Total Synthesis of 4-epi-Bengamide E.

Bengamide E is a bioactive natural product that was isolated from Jaspidae sponges by Crews and co-workers in 1989. It displays a wide range of biological activities, including antitumor, antibiotic, and anthelmintic properties. With the aim of investigating the structural feature essential for their activity, several total syntheses of Bengamide E and its analogues have been reported in the literature. Nevertheless, no synthesis of the stereoisomer with modification of its configuration at C-4 carbon has been reported so far. Here, we report the first total synthesis of the 4-epi-Bengamide E. Key reactions in the synthesis include a chemoenzimatic desymmetrization of biobased starting materials and a diastereoselective Passerini reaction using a chiral, enantiomerically pure aldehyde, and a lysine-derived novel isocyanide.

The Groebke-Blackburn-Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019-2023).

The Groebke-Blackburn-Bienaymé (GBB) three-component reaction, discovered in 1998, is a very efficient strategy to assemble imidazo[1,2-a]-heterocycles starting from amidines, aldehydes and isocyanides. This review aims to exhaustively describe innovative aspects of this reaction achieved during the last five years, and classifies them into five categories: synthetic methods, building blocks, scaffolds, biological activities and physical properties.

Probable airborne transmission in a nosocomial Sars-CoV-2 outbreak with an high attack rate.

Throughout the current COVID-19 pandemic, preventing nosocomial COVID-19 outbreaks has been a significant challenge for hospitals. It is essential to understand the ways in which SARS-CoV-2 spreads in healthcare settings to apply proper infection prevention and control (IPC) measures. The objectives of this study are to report on the hospital's response to a COVID-19 cluster and the transmission dynamics in a hospital ward of Geriatrics, Rehabilitation and Long term care. The study will focus specifically on how insufficient air replacement and directional airflow in indoor settings may have contributed to the transmission of the virus.

Catalyst-free [2 + 2] photocycloadditions between benzils and olefins under visible light.

The catalyst-free [2 + 2] photocycloaddition between benzils and simple olefins is reported. The adoption of visible light proved essential for the transformation, as shorter wavelengths led to uncontrolled decomposition. When cyclic olefins were used, the reaction occurred smoothly to afford the expected oxetanes regio- and stereoselectively after 24 h of irradiation. In contrast, in the case of acyclic olefins, longer reaction times were typically required and small amounts (ca. 20%) of [4 + 2] photocycloadducts and by-products deriving from competitive hydrogen atom abstraction were observed. The selectivity of the transformation could be consistently improved by decreasing the reaction temperature, thus restoring the desired [2 + 2] reactivity. An overall mechanistic picture is also offered based on the chemical and photophysical quenching experiments and the stereochemical output is rationalized based on Griesbeck models.

Into the Blue: Ketene Multicomponent Reactions under Visible Light.

For the first time, a detailed study on the photophysical properties of variously substituted diazoketones and on their photoreactivity under blue LED irradiation was carried out. Despite very limