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Abstract Background This study assesses whether comparatively high prostate cancer incidence rates among white men in Utah represent higher rates among members of the Church of Jesus Christ of Latter-day Saints (LDS or Mormons), who comprise about 70% of the state's male population, and considers the potential influence screening has on these rates. Methods Analyses are based on 14,693 histologically confirmed invasive prostate cancer cases among men aged 50 years and older identified through the Utah Cancer Registry between 1985 and 1999. Cancer records were linked to LDS Church membership records to determine LDS status. Poisson regression was used to derive rate ratios of LDS to nonLDS prostate cancer incidence, adjusted for age, disease stage, calendar time, and incidental detection. Results LDS men had a 31% (95% confidence interval, 26% – 36%) higher incidence rate of prostate cancer than nonLDS men during the study period. Rates were consistently higher among LDS men over time (118% in 1985–88, 20% in 1989–92, 15% in 1993–1996, and 13% in 1997–99); age (13% in ages 50–59, 48% in ages 60–69, 28% in ages 70–79, and 16% in ages 80 and older); and stage (36% in local/regional and 17% in unstaged). An age- and stage-shift was observed for both LDS and nonLDS men, although more pronounced among LDS men. Conclusions Comparatively high prostate cancer incidence rates among LDS men in Utah are explained, at least in part, by more aggressive screening among these men.

We report here a practical and cost-effective method for the synthesis of CHF 2 -containing benzimidazo- and indolo[2,1, a ]-isoquinolin-6(5 H )-ones through a visible light-mediated difluoromethylation/cyclization cascade. The method, which affords functionalized multifused N-heterocyclic scaffolds in moderate to high yields under mild reaction conditions, is also easily scalable using low-cost 3D printed photoflow reactors.

We report here a highly straightforward access to a variety of CHF 2 -containing heterocycles, including lactones, tetrahydrofurans, tetrahydropyrans, benzolactones, phthalanes, and pyrrolidines, through a visible light-mediated intramolecular oxy-difluoromethylation under continuous flow. The method, which relies on the use of readily available starting materials, low-cost 3D printed photoflow reactors, and difluoromethyltriphenylphosphonium bromide used here as a CHF 2 radical precursor, is practical and scalable and provides the desired products in moderate to excellent yields and excellent regio- and stereoselectivities.

We describe the development of Lewis acid (LA) catalyst-impregnated 3D-printed stirrer devices and demonstrate their ability to facilitate the rapid screening of reaction conditions to synthesize heterocycles. The stereolithography 3D-printed stirrer devices were designed to fit round-bottomed flasks and Radleys carousel tubes using our recently reported solvent-resistant resin, and using CFD modeling studies and experimental data, we demonstrated that the device design leads to rapid mixing and rapid throughput over the device surface. Using a range of LA 3D-printed stirrers, the reaction between a diamine and an aldehyde was optimized for the catalyst and solvent, and we demonstrated that use of the 3D-printed catalyst-embedded devices led to higher yields and reduced reaction times. A library of benzimidazole and benzothiazole compounds were synthesized, and the use of devices led to efficient formation of the product as well as low levels of the catalyst in the resultant crude mixture. The use of these devices makes the process of setting up multiple reactions simpler by avoiding weighing out of catalysts, and the devices, once used, can be simply removed from the reaction, making the process of compound library synthesis more facile.

