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The new thiosemicarbazones (3a-d) of 3-acetylumbelliferone and Schiff’s bases (4a-b) of 3-acetylcoumarin were synthesized, characterized by elemental analysis, UV–Vis, FT-IR, NMR, and ESI-HR MS, and evaluated for their anticancer potency against the human breast cancer (MCF-7) cell line. All the tested compounds exhibited good to moderate anticancer efficacy in a dose-dependent manner. The synthesized compounds exhibited potent preferential inhibition effects against the MCF-7 cell line, with IC50 range of 147.8–505.1 µg/mL. The most potent compound, (E)-N-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidine)-2,6-dimethylmorpholine-4-carbothiohydrazide (3c), showed significant cytotoxicity with an IC50 value of 147.8 µg/mL against the tested cell line. It showed a higher proportion of cells in G1 (37.21 %) and S (26.86 %) phases and a lower proportion of cells in G2 phase (26.37 %), with respect to control. Molecular docking of all the synthesized compounds with target proteins VEGFR2 and EGFR demonstrated their significant binding affinity and interactions with key residues compared to the reference drug (erlotinib). DFT-based analysis showed that all the compounds have effective reactivity due to the low band gap energy of HOMO and LUMO relative to the reference drug, erlotinib (4.26 eV). The reactivity-related quantum mechanical parameters η, S, χ, μ, and ω indicated that these compounds have a high efficacy towards the target enzymes VEGFR2 and EGFR. All of the synthesized compounds had drug-like action, according to ADMET predictions. more...

Schwannoma and angiosarcoma are rare occurrences. Angiosarcoma’s occurrence in a preexisting schwannoma is a very rare event with only fifteen cases reported in the literature. We report the sixteenth case of angiosarcoma arising in a schwannoma, a 30-year-old male patient with a long-standing (15 years) history of right neck lump. The lump measured around 10x7 cm at the time of presentation and all cranial nerves were intact. We performed a fiberoptic laryngoscopy and a computed tomography scan of the head and neck with contrast. Our provisional diagnosis was a parapharyngeal space neoplasm, most likely a salivary gland malignancy. The tumor was excised surgically. On histopathology it contained two distinct tissue architectures representing a schwannoma and epithelioid angiosarcoma, also confirmed on immunohistochemistry. Literature review of these limited cases implicates a poor prognosis of the disease. The pathogenesis is uncertain, but the theories put forward suggest chronic vascular stasis or vascular endothelial proliferation as possible etiologies. The main takeaway of our report is to consider the potential of malignancy in long standing cases of schwannomas. Prompt surgical treatment should be offered, and the patient and their family be counselled for postoperative adjuvant treatment for better prognosis. more...

The title compound, C14H12N4O2·0.5HCl·H2O or H(C14H12N4O2)2+·Cl−·2H2O, arose from the unexpected cyclization of isonicotinoyl-N-phenyl hydrazine carbothioamide catalysed by cobalt(II) acetate. The organic molecule is almost planar and a symmetric N...H+...N hydrogen bond links two of them together, with the H atom lying on a crystallographic twofold axis. The extended structure features N—H...O and O—H...Cl hydrogen bonds, which generate [001] chains. Weak C—H...Cl interactions cross-link the chains. The chloride ion has site symmetry 2. The major contributions to the Hirshfeld surface are from H...H (47.1%), Cl...H/H...Cl (total 10.8%), O...H/H...O (7.4%) and N...H/H...N (6.7%) interactions. more...

