Synthesis of ß-Pyridyl α-Amino Acids: Conformationally Sensitive Charge Transfer-Based Fluorophores.

Unnatural α-amino acids with charge transfer-based poly aromatic side chains have been designed as conformationally sensitive fluorophores. These were prepared using a hetero-Diels-Alder reaction and a Knoevenagel-Stobbe process to generate a biaryl pyridyl unit, followed by iron-catalyzed bromination and a Suzuki-Miyaura cross-coupling reaction to complete the triaryl system. A photophysical study led to the discovery of a p-methoxy analogue which exhibited viscosity-sensitive fluorescence in which emission could be controlled between twisted and planar conformations.

Hot off the Press.

A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products, such as penihemeroterpenoid A from Penicillium herquei.

Fluorescent carbazole-derived α-amino acids: structural mimics of tryptophan.

Fluorescent tags are commonly used for imaging of proteins and peptides during biological events; however, the large size of dyes can disrupt protein structure and function, and typically require the use of a chemical spacer. Herein, we report the synthesis of a new class of fluorescent unnatural α-amino acid, containing carbazole side-chains designed to mimic l-tryptophan and thus, readily incorporated into peptides. The amino acids were constructed using a Negishi cross-coupling reaction as the key step and exhibited strong fluorescent emission, with high quantum yields in both organic solvents and water. Compatible with solid phase peptide synthesis, the carbazole amino acids were used to replace tryptophan in a ß-hairpin model peptide and shown to be a close structural mimic with retention of conformation. They were also found to be effective fluorescent molecular reporters for biological events. Incorporation into a proline-rich ligand of the WW domain protein demonstrated that the fluorescent properties of a carbazole amino acid could be used to measure the protein-protein binding interaction of this important biological signalling process.

Hot off the Press.

A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as eugeniinaline A from Leuconotis eugeniifolia.

Sexually dimorphic murine brain uptake of the 18†kDa translocator protein PET radiotracer [18F]LW223.

The 18 kDa translocator protein is a well-known biomarker of neuroinflammation, but also plays a role in homeostasis. PET with 18 kDa translocator protein radiotracers [11C]PBR28 in humans and [18F]GE180 in mice has demonstrated sex-dependent uptake patterns in the healthy brain, suggesting sex-dependent 18 kDa translocator protein expression, although humans and mice had differing results. This study aimed to assess whether the 18 kDa translocator protein PET radiotracer [18F]LW223 exhibited sexually dimorphic uptake in healthy murine brain and peripheral organs. Male and female C57Bl6/J mice (13.6 ± 5.4 weeks, 26.8 ± 5.4 g, mean ± SD) underwent 2 h PET scanning post-administration of [18F]LW223 (6.7 ± 3.6 MBq). Volume of interest and parametric analyses were performed using standard uptake values (90-120 min). Statistical differences were assessed by unpaired t-test or two-way ANOVA with Sidak's test (alpha = 0.05). The uptake of [18F]LW223 was significantly higher across multiple regions of the male mouse brain, with the most pronounced difference detected in hypothalamus (P < 0.0001). Males also exhibited significantly higher [18F]LW223 uptake in the heart when compared to females (P = 0.0107). Data support previous findings on sexually dimorphic 18 kDa translocator protein radiotracer uptake patterns in mice and highlight the need to conduct sex-controlled comparisons in 18 kDa translocator protein PET imaging studies.

The impact of time to death in donors after circulatory death on recipient outcome in simultaneous pancreas-kidney transplantation.

The time to arrest donors after circulatory death is unpredictable and can vary. This leads to variable periods of warm ischemic damage prior to pancreas transplantation. There is little evidence supporting procurement team stand-down times based on donor time to death (TTD). We examined what impact TTD had on pancreas graft outcomes following donors after circulatory death (DCD) simultaneous pancreas-kidney transplantation. Data were extracted from the UK transplant registry from 2014 to 2022. Predictors of graft loss were evaluated using a Cox proportional hazards model. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. Three-hundred-and-seventy-five DCD simultaneous kidney-pancreas transplant recipients were included. Increasing TTD was not associated with graft survival (adjusted hazard ratio HR 0.98, 95% confidence interval 0.68-1.41, P = .901). Increasing asystolic time worsened graft survival (adjusted hazard ratio 2.51, 95% confidence interval 1.16-5.43, P = .020). Restricted cubic spline modeling revealed a nonlinear relationship between asystolic time and graft survival and no relationship between TTD and graft survival. We found no evidence that TTD impacts pancreas graft survival after DCD simultaneous pancreas-kidney transplantation; however, increasing asystolic time was a significant predictor of graft loss. Procurement teams should attempt to minimize asystolic time to optimize pancreas graft survival rather than focus on the duration of TTD.

Hot off the press.

A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as dcalycinumine A from Daphniphyllum calycinum.

Ligand-Enabled Copper-Mediated Radioiodination of Arenes.