In this paper, we describe a modular post-printing loading protocol for a 3D printed gastro-retentive drug delivery system. Fused Deposition Modelling (FDM) 3D printing was exploited for the rapid prototyping of a modular floating system (caps-in-cap). Optimized models were produced as blank PVA scaffolds, and a morphological analysis of the FDM printed models was conducted to develop a straightforward protocol for drug-loading. The 3D printed gastro-retentive systems were then subjected to microwave irradiation in oversaturated solutions of anhydrous caffeine for drug loading, and research focused on an analysis of the impact of microwave irradiation on the chemical and physical properties of the polymer and the drug. The drug-loading efficiency, thermal and chemical characteristics of components, the stability of the drug and the morphology of processed printouts are characterised and described. Parameters of this unexplored microwave-assisted post-printing loading technique were evaluated and adequately set up, and the process resulted in the preservation of the polymeric matrix and enhancement of drug loading. Hence, microwave impregnation confirmed its potential in superseding the traditional pre- and post-printing loading methods, such as soaking techniques, being faster and more efficient and providing a new paradigm approach to personalised drug delivery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Laboratory in vitro permeation processes require the use of modified Franz type diffusion cells which are conventionally fabricated from glass. Fragility and high cost are frequently associated with this type of laboratory apparatus. The purpose of our present research was to develop a simple, economical and versatile approach to manufacture Franz type cells using additive manufacturing (AM)., Methods: Graphical Franz diffusion cell designs were reproduced with a stereolithography (SLA) 3D printer and assessed over a minimum period of 24 h. The surface morphology of AM printouts was analysed before and after compatibility studies using scanning electron microscopy (SEM). Comparative permeation studies in both glass and AM Franz type diffusion cells were conducted using a caffeine solution (1.5 mg mL -1 ), applied to a model silicone membrane., Results: Testing of the 3D printed scaffolds confirmed similar recovery of the permeant when compared to glass cells: 1.49 ± 0.01 and 1.50 ± 0.01 mg mL -1 , respectively, after 72 h. No significant differences were visible from the SEM micrographs demonstrating consistent, smooth and non-porous surfaces of the AM Franz cells' core structure. Permeation studies using transparent 3D printed constructs resulted in 12.85 ± 0.53 µg cm -2 caffeine recovery in the receptor solution after 180 min with comparable permeant recovery, 11.49 ± 1.04 µg cm -2 , for the glass homologues., Conclusion: AM constructs can be considered as viable alternatives to the use of conventional glass apparatus offering a simple, reproducible and cost-effective method of replicating specialised laboratory glassware. A wider range of permeants will be investigated in future studies with these novel 3D printed Franz diffusion cells., (© 2020 The Authors. International Journal of Cosmetic Science published by John Wiley & Sons Ltd on behalf of Society of Cosmetic Scientists and Société Française de Cosmetologié.)

Focused libraries of multi-substituted epidithiodiketopiperazines (ETP) were prepared and evaluated for efficacy of inhibiting the nucleocapsid protein function of the Feline Immunodeficiency Virus (FIV) as a model for HIV. This activity was compared and contrasted to observed toxicity utilising an in-vitro cell culture approach. This resulted in the identification of several promising lead compounds with nanomolar potency in cells with low toxicity and a favorable therapeutic index., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In vitro permeation studies using nail clippings or nail plates are commonly used in the development of transungual formulations. However, there are ethical, safety and cost issues associated with sourcing such tissues. Herein, we describe a preliminary approach is described for the design and manufacture of a human nail model surrogate based on 3D printing. To evaluate these 3D printed constructs, nails were mounted in conventional glass Franz cells and a commercial antifungal lacquer formulation containing ciclopirox olamine was applied daily to the surrogate printed surfaces for a period of 14 days. On days 8 and 14, the surfaces of the 3D printed nails were washed with ethanol to remove excess formulation. Confocal Raman spectroscopy (CRS) was used to profile the drug in the 3D printed nail. At the end of the Franz cell studies, no drug was observed in the receptor phase. CRS studies confirmed penetration of the active into the model nails with reproducible depth profiles. Our ongoing work is focused on synthesising commercial and non-commercial printable resins that can replicate the physical and chemical characteristics of the human nail. This will allow further evaluation of actives for ungual therapy and advance the development of the surrogate nail tissue model., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