Functionalization of chitosan as salicylaldehyde and 2-acetylphenol-based chitosan thiosemicarbazone involving amino group at C2 position of pyranose ring was confirmed by comprehensive characterization by spectroscopic and analytical ways. Both the low molecular weight (Mw) chitosan oligosaccharide (CS) (Mw < 3000 Da, degree of deacetylation (DDA) = 87 %) and the crab shell chitosan (CCS) (Mw = 350 kDa, DDA = 67 %) functionalized thiosemicarbazones behaved as ONS tridentate ligand to form the square planar copper(II) complexes with a chloride ion as an additional ligand to satisfy the co-ordination sphere. All the derivatives were found thermally stable till the commencement of chitosan backbone disruption at 200 °C. The MTT assay profiles showed a conspicuous enhancement in the in vitro antitumorigenic and anticancer activity of native chitosan upon its functionalization as phenolic carbaldehyde chitosan thiosemicarbazones. Further, the assays more often revealed a further lowering of cell viability with chitosan oligosaccharide derivatives in comparison to high molecular weight chitosan derivatives, and a lower viability of the MCF-7 cancer cells than the tumorigenic MDCK cells. Both the low Mw chitosan with high DDA and high Mw chitosan with low DDA, the chitosan-functionalized salicylaldehyde based thiosemicarbazones, and their copper(II) chitosan thiosemicarbazone complexes were found to have minimal toxicity with IC50 >600 μgmL−1 against the mouse embryonic normal fibroblast NIH3T3 cells. These results were indicatives of more protonation and enhanced anticancer activity of chitosan oligosaccharide derivatives, and preferential cytotoxicity of chitosan biomaterials against the tumorigenic and cancer cells with more negatively charged cell surfaces. more...

Background: Xerostomia, one of the most major side effects of radiotherapy in patients with oropharyngeal cancer, has a compromising effect on the quality of life. The aim of this study was to evaluate the effect of 635nm low-level laser on salivary flow rate and quality of life (QoL) in post-radiotherapy oropharyngeal cancer patients. Methods: A prospective study was conducted on patients (n=34) with persistent post-radiotherapy xerostomia received low level laser therapy (LLLT) (635nm) on the three major salivary glands twice a week for 12 weeks. For each point, dose was 18.75 J/cm2, irradiation time was 15 s, energy was 1.5 J. Energy for each session was 33 J and laser tip diameter was 0.08cm2. Extra oral points were marked over the parotid gland (6 points), submandibular (3points) and sublingual gland (2 points). Unstimulated and stimulated salivary flow rate (SFR) and quality of life (QoL) using University of Washington (UW) QoL questionnaire were assessed. Unstimulated SFR and QOL scores were normally distributed and hence paired t-test was used. A p-value ≤0.05 was considered as statistically significant. Results: The mean unstimulated SFR was significantly increased by 0.16 units after LLLT (p=0.001). Similarly, the median stimulated SFR significantly increased by 0.45 units post LLLT respectively (p=0.001). The mean QoL was significantly increased by 591.32 units after LLLT (p≤0.05). Conclusion: Low level laser therapy (LLLT) demonstrates to be effective in increasing salivary flow rate and the QoL scores hence mitigating salivary hypofunction and improving overall quality of life of patients. Keywords: Low-Level Laser Therapy; Xerostomia. more...

Abstract Decays of charmonia(-like) particles with definite J PC (e.g. χ c1(3872)) to a D 0 D ¯ 0 $$ {D}^0{\overline{D}}^0 $$ system and any combination of C-definite decay particles, are sources of quantum-correlated D 0 D ¯ 0 $$ {D}^0{\overline{D}}^0 $$ systems with C = P = ±1. Several b-hadron decays also produce quantum-correlated D 0 D ¯ 0 $$ {D}^0{\overline{D}}^0 $$ systems. Advantages of isolating these systems in their C = +1 components for amplitude analyses and studies of lineshapes are discussed. Methods to separate the C = ±1 D 0 D ¯ 0 $$ {D}^0{\overline{D}}^0 $$ components from χ c1(3872) decay samples are presented. Studies of T and CPT conservation in C = +1 D 0 D ¯ 0 $$ {D}^0{\overline{D}}^0 $$ systems can be performed with more easily reconstructible final states, when compared to C = −1 D 0 D ¯ 0 $$ {D}^0{\overline{D}}^0 $$ systems. Experimental mechanisms that can produce C = ±1 D 0 D ¯ 0 $$ {D}^0{\overline{D}}^0 $$ systems are described in an appendix. more...

