. The sheets are connected by cation-to-cluster N-H⋯O hydrogen bonds, and cation-to-water N-H⋯O links also occur. The O atom of one of the water mol-ecules is disordered over two sites in a 0.703 (17):0.297 (17) ratio.

Crystal structure of ammonium divanadium(IV,V) tellurium(IV) hepta-oxide.

The polyhedral building blocks of the layered inorganic network in the mixed-valence title compound, (NH4)(V(IV)O2)(V(V)O2)(TeO3), are vertex-sharing V(V)O4 tetra-hedra, distorted V(IV)O6 octa-hedra and TeO3 pyramids, which are linked by V-O-V and V-O-Te bonds, forming double layers lying parallel to (100). The presumed Te(IV) lone-pairs of electrons appear to be directed inwards into cavities in the double layers. The charge-balancing ammonium cations lie between the layers and probably inter-act with them via N-H⋯O hydrogen bonds.

Crystal structure of bis-[3-meth-oxy-17ß-estra-1,3,5(10)-trien-17-yl] oxalate.

In the title compound, C40H50O6, a symmetrical steroid oxalate diester, the dihedral angle between the CO2 planes of the oxalate linker is 61.5 (5)° and the C-C bond length is 1.513 (6) Å. The steroid B, C and D rings adopt half-chair, chair and envelope conformations, respectively, in both halves of the mol-ecule, which adopts an overall shallow V-shaped conformation. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming a three-dimensional network.