A small diverse library of pentathiepin derivatives were prepared to evaluate their efficacy against the nucleocapsid protein function of the feline immunodeficiency virus (FIV) as a model for HIV, using an in vitro cell culture approach. This study led to the development of nanomolar active compounds with low toxicity., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Franz cells are routinely used to measure in vitro skin permeation of actives and must be inert to the permeant under study. The aim of the present work was to develop and manufacture transparent Franz-type diffusion cells using 3D printing. Printouts were then tested using a range of model active compounds. The study also aims to identify the critical 3D-printing parameters necessary for the process, including object design, choice of printing resin, printout curing and post-curing settings and introduction of model coatings., Methods: Transparent Franz cells were constructed using an online computer aided design program and reproduced with different stereolithography 3D printers. The two acrylate-based resins used for the fabrication process were a commercially available product and a polymer synthesised in-house. Comparative studies between glass and 3D-printed Franz cells were conducted with selected model actives: terbinafine hydrochloride (TBF), niacinamide (NIA), diclofenac free acid (DFA) and n-methyl paraben (MPB). In preliminary studies, MPB showed the lowest recovery when exposed to the receptor compartment of 3D printed cells. Consequently, in vitro permeation studies were carried out using only MPB with polydimethylsiloxane (PDMS) membrane., Results: A decrease in the amounts of selected compounds was observed for transparent 3D-printed Franz cells compared to glass cells. MPB showed the lowest recovery (53.8 ± 13.1%) when compared with NIA (74.9 ± 4.0%), TBF (81.5 ± 12.0%) and DFA (90.2 ± 12.9%) after 72 h. Permeation studies conducted using 3D-printed transparent cells with PDMS membrane also showed a decrease in MPB recovery of 51.4 ± 3.7% for the commercial resin and 94.4 ± 3.5% for the polymer synthesised in-house, when compared to glass cells. Although hydrophobic coatings were subsequently applied to the 3D-printed cells, the same reduction in MPB concentration was observed in the receptor solution., Conclusion: Transparent Franz cells were successfully prepared using 3D printing and were observed to be robust and leak-proof. There are few resins currently available for preparation of transparent materials and incompatibilities between the actives investigated and the 3D-printed cells were evident. Hydrophobic coatings applied as barriers to the printed materials did not prevent these interactions., (© 2018 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

The 26S proteasome is the major proteolytic machine for breaking down cytosolic and nuclear proteins in eukaryotes. Due to the lack of a suitable assay, it is difficult to measure routinely and quantitatively the breakdown of proteins by the 26S proteasome in vitro. In the present study, we developed an assay to monitor proteasome-mediated protein degradation. Using this assay, we discovered that epidithiodiketopiperazine (ETPs) blocked the degradation of our model substrate in vitro. Further characterization revealed that ETPs inhibited proteasome function by targeting the essential proteasomal deubiquitinase Rpn11 (POH1/PSMD14). ETPs also inhibited other JAMM (JAB1/MPN/Mov34 metalloenzyme) proteases such as Csn5 and AMSH. An improved ETP with fewer non-specific effects, SOP11, stabilized a subset of proteasome substrates in cells, induced the unfolded protein response, and led to cell death. SOP11 represents a class of Rpn11 inhibitor and provides an alternative route to develop proteasome inhibitors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We have synthesized a novel small molecule based on the pyrrolidinone-containing core structure of clausenamide, which is a candidate anti-dementia drug. The synthetic route yielded multi-gram quantities of an isomeric racemate mixture in a short number of steps. When tested in hippocampal slices from young adult rats the compound enhanced AMPA receptor-mediated signalling at mossy fibre synapses, and potentiated inward currents evoked by local application of l-glutamate onto CA3 pyramidal neurons. It facilitated the induction of mossy fibre LTP, but the magnitude of potentiation was smaller than that observed in untreated slices. The racemic mixture was separated and it was shown that only the (-) enantiomer was active. Toxicity analysis indicated that cell lines tolerated the compound at concentrations well above those enhancing synaptic transmission. Our results unveil a small molecule whose physiological signature resembles that of a potent nootropic drug., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate in situ Enterococcus faecalis biofilm removal from the lateral canal of a simulated root canal system using passive or active irrigation protocols., Methodology: Root canal models (n = 43) were manufactured from transparent resin materials using 3D printing. Each canal was created with an 18 mm length, apical size 30, a .06 taper and a lateral canal of 3 mm length, with 0.3 mm diameter. Biofilms were grown in the lateral canal and apical 3 mm of the main canal for 10 days. Three models from each group were examined for residual biofilm using SEM. The other forty models were divided into four groups (n = 10). The models were observed under a fluorescence microscope. Following 60 s of 9 mL of 2.5% NaOCl irrigation using syringe and needle, the irrigant was either left stagnant in the canal or activated using gutta-percha, sonic or ultrasonic methods for 30 s. Images were then captured every second using an external camera. The residual biofilm percentages were measured using image analysis software. The data were analysed using generalized linear mixed models. A significance level of 0.05 was used throughout., Results: The greatest level of biofilm removal was obtained with ultrasonic agitation (66.76%) followed by sonic (45.49%), manual agitation (43.97%) and passive irrigation groups (38.67%), respectively. The differences were significant between the residual biofilm in the passive irrigation and both sonic and ultrasonic groups (P = 0.001)., Conclusion: Agitation resulted in better penetration of 2.5% NaOCl into the lateral canal of an artificial root canal model. Ultrasonic agitation of NaOCl improved the removal of biofilm., (© 2017 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