Background: Childhood epilepsy is a prevalent neurological disorder. Imaging, especially MRI of the brain, plays a pivotal role in diagnosing the underlying cause. This study aimed to assess the frequency of causative factors of epilepsy detected in MRI. Materials and Methods: This hospital-based prospective observational study was conducted in the Radiology Department at Rajendra Institute of Medical Sciences (RIMS), Ranchi, Jharkhand, India from November 2021 to October 2022 in 100 children of 0 to 12 years of age referred from Pediatrics department for an MRI brain scan. MRI of the brain was performed in all cases and findings were analyzed and causes of epilepsy were assessed. Magnetic resonance spectroscopy (MRS) was also done when required for confirmation of diagnosis. Results: Positive findings in MRI were detected in 87% of children, and no abnormalities were detected in 13%. The majority of children belonged to the age group of 10-12 years (37%) and were predominantly males (66%). The most common cause of epilepsy was infections (27%) followed by hypoxic ischemic encephalopathy (22%). Tuberculoma was the most common infective cause of epilepsy in 59.3%. These were further followed by temporal lobe epilepsy and congenital malformations (11% each). The rest were other miscellaneous and idiopathic causes. Conclusion: MRI findings were specific to various conditions, helping in the localization and characterization of etiologies and playing a significant role in the evaluation of children who were newly diagnosed with epilepsy, especially those with partial seizures. Recommendation: Further research with a larger sample size and meta-analysis is recommended for more conclusive results. more...

The consumption of various enzymes in industrial applications around the world has increased immensely. Nowadays, industries are more focused on incorporating microbial enzymes in multiple processes to avoid the hazardous effects of chemicals. Among these commercially exploited enzymes, proteases are the most abundantly used enzymes in different industries. Numerous bacterial alkaline proteases have been studied widely and are commercially available; however, fungi exhibit a broader variety of proteases than bacteria. Additionally, since fungi are often recognized as generally regarded as safe (GRAS), using them as enzyme producers is safer than using bacteria. Fungal alkaline proteases are appealing models for industrial use because of their distinct spectrum of action and enormous diversity in terms of being active under alkaline range of pH. Unlike bacteria, fungi are less studied for alkaline protease production. Moreover, group of fungi growing at alkaline pH has remained unexplored for their capability for the production of commercially valuable products that are stable at alkaline pH. The current review focuses on the detailed classification of proteases, the production of alkaline proteases from different fungi by fermentation (submerged and solid–state), and their potential applications in detergent, leather, food, pharmaceutical industries along with their important role in silk degumming, waste management and silver recovery processes. Furthermore, the promising role of alkali–tolerant and alkaliphilic fungi in enzyme production has been discussed briefly. This will highlight the need for more research on fungi growing at alkaline pH and their biotechnological potential. more...

Zinc(II) complexes of 3-hydroxy-2-formylpyridine N(4)-methylthiosemicarbazone (1) and 3-hydroxy-2-formylpyridine N(4)-pyrrolidinyl thiosemicarbazone (2) respectively have been synthesized and characterized by elemental analysis, IR, UV–Vis, 1H NMR spectroscopy and mass spectrometry. These compounds were investigated for their antiproliferative potential against PC3 (Prostate Cancer), DU145 (Prostate Cancer), A549 (Lung Cancer), A431 (skin cancer) and Hela (Cervical Cancer cell) cell lines. All the compounds showed good antiproliferative activity against the tested cell lines. However, compound HHyPyPyrd showed remarkable antiproliferative activity against PC3 cell line with an IC50 of 0.69 µM. Cell death analysis by propidium iodide staining showed significant increase in cell death of PC3 cells in a concentration dependent manner. Furthermore, cell cycle analysis showed cell cycle arrest of PC3 cells at S phase. Our study shows that compound HHyPyPyrd induces the downregulation of JNK, c-Jun and Erk. more...