The discovery of a copper precatalyst that facilitates the key mechanistic steps of arene halodeboronation has allowed a step change in the synthesis of radioiodine-containing arenes. The active precatalyst [Cu(OAc)(phen)2]OAc was shown to perform room temperature radio-iododeboronation of aryl boronic acids with 1-2 mol % loadings and 10 min reaction times. These mild conditions enable particularly clean reactions, as demonstrated with the efficient preparation of the radiopharmaceutical and SPECT tracer, meta-iodobenzylguanidine (MIBG).

Correction: Hot off the Press.

Correction for 'Hot off the Press' by Robert A. Hill et al., Nat. Prod. Rep., 2023, 40, 1816-1821, https://doi.org/10.1039/d3np90052e.

Insulin independence following islet transplantation improves long-term metabolic outcomes.

AIMS: Pancreatic islet allotransplantation is an effective therapy for type 1 diabetes mellitus, restoring glycaemic control and hypoglycaemic awareness in patients with recurrent severe hypoglycaemia. Insulin independence following transplant is being increasingly reported; however, this is not a primary endpoint in the UK. Having surpassed 10 years of islet transplantation in Scotland, we aimed to evaluate the impact of insulin independence following transplant on metabolic outcomes and graft survival. METHODS: We conducted a retrospective analysis on data collected prospectively between 2011 and 2022. Patients who underwent islet transplantation in Scotland up to the 31st January 2020 were included. Primary endpoint was graft survival (stimulated C-peptide >50 pmol/L). Secondary endpoints included GOLD score, HbA1c, C-peptide and insulin requirement. Outcomes were compared between patients who achieved insulin independence at any point following transplant versus those who did not. RESULTS: 60 patients were included. 74.5% experienced >50 severe hypoglycaemic episodes in the year preceding transplant. There was a 55.0% decrease in insulin requirement following transplant and 30.0% achieved insulin independence. Mean graft survival time was 9.0 years (95% CI 7.2-10.9) in patients who achieved insulin independence versus 4.4 years (95% CI 3.4-5.3) in patients who did not. Insulin independence was associated with significantly improved graft function, glycaemic control and hypoglycaemic awareness at 1 year. CONCLUSIONS: This is the largest UK single-centre study on islet transplant to date. Our findings demonstrate significantly improved outcomes in patients who achieved insulin independence following islet transplantation.

British Transplantation Society guidelines on abdominal organ transplantation from deceased donors after circulatory death.

The British Transplantation Society (BTS) 'Guideline on transplantation from deceased donors after circulatory death' has recently been updated and this manuscript summarises the relevant recommendations in abdominal organ transplantation from Donation after Circulatory Death (DCD) donors, encompassing the chapters on liver, kidney, pancreas and islet cell transplantation.

[18F]LW223 has low non-displaceable binding in murine brain, enabling high sensitivity TSPO PET imaging.

Neuroinflammation is associated with a number of brain diseases, making it a common feature of cerebral pathology. Among the best-known biomarkers for neuroinflammation in Positron Emission Tomography (PET) research is the 18 kDa translocator protein (TSPO). This study aims to investigate the binding kinetics of a novel TSPO PET radiotracer, [18F]LW223, in mice and specifically assess its volume of non-displaceable binding (VND) in brain as well as investigate the use of simplified analysis approaches for quantification of [18F]LW223 PET data. Adult male mice were injected with [18F]LW223 and varying concentrations of LW223 (0.003-0.55 mg/kg) to estimate VND of [18F]LW223. Dynamic PET imaging with arterial input function studies and radiometabolite studies were conducted. Simplified quantification methods, standard uptake values (SUV) and apparent volume of distribution (VTapp), were investigated. [18F]LW223 had low VND in the brain (<10% of total binding) and low radiometabolism (∼15-20%). The 2-tissue compartment model provided the best fit for [18F]LW223 PET data, although its correlation with SUV90-120min or VTapp allowed for [18F]LW223 brain PET data quantification in healthy animals while using simpler experimental and analytical approaches. [18F]LW223 has the required properties to become a successful TSPO PET radiotracer.

Trifluoromethylthiolation of Arenes Using Lewis Acid and Lewis Base Dual Catalysis.

Incorporation of the highly lipophilic trifluoromethanesulfenyl group into bioactive molecules facilitates transport through lipid membranes, and thus, CF3S-containing compounds are important for drug discovery. Although reagents and procedures have been reported for arene trifluoromethylthiolation, methods are still required that are applicable to a diverse substrate scope and can be performed under mild conditions. Here, we describe a rapid and efficient approach for the trifluoromethylthiolation of arenes by catalytic activation of N-trifluoromethylthiosaccharin using a combination of iron(III) chloride and diphenyl selenide. This dual catalytic process allowed regioselective functionalization of a wide range of arenes and N-heterocycles under mild conditions and was used for the trifluoromethylthiolation of bioactive compounds such as tyrosine and estradiol.

