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3,4-Dihydro-2-amino-6 methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (AG337) is a water-soluble, lipophilic inhibitor of thymidylate synthase (TS) designed using X-ray structure - based methodologies to interact at the folate cofactor binding site of the enzyme. The aim of the design program was to identify TS inhibitors with different pharmacological characteristics from classical folate analogs and, most notably, to develop non-glutamate-containing molecules which would not require facilitated transport for uptake and would not undergo intracellular polyglutamylation. One molecule which resulted from this program, AG337, inhibits purified recombinant human TS with a Ki of 11 nM, and displays non-competitive inhibition kinetics. It was further shown to inhibit cell growth in a panel of cell lines of murine and human origin, displaying an IC50 of between 0.39 microM 6.6 microM. TS was suggested as the locus of action of AG337 by the ability of thymidine to antagonize cell growth inhibition and the direct demonstration of TS inhibition in whole cells using a tritium release assay. The demonstration, by flow cytometry, that AG337-treated L1210 cells were arrested in the S phase of the cell cycle was also consistent with a blockage of TS, as was the pattern of ribonucleotide and deoxyribonucleotide pool modulation in AG337-treated cells, which showed significant reduction in TTP levels. The effects of AG337 were quickly reversed on removal of the drug, suggesting, as would be expected for a lipophilic agent, that there is rapid influx and efflux from cells and no intracellular metabolism to derivatives with enhanced retention. In vivo, AG337 was highly active against the thymidine kinase-deficient murine L5178Y/TK-lymphoma implanted either i.p. or i.m. following i.p. or oral delivery. Prolonged dosing periods of 5 or 10 days were required for activity, and efficacy was improved with twice-daily dose administration. Dose levels of 25 mg/kg delivered i.p. twice daily for 10 days, 50 mg/kg once daily for 10 days, or 100 mg/kg once daily for 5 days elicited 100% cures against the i.p. tumor. Doses required for activity against the i.m. tumor were higher (100 mg/kg i.p. twice daily for 5 or 10 days) but demonstrated the ability of AG337 to penetrate solid tissue barriers. Oral delivery required doses of > or = 150 mg/kg twice daily for periods of 5-10 days to produce 100% cure rates against both i.m. and i.p. implanted tumors. These results were consistent with the pharmacokinetics parameters determined in rats, for which oral bioavailability of 30-50% was determined, together with a relatively short elimination half life of 2h. Clinical studies with AG337 are currently in progress. [ABSTRACT FROM AUTHOR]

Virtual reality (VR) is considered as one of the technological megatrends of 2020s, and today, VR systems are used in various settings, digital gaming being among the most popular ones. However, there has been a dearth of understanding regarding the central factors behind VR gaming acceptance and use. The present study therefore aimed to explain the factors that drive the use and acceptance of VR games. We extended the hedonic-motivation system acceptance model with utilitarian and inconvenience factors to capture the pertinent features of VR systems more holistically. We proposed a theoretical model and analyzed it through covariance-based structural equation modeling using an online survey sample of 473 VR gamers. Our findings help explain the role of different antecedents behind VR gaming acceptance and demonstrate that VR gaming is driven more by the hedonic gaming aspects than by the utilitarian health and well-being aspects of VR games, enjoyment being the strongest driver behind VR gaming intention and immersion. Moreover, findings also suggested that use intentions and immersion levels are not significantly diminished by physical discomfort and VR sickness. The findings, which potentially extend to other VR systems as well, also pose important implications for the providers of VR games. As the main contribution, based on our empirical findings, we provide a greater theoretical understanding on VR gaming acceptance and use., Competing Interests: Conflict of interestThe authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article., (© The Author(s) 2023.)

Covid-19 has prompted a surge of data visualizations that have been published for public consumption, yet, many have not had broad appeal or may have not been well-understood by laypeople. A data storytelling platform called Flow Immersive has been created to successfully engage both laypeople and experts in understanding complex information. This tool integrates emerging technologies [e.g., augmented reality (AR) and virtual reality (VR)] with a multiplatform, multiuser publishing approach. From October 2020 to December 2020, Flow's Covid-19 AR videos captured 9 million (9,000,000) views, and have been used in multiple professional presentations. This paper documents the journey from development to deployment, and some user feedback which all led to breakthroughs in scalability and higher levels of engagement., Competing Interests: MD is the cofounder of the company Flow Immersive.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 DiBenigno, Kosa and Johnson-Glenberg.)

An eight-member series of CF 3 -substituted difluorophosphorus corroles was prepared for establishing a structure-activity profile of these high-potential photosensitizers. It consisted of preparing all four possible isomers of the monosubstituted corrole and complexes with 2-, 3-, 4-, and 5-CF 3 groups on the macrocycle's periphery. The synthetic pathway to these CF 3 -substituted derivatives, beginning with (tpfc)PF 2 , involves two different initial routes: (i) direct electrophilic CF 3 incorporation using FSO 2 CF 2 CO 2 Me and copper iodide, or (ii) bromination to achieve the 2,3,8,17,18-pentabrominated compound using excess bromine in methanol. Crystallographic investigations revealed that distortion of the original planar macrocycle is evident even in the monosubstituted case and that it becomes truly severe for the penta-CF 3 -substituted derivative 5. There is a shift in redox potentials of about 193 mV per -CF 3 group, which decreases to only 120 mV for the fifth one in 5. Differences in the electronic spectra suggest that the Gouterman four orbital model decreases in relevance upon gradual -CF 3 substitution, a conclusion that was corroborated by DFT calculations. The very significant energy lowering of the frontier orbitals suggested that photoexcitation should lead to a highly oxidizing photocatalyst. This hypothesis was proven true by finding that the most synthetically accessible CF 3 -substituted derivative is an excellent catalyst for the photoinduced conversion of bromide to bromine (phenol, toluene, and benzene assay).