Abstract For the first time, the strong phase difference between D 0 and D¯0→π+π−π+π− $$ {\overline{D}}^0\to {\pi}^{+}{\pi}^{-}{\pi}^{+}{\pi}^{-} $$ amplitudes is determined in bins of the decay phase space. The measurement uses 818 pb−1 of e + e − collision data that is taken at the ψ(3770) resonance and collected by the CLEO-c experiment. The measurement is important for the determination of the CP -violating phase γ in B ± → DK ± (and similar) decays, where the D meson (which represents a superposition of D 0 and D¯0 $$ {\overline{D}}^0 $$) subsequently decays to π + π − π + π −. To obtain optimal sensitivity to γ, the phase space of the D → π + π − π + π − decay is divided into bins based on a recent amplitude model of the decay. Although an amplitude model is used to define the bins, the measurements obtained are model-independent. The CP -even fraction of the D → π + π − π + π − decay is determined to be F +4π = 0.769 ± 0.021 ± 0.010, where the uncertainties are statistical and systematic, respectively. Using simulated B ± → DK ±, D → π + π − π + π − decays, it is estimated that by the end of the current LHC run, the LHCb experiment could determine γ from this decay mode with an uncertainty of (±10 ± 7)°, where the first uncertainty is statistical based on estimated LHCb event yields, and the second is due to the uncertainties on the parameters determined in this paper. more...

The title complex, [Hg(C6H5)(C7H7S)], was synthesized from benzyl 4-methylpiperidine-1-carbodithioate. In the complex, the HgII cation binds to a C atom of a phenyl ring and the S atom of a benzylthiolate ligand in a linear coordination geometry. The molecule is bent at the methylene C atom and the S atom, resulting in a syn conformation with respect to the benzyl and phenyl rings. The dihedral angle between the phenyl and benzyl rings is 64.6 (2)°. The crystal structure is stabilized by intermolecular Hg...S [3.290 (3) Å] contacts and C—H...π interactions, generating a three-dimensional network. more...

In the title compound, C11H14N2O2S2, the diethyl dithioate groups are inclined slightly to the benzoyl ring, making a dihedral angle of 14.0 (3)°. A short intramolecular N—H...O contact generates an S(6) ring. In the crystal, C—H...O contacts generate a C(8) chain motif along [010]. more...

Aggression can ensue due to exposure to an intimidating situation. Aggression is prominently seen when a disturbance occurs in the fine balance of neurotransmitters such as 5-hydroxytryptamine, gamma-aminobutyric acid, dopamine and their receptor subtypes. The present study investigated the ability of 100, 200 and 400 mg/kg of ethanolic extract of Capparis zeylanica root (EECZ) circumvent aggression. Foot shock induced aggression, isolation-induced aggression, resident-intruder aggression and water competition test were utilized as models for screening of antiaggressive activity. Extract was given orally at three different dose levels (100, 200 and 400 mg/kg) once daily for three consecutive days, while Diazepam (2.5 mg/kg), was administered as positive control. EECZ significantly (p more...

Introduction: The post-menopausal phase is characterized by a decline in the serum oestrogen and progesterone levels. This phase is also associated with higher incidence of peripheral neuropathy. Aim: To explore the relationship between the peripheral motor nerve status and serum oestrogen and progesterone levels through assessment of Motor Nerve Conduction Velocity (MNCV) in post-menopausal women with peripheral neuropathy. Materials and Methods: This cross-sectional study was conducted at Jawaharlal Nehru Medical College during 2011- 2013. The study included 30 post-menopausal women with peripheral neuropathy (age: 51.4±7.9) and 30 post-menopausal women without peripheral neuropathy (control) (age: 52.5±4.9). They were compared for MNCV in median, ulnar and common peroneal nerves and serum levels of oestrogen and progesterone estimated through enzyme immunoassays. To study the relationship between hormone levels and MNCV, a stepwise linear regression analysis was done. Results: The post-menopausal women with peripheral neuropathy had significantly lower MNCV and serum oestrogen and progesterone levels as compared to control subjects. Stepwise linear regression analysis showed oestrogen with main effect on MNCV. Conclusion: The findings of the present study suggest that while the post-menopausal age group is at a greater risk of peripheral neuropathy, it is the decline in the serum estrogen levels which is critical in the development of peripheral neuropathy. more...