To investigate the effect of sodium hypochlorite concentration and needle extension on removal of Enterococcus faecalis biofilm, sixty root canal models were 3D printed. Biofilms were grown on the apical 3 mm of the canal for 10 days. Irrigation for 60s with 9 mL of either 5.25% or 2.5% NaOCl or water was performed using a needle inserted either 3 or 2 mm from the canal terminus and imaged using fluorescence microscopy and residual biofilm percentages were calculated using imaging software. The data were analysed using analysis of covariance and two-sample t-tests. A significance level of 0.05 was used throughout. Residual biofilm was less using 5.25% than with 2.5% NaOCl. Statistically significant biofilm removal was evident with the needle placed closer to the canal terminus. A greater reduction of available chlorine and pH was noted as the concentration increased. One-minute irrigation was not sufficient for complete biofilm removal., (© 2017 Australian Society of Endodontology Inc.)

Root canal irrigation is an important adjunct to control microbial infection. The aim of this study was to investigate the effect of 2.5% (wt/vol) sodium hypochlorite (NaOCl) agitation on the removal, killing, and degradation of Enterococcus faecalis biofilm. A total of 45 root canal models were manufactured using 3D printing with each model comprising an 18 mm length simulated root canal of apical size 30 and taper 0.06. E. faecalis biofilms were grown on the apical 3 mm of the models for 10 days. A total of 60 s of 9 ml of 2.5% NaOCl irrigation using syringe and needle was performed, the irrigant was either left stagnant in the canal or agitated using manual (Gutta-percha), sonic, and ultrasonic methods for 30 s. Following irrigation, the residual biofilms were observed using confocal laser scanning, scanning electron, and transmission electron microscopy. The data were analyzed using one-way ANOVA with Dunnett post hoc tests at a level of significance p ≤ .05. Consequence of root canal irrigation indicate that the reduction in the amount of biofilm achieved with the active irrigation groups (manual, sonic, and ultrasonic) was significantly greater when compared with the passive and untreated groups (p < .05). Collectively, finding indicate that passive irrigation exhibited more residual biofilm on the model surface than irrigant agitated by manual or automated (sonic, ultrasonic) methods. Total biofilm degradation and nonviable cells were associated with the ultrasonic group., (© 2017 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

The increasing prevalence of wound infections caused by antibiotic resistant bacteria is an urgent challenge facing modern medicine. To address this issue the expedient use of antimicrobial metals such as zinc, copper and silver were incorporated into an FDA-approved polymer (polycaprolactone - PCL) to produce filaments for 3D printing. These metals have broad-spectrum antimicrobial properties, and moreover, copper and zinc can enhance the wound healing process. 3D scanning was used to construct 3D models of a nose and ear to provide the opportunity to customize shape and size of a wound dressing to an individual patient. Hot melt extrusion was used to extrude pellets obtained by vacuum-drying of solutions of PCL and the different metals in order to manufacture metal-homogeneously-loaded filaments. Wound dressings with different shapes were produced with the filaments containing different concentrations of metals. Release of the metals from the dressings was determined by inductively coupled plasma atomic emission spectroscopy. All the different metal dressings show fast release (up to 24h) followed by slow release (up to 72h). The antibacterial efficacy of the wound dressings was tested using a thermal activity monitor system, revealing that silver and copper wound dressings had the most potent bactericidal properties. This study shows that 3D scanning and 3D printing, which are becoming simpler and more affordable, have the potential to offer solutions to produce personalised wound dressings., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