Hot off the Press.

A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as alscholarine A from Alstonia scholaris.

Synthesis of Thiazoloindole α-Amino Acids: Chromophores Amenable to One- and Two-Photon Induced Fluorescence.

Thiazoloindole α-amino acids have been synthesized in four steps from tryptophan using a dual-catalytic thiolation reaction and a copper-mediated intramolecular N-arylation process. Late-stage diversification of the thiazoloindole core with electron-deficient aryl substituents produced chromophores that on one-photon excitation displayed blue-green emission, mega-Stokes shifts, and high quantum yields. The thiazoloindole amino acids could also be excited via two-photon absorption in the near-infrared, demonstrating their potential for biomedical imaging applications.

Phylogenetic analyses of Reticulitermes (Blattodea: Rhinotermitidae) from California and other western states: multiple genes confirm undescribed species identified by cuticular hydrocarbons.

Subterranean termites in the genus Reticulitermes Holmgren 1913 are among the most economically important wood-destroying pests in the western United States. Yet, there remains uncertainty regarding the taxonomy and biology of the species in this genus. The 2 species described as having distributions in this region are the western subterranean termite, Reticulitermes hesperus Banks, and the arid land subterranean termite, Reticulitermes tibialis Banks. Taxonomic studies utilizing cuticular hydrocarbon (CHC) profiles, agonistic behavior, flight phenology, and mitochondrial DNA (mtDNA) suggested that R. hesperus is a species complex comprised of 2 or more sympatric, yet reproductively isolated species. To further delineate these taxa, we examined multiple genes from samples of Reticulitermes collected in the western United States. Alates collected after recent spring and fall mating flights, as well as previously collected workers, were subjected to CHC phenotyping and DNA sequence analyses that targeted mitochondrial cytochrome oxidase subunit II (COII), mitochondrial 16S rRNA, and nuclear Internal Transcribed Spacer 1 and 2 (ITS1 and 2). Phylogenetic analyses conducted also included published sequences of other putative western Reticulitermes species. Results suggest that at least 5 species of Reticulitermes may be present in California and that Reticulitermes in Arizona consistently group into multiple clades, including samples previously identified as R. tibialis in a sister clade. These analyses further support the species status of qualitatively different CHC phenotypes and that alates swarming in spring vs. fall are reproductively isolated species.

Colo-colonic intussusception secondary to a lipomatous lesion in an asymptomatic patient.

Colo-colonic intussusception is a rare clinical condition in adults. The predominant aetiology of intussusception in adults is a pathological lead point, with malignant lesions being the most common type. Lipomas are benign tumours of adipocytes that can sometimes be difficult to diagnose without histopathological confirmation as we highlight with this case report. We report a case of an asymptomatic female patient in her 50s who presented with an intussusception due to a giant colonic lipoma. Her CT imaging showed the possibility of a low-grade liposarcomatous component or atypical lipomatous tumour component. A laparoscopic right hemicolectomy was performed due to intussusception with the possibility of leading to colonic obstruction as well as diagnostic uncertainty of the risk of malignancy. Histopathology confirmed the diagnosis of a lipomatous lesion. In cases such as this, early surgical management is appropriate to rule out malignancy and prevent emergency presentation and surgery.

Synthesis and Photophysical Properties of Charge-Transfer-Based Pyrimidine-Derived α-Amino Acids.

The four-step synthesis of fluorescent pyrimidine-derived α-amino acids from an l-aspartic acid derivative is described. The key synthetic steps involved preparation of ynone intermediates via the reaction of alkynyl lithium salts with a Weinreb amide, followed by an ytterbium-catalyzed heterocyclization reaction with amidines. Variation of substituents at the C2- and C4-position of the pyrimidine ring allowed tuning of the photoluminescent properties of the α-amino acids. This revealed that a combination of highly conjugated or electron-rich aryl substituents with the π-deficient pyrimidine motif resulted in fluorophores with the highest quantum yields and overall brightness. Further analysis of the most fluorogenic α-amino acid demonstrated solvatochromism and sensitivity to pH.

Fluorescent α-amino acids via Heck-Matsuda reactions of phenylalanine-derived arenediazonium salts.

The Heck-Matsuda coupling reaction of arenediazonium salts derived from L-phenylalanine with various alkenes has been developed. A two-step process involving the preparation of a tetrafluoroborate diazonium salt from a 4-aminophenylalanine derivative, followed by a palladium(0)-catalysed Heck-Matsuda coupling reaction allowed access to a range of unnatural α-amino acids with cinnamate, vinylsulfone and stilbene side-chains. Analysis of the photophysical properties of these unnatural α-amino acids demonstrated that the (E)-stilbene analogues exhibited fluorescent properties with red-shifted absorption and emission spectra and larger quantum yields than L-phenylalanine.