Many filamentous fungi were isolated from the soils of Ny-Ålesund, Spitsbergen, Svalbard, and were screened in vitro for their phosphate solubilizing ability. Two strains of Aspergillus niger showed good tricalcium phosphate (TCP) solubilizing ability in Pikovskaya's medium. The TCP solubilization index was calculated at varying levels of pH and temperatures. The ability of Aspergillus niger strain-1 to solubilize and release inorganic-P was 285 µg ml–1, while Aspergillus niger strain-2 solubilized 262 µg ml–1 from 0.5% TCP after seven days. This is the first report of TCP solubilization by Arctic strains that may serve as very good phosphate solubilizers in the form of biofertilizer. more...

The asymmetric unit of the title salt, 2C13H11N4S+·SO4−, comprises two 4-(5-anilino-1,3,4-thiadiazol-2-yl)pyridinium cations and one sulfate anion. In one cation, the phenyl ring is inclined to the pyridinium ring at a dihedral angle of 34.82 (6)°, while in other cation the rings are almost coplanar with a corresponding dihedral angle 5.33 (10)°. Strong N—H...O hydrogen bonds link the cations to the sulfate anion in the asymmetric unit. Additional N—H...O, C—H...N, C—H...O and C—H...S hydrogen bonds further stabilize the crystal structure. Weak C—H...π and π–π interactions are also observed in the crystal structure. more...

In the title compound, C13H18N2O3S2, the amide group is in the plane of the benzoyl ring with a C—N—N—C torsion angle of 177.63 (12)°. The two dithioate groups are in an anti conformation [torsion angles = 173.68 (8) and −9.98 (10)°]. An intramolecular N—H...O hydrogen bond is observed. In the crystal, an O—H...O hydrogen bond and a weak C—H...O contact involving the same acceptor atom generate an S(6) ring motif and give rise to chains along [010]. more...

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by accumulation of α-synuclein cross-β amyloid filaments in the brain. Previous structural studies of these filaments by cryo-electron microscopy (cryo-EM) revealed three discrete folds distinct from α-synuclein filaments associated with other neurodegenerative diseases. Here, we use cryo-EM to identify a novel, low-populated MSA filament subtype (designated Type I 2 ) in addition to a predominant class comprising MSA Type II 2 filaments. The 3.3-Å resolution structure of the Type I 2 filament reveals a fold consisting of two asymmetric protofilaments, one of which adopts a novel structure that is chimeric between two previously reported protofilaments. These results further define MSA-specific folds of α-synuclein filaments and have implications for designing MSA diagnostics and therapeutics., (© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.) more...

The blood-brain barrier (BBB) poses a significant obstacle in developing therapeutics for neurodegenerative diseases and central nervous system (CNS) disorders. P-glycoprotein (P-gp), a multidrug resistance protein, is a critical gatekeeper in the BBB and plays a role in cancer chemoresistance. This paper uses cryo-EM P-gp structures as starting points with an induced fit docking (IFD) model to evaluate 19 pairs of compounds with known P-gp efflux data. The study reveals significant differences in binding energy and sheds light on structural modifications' impact on efflux properties. In the cases examined, fluorine incorporation influences the efflux by altering the molecular conformation rather than proximal heteroatom basicity. Although there are limitations in addressing covalent interactions or when binding extends into the more flexible vestibule region of the protein, the results provide valuable insights and potential strategies to overcome P-gp efflux, contributing to the advancement of drug development for both CNS disorders and cancer therapies. more...

Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases., (© 2023. The Author(s).) more...

In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations, such as the labor and preparation formats needed to produce different image channels, hinders the use of certain fluorescent markers. Consequently, completed screens may lack biologically informative but experimentally impractical markers. Here, we present a deep learning method for overcoming these limitations. We accurately generated predicted fluorescent signals from other related markers and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of biologically active compounds for Alzheimer's disease (AD) from a completed high-content high-throughput screen (HCS) that had only contained the original markers. The ML method identified novel compounds that effectively blocked tau aggregation, which had been missed by traditional screening approaches unguided by ML. The method improved triaging efficiency of compound rankings over conventional rankings by raw image channels. We reproduced this ML pipeline on a biologically independent cancer-based dataset, demonstrating its generalizability. The approach is disease-agnostic and applicable across diverse fluorescence microscopy datasets., Competing Interests: Competing Interests Statement The authors declare no competing interests. Stanley B. Prusiner is a member of the Scientific Advisory Board of ViewPoint Therapeutics and a member of the Board of Directors of Trizell, Ltd., neither of which have contributed financial or any other support to the studies discussed here. more...

The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies., Competing Interests: Competing interest statement: S.B.P. is a member of the Scientific Advisory Boards of ViewPoint Therapeutics and New Ventures Inc. and a member of the Supervisory Board of Priavoid, none of which have contributed financial or any other support to these studies., (Copyright © 2022 the Author(s). Published by PNAS.) more...

The development of a water-soluble iridium catalyst enables the trifluoromethylation of polar small molecules and peptides in DMSO solution or aqueous media. The reaction was optimized in a microtiter plate format under ambient air, using commercial Langlois reagent as a CF 3 radical source, blue LEDs for excitation, and using DPBS as solvent to provide up to 60% CF 3 - peptide. more...

In the literature, C-N coupling methods for the reaction of iodo-oxazole with 2-pyridinone were found to be low yielding. C-N coupling using silver benzoate additives with CuI catalysts and 4,7-dimethoxy-1,10-phenanthroline ligands has been developed to afford synthetically useful yields of the desired heterobicycle product. The reaction conditions are applied to the coupling of a range of iodo-heterocycles with 2-pyridinone. The coupling of a variety of NH-containing heterocycles with 4-iodo-oxazole is also demonstrated. The use of 2-, 4-, or 5-iodo-oxazole allows for the coupling of pyridinone to each oxazole position., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.) more...

The addition of electron deficient radicals to the C2 position of indoles has been described in the literature as opposed to electrophilic addition at the C 3 position. Density functional theory calculations were used to understand the switch in regioselectivity from C3 to C2 for indole to undergo radical additions. Electron deficient radicals have a lower barrier for reaction at C 2 and a lower energy radical intermediate that benefits from benzylic radical stabilization. Trifluoromethyl radical addition has a lower energy barrier than acetonitrile radical, and the C 3 addition transition state is just 0.8 kcal/mol higher than C2 . This is supported by experimental observations. more...

Prions were initially discovered in studies of scrapie, a transmissible neurodegenerative disease (ND) of sheep and goats thought to be caused by slow viruses. Once scrapie was transmitted to rodents, it was discovered that the scrapie pathogen resisted inactivation by procedures that modify nucleic acids. Eventually, this novel pathogen proved to be a protein of 209 amino acids, which is encoded by a chromosomal gene. After the absence of a nucleic acid within the scrapie agent was established, the mechanism of infectivity posed a conundrum and eliminated a hypothetical virus. Subsequently, the infectious scrapie prion protein (PrPSc) enriched for β-sheet was found to be generated from the cellular prion protein (PrPC) that is predominantly α-helical. The post-translational process that features in nascent prion formation involves a templated conformational change in PrPC that results in an infectious copy of PrPSc. Thus, prions are proteins that adopt alternative conformations, which are self-propagating and found in organisms ranging from yeast to humans. Prions have been found in both Alzheimer's (AD) and Parkinson's (PD) diseases. Mutations in APP and α-synuclein genes have been shown to cause familial AD and PD. Recently, AD was found to be a double prion disorder: both Aβ and tau prions feature in this ND. Increasing evidence argues for α-synuclein prions as the cause of PD, multiple system atrophy, and Lewy body dementia., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society and the Royal Society of Biology.) more...