An intramolecular acylal cyclisation (IAC) approach to the synthesis of a range of bicyclic heterocycles is reported. As an example of the utility of the IAC reaction, the methodology was applied in a protecting-group-free five-step total synthesis of (±)-γ-lycorane, incorporating a new intramolecular Heck addition reaction to generate the pentacyclic core structure of the natural product in good yield., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The aims were to compare the physico-chemical properties (zeta-potential, wettability, surface free energy) of stereolithography materials (STL) (Photopolymer, Accura) to dentine and to evaluate the potential of each material to develop Enterococcus faecalis biofilm on their respective surfaces. Eighteen samples of each test material (Photopolymer, Accura, dentine) were employed (total n = 54) and sectioned to 1 mm squares (5 mm x 5 mm) (n = 15) or ground into a powder to measure zeta-potential (n = 3). The zeta-potential of the powder was measured using the Nano-Zetasizer technique. The contact angle (wettability, surface free energy tests) were measured on nine samples using goniometer. The biofilm attachment onto the substrate was assessed on the samples of each material using microscope and image processing software. The data were compared using one-way ANOVA with Dunnett post-hoc tests at a level of significance P ≤ 0.05. Both STL materials showed similar physico-chemical properties to dentine. The materials and dentine had negative charge (Accura: -23.7 mv, Photopolymer: -18.8 mv, dentine: -9.11 mv). The wettability test showed that all test materials were hydrophilic with a contact angle of 47.5°, 39.8°, 36.1° for Accura, Photopolymer and dentine respectively, and a surface free energy of 46.6, 57.7, 59.6 mN/m for Accura, Photopolymer and dentine, respectively. The materials and dentine proved suitable for attachment and growth of E. faecalis biofilm with no statistical differences (P > 0.05). Stereolithography materials show similar physico-chemical properties and growth of E. faecalis biofilm to dentine. Therefore, they may be an alternative to tests requiring dentine., (© 2016 Wiley Periodicals, Inc.)

The objective of this study was to examine the effect of pulsed light (PL) treatment on the color, oxidative stability, and onset of molding of Cheddar cheese. Slices of sharp white Cheddar cheese of 2.5 × 5 cm were treated on one side with PL doses from 1.02 to 12.29 J/cm 2 , sealed in polyethylene bags, and stored at 6°C for up to 1 mo. Peroxide value, color parameters, and the onset of molding were evaluated. No significant changes in color or peroxide value were observed for PL-treated samples compared with the untreated controls. Pulsed light was able to significantly delay surface molding during refrigerated storage, with a PL dose of 9.22 J/cm 2 delaying the onset of molding by 7 d. The effect of PL on the taste, appearance, and acceptability of Cheddar cheese slices treated with a PL dose of 9.22 J/cm 2 on each side was assessed. In triangle tests, 60 untrained panelists were unable to detect significant differences between the control and PL-treated samples, although PL had a significant effect on overall liking, flavor, and appearance. These findings suggest that although PL can be effective for surface decontamination of cheese, it may have some detrimental effects on sensory properties., (Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

A diverse library of 5-thieno-, 5-oxo-, and 5-imino-1,2,3-dithiazole derivatives was synthesized and evaluated for efficacy against the feline immunodeficiency virus (FIV) as a model for HIV in cells. Several diverse compounds from this series displayed nanomolar activity and low toxicity, representing a potential new class of compounds for the treatment of FIV and HIV., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Root canal irrigation is an important adjunct to control microbial infection. This study aimed primarily to develop a transparent root canal model to study in situ Enterococcus faecalis biofilm removal rate and remaining attached biofilm using passive or active irrigation solution for 90s. The change in available chlorine and pH of the outflow irrigant were assessed., Methods: A total of forty root canal models (n=10 per group) were manufactured using 3D printing. Each model consisted of two longitudinal halves of an 18mm length simulated root canal with size 30 and taper 0.06. E. faecalis biofilms were grown on the apical 3mm of the models for 10days in Brain Heart Infusion broth. Biofilms were stained using crystal violet for visualization. The model halves were reassembled, attached to an apparatus and observed under a fluorescence microscope. Following 60s of 9mL of 2.5% NaOCl irrigation using syringe and needle, the irrigant was either left stagnant in the canal or activated using gutta-percha, sonic and ultrasonic methods for 30s. Images were then captured every second using an external camera. The residual biofilm percentages were measured using image analysis software. The data were analyzed using Kruskal-Wallis test and generalized linear mixed model., Results: The highest level of biofilm removal was with ultrasonic agitation (90.13%) followed by sonic (88.72%), gutta-percha (80.59%), and passive irrigation group (control) (43.67%) respectively. All agitation groups reduced the available chlorine and pH of NaOCl more than that in the passive irrigation group., Significance: The 3D printing method provided a novel model to create a root canal simulation for studying and understanding a real-time biofilm removal under microscopy. Ultrasonic agitation of NaOCl left the least amount of residual biofilm in comparison to sonic and gutta-percha agitation methods., (Copyright © 2016 The Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.)