Metal-ligand coordination is a key interaction in the self-assembly of both biopolymers and synthetic oligomers. Although the binding of metal ions to synthetic proteins and peptides is known to yield high-order structures, the self-assembly of peptidomimetic molecules upon metal binding is still challenging. Herein we explore the self-assembly of three peptoid trimers bearing a bipyridine ligand at their C-terminus, a benzyl group at their N-terminus, and a polar group (N-ethyl-R) in the middle position (R=OH, OCH 3 , or NH 2 ) upon Cu 2+ coordination. X-ray diffraction analysis revealed unique, highly symmetric, dinuclear cyclic structure or aqua-bridged dinuclear double-stranded peptoid helicates, formed by the self-assembly of two peptoid molecules with two Cu 2+ ions. Only the macrocycle with the highest number of intermolecular hydrogen bonds is stable in solution, while the other two disassemble to their corresponding monometallic complexes., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We describe the construction of synthetically challenging heteroleptic complexes by capitalizing on the solubility properties of their corresponding favored homoleptic complexes. We demonstrate that the formation of a heteroleptic Cu 2+ complex based on 2,2':6',2''-terpyridine (Terpy) and 8-hydroxyquinoline (HQ) is not possible due to the insolubility of (HQ) 2 Cu 2+ . Replacing HQ with 8-hydroxy-2-quinolinecarbonitrile (HQCN) enabled the solubility of (HQCN) 2 Cu 2+ in acetonitrile, leading to the formation of the heteroleptic complex Terpy(HQCN)Cu 2+ , TQCu. Applying these conditions to the synthesis of the corresponding heteroleptic Co 2+ complex resulted in TerpyCo 2+ (acetate) 2 , which is insoluble in acetonitrile. Upon changing the solvent to methanol, the carbonitrile group of HQCN was converted to carboxyimidate HQOMe yielding a heteroleptic complex Terpy(HQOMe)Co 2+ , TQ'Co. Using this method, we also generated the heteroleptic complex TQ'Ni and the polynuclear heteroleptic complex Q'4Q''2Mn4 (Q'' = HQO 2 Me). Detailed analysis of the complexes included characterization by X-ray diffraction, EPR, UV-Vis, high resolution ESI MS, DFT calculations and electrochemistry. X-ray analysis of TQCu revealed distorted square pyramidal geometry, while TQ'Co and TQ'Ni exhibit distorted octahedral geometry, which includes metal coordination via the carboxyimidate nitrogen site. Interestingly, Q'4Q''2Mn4 was found to contain a [Mn(μ 3 -O) 2 (μ 2 -O) 4 N 10 ] 2+ core, which adopts a distorted octahedral geometry, and two types of HQ chelators. Thus, Q'4Q''2Mn4 is also heteroleptic even though it does not contain a Terpy ligand. Solution studies revealed that while TQCu is stable in solution, TQ'Co and TQ'Ni go through ligand exchange and are partially converted to their corresponding homoleptic complexes. Based on these data we could propose a mechanism for the formation of TQ'Co and TQ'Ni and show that TQ'Co can be prepared directly from Terpy and HQOMe.

Palbociclib free base capsule is a weak base drug with highly pH-dependent solubility. In vitro and in vivo studies evaluated the impact of acid-reducing agents on exposure of palbociclib and determined whether the impact, if any, can be mitigated by food. A drug-drug interaction study (study 1) was conducted first under fasted conditions and showed that coadministration of multiple doses of the proton-pump inhibitor rabeprazole substantially reduced palbociclib mean area under the concentration-time curve from time 0 to infinity and maximum observed plasma concentration by 62% and 80%, respectively. In vitro assessment suggested that the presence of bile salt mixed micelles to mimic the fed state can significantly enhance the solubility of palbociclib. Subsequently, study 2 was conducted under fed conditions and demonstrated that coadministration of rabeprazole decreased palbociclib maximum observed plasma concentration by 41% but had limited impact on area under the concentration-time curve from 0 to infinity (13% decrease). This study also showed that the histamine-2 receptor antagonist famotidine and local antacid with staggered dosing had no impact on palbociclib exposure under fed conditions. Food intake effectively mitigated the impact of acid-reducing agents on palbociclib exposure. Palbociclib free base capsule should be taken with food, and acid-reducing agent use does not need to be avoided., (© 2017, The American College of Clinical Pharmacology.)

Gold corroles are not readily accessible and they display no interesting physical or chemical properties. A facile methodology has now been developed for obtaining selectively CF 3 -substituted gold(III) corroles and the introduction of these groups has been found to have an immense effect on the structures of the complexes, their photophysical and redox properties, and on their ability to participate in catalytic processes., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)