Tau prions feature in the brains of patients suffering from Alzheimer's disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound ( 1 ) was identified as a hit with an EC 50 value of 390 nM and 0.04 K p,uu . Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC 50 = 15 nM; K p,uu = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors., Competing Interests: The authors declare the following competing financial interest(s): The Institute for Neurodegenerative Diseases has a research collaboration with Daiichi Sankyo (Tokyo, Japan). Stanley B. Prusiner is a member of the Scientific Advisory Board of ViewPoint Therapeutics and a member of the Board of Directors of Trizell, Ltd., neither of which have contributed financial or any other support to these studies., (Copyright © 2020 American Chemical Society.) more...

The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers. See related commentary by Leber et al., p. 1511 . This article is highlighted in the In This Issue feature, p. 1494 ., (©2018 American Association for Cancer Research.) more...

The direct cyanomethylation of indoles at the 2- or 3-position was achieved via photoredox catalysis. The versatile nitrile synthon is introduced as a radical generated from bromoacetonitrile, a photocatalyst, and blue LED as a light source. The mechanism of the reaction is explored by determination of the Stern-Volmer quenching constants. By combining photophysical data and mass spectrometry to follow the catalyst decomposition, the catalyst ligands were tuned to enable synthetically useful yields of radical coupling products. A range of indole substrates with alkyl, aryl, halogen, ester, and ether functional groups participate in the reaction, affording products in 16-90% yields. The reaction allows the rapid construction of synthetically useful cyanomethylindoles, products that otherwise require several synthetic steps. more...

A convenient synthesis of α-chiral sulfinates from readily available precursors has been accomplished via the corresponding heterocyclic thioethers and sulfones. Treatment of the sulfinates with hydroxylamine sulfonate in aqueous solution provides α-C-chiral primary sulfonamides in good yield (14 examples) with retention of stereochemical purity. more...

The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models. more...

Compounds containing the tetrahydroisoquinoline ring system were prepared using solid-supported ester derivatives on a nucleophile-sensitive resin, starting from the corresponding BOC-protected amino acids. The key heterocyclic intermediates were obtained from the Pictet-Spengler reaction between ethyl glyoxylate or methyl 4-formylbenzoate and dopamine or 3-hydroxyphenethylamine. After the resulting amino esters were converted to the BOC derivatives, the phenolic hydroxyl groups were alkylated with a series of alkyl halides to afford the corresponding ethers. Ester hydrolysis afforded the BOC-protected tetrahydroisoquinoline carboxylic acid scaffolds, which were then attached to (4-hydroxyphenyl)sulfide resin (Marshall linker) as the corresponding ester. The BOC group was removed under acidic conditions, and the resulting support-bound amine hydrochlorides were converted to the corresponding amides using a set of carboxylic acids. The support-bound amides were liberated with amines to produce the desired tetrahydroisoquinoline carboxamides. Optimization of the resin loading conditions is described in addition to the identification of impurities observed during the development of the optimum conditions for solid-phase synthesis. more...

The first enantioselective organocatalytic alkylation of electron-rich benzene rings with alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective construction of benzylic stereogenicity, an important chiral synthon for natural product and medicinal agent synthesis. The (2S,5S)-5-benzyl-2-tert-butylimidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted anilines to unsaturated aldehydes. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 10 mol % were generally employed in this study, successful alkylations conducted with catalyst loadings as low as 1 mol % are described. more...