The cost of 3D printing has reduced dramatically over the last few years and is now within reach of many scientific laboratories. This work presents an example of how 3D printing can be applied to the development of custom laboratory equipment that is specifically adapted for use with the novel brain tissue clearing technique, CLARITY. A simple, freely available online software tool was used, along with consumer-grade equipment, to produce a brain slicing chamber and a combined antibody staining and imaging chamber. Using standard 3D printers we were able to produce research-grade parts in an iterative manner at a fraction of the cost of commercial equipment. 3D printing provides a reproducible, flexible, simple and cost-effective method for researchers to produce the equipment needed to quickly adopt new methods., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Compounds that comprise the erythrina alkaloid class of natural products are based on a tetracyclic spiroamine framework and exhibit a range of biological activities on the central nervous system. Herein, we report a new and efficient total synthesis of this multiple-ring system based on an intramolecular acylal cyclisation (IAC) approach. Using this methodology, the tetracyclic core was rapidly assembled over a two-step domino process catalysed by a Lewis acid. The effect of heteroatoms, substituents and ring size on the IAC has also been investigated, and the broad application of this procedure is demonstrated by the synthesis of a library of derivatives in good yields with excellent regioselectivity., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel series of fused tetrathiocines were prepared for evaluation of activity against the nucleocapsid protein of the feline immunodeficiency virus (FIV) in an in vitro cell culture approach. The results demonstrated that the compounds display potent nanomolar activity and low toxicity against this key model of HIV infection., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

A diverse library of bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrrole derivatives were prepared for evaluation of activity against the nucleocapsid protein of the Feline Immunodeficiency Virus (FIV) as a model for HIV, using an in vitro cell culture approach, yielding nanomolar active compounds with low toxicity., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

The synthesis together with biophysical and biological evaluation of a series of tetra-substituted naphthalene diimide (ND) compounds, are presented. These compounds are positional isomers of a recently-described series of quadruplex-binding ND derivatives, in which the two N-methyl-piperidine-alkyl side-chains have now been interchanged with the positions of side-chains bearing a range of end-groups. Molecular dynamics simulations of a pair of positional isomers are in accord with the quadruplex stabilization and biological data for these compounds. Analysis of structure-activity data indicates that for compounds where the side-chains are not of equivalent length then the positional isomers described here tend to have improved cell proliferation potency and in some instances, superior quadruplex stabilization ability., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The hypoxic response in humans is regulated by the hypoxia-inducible transcription factor system; inhibition of hypoxia-inducible factor (HIF) activity has potential for the treatment of cancer. Chetomin, a member of the epidithiodiketopiperazine (ETP) family of natural products, inhibits the interaction between HIF-alpha and the transcriptional coactivator p300. Structure-activity studies employing both natural and synthetic ETP derivatives reveal that only the structurally unique ETP core is required and sufficient to block the interaction of HIF-1alpha and p300. In support of both cell-based and animal work showing that the cytotoxic effect of ETPs is reduced by the addition of Zn(2+) through an unknown mechanism, our mechanistic studies reveal that ETPs react with p300, causing zinc ion ejection. Cell studies with both natural and synthetic ETPs demonstrated a decrease in vascular endothelial growth factor and antiproliferative effects that were abrogated by zinc supplementation. The results have implications for the design of selective ETPs and for the interaction of ETPs with other zinc ion-binding protein targets involved in gene expression.

Primary alcohols can be coupled with secondary benzylic alcohols by an air-stable catalytic system involving terpyridine ruthenium or iridium complexes.

A range of thiyl radicals derived from the reduced form of epidithiodiketopiperazines (ETPs) act as polarity reversal catalysts for the hydrosilylation of an enol lactone but not for H-atom abstraction from a model ribose ester.

[reaction: see text]Reaction of indole amides 5 with tributylstannane gave spiroindolenines 9 which are readily converted into spiropyrrolidinyloxindoles. This tricyclic system is found in a number of interesting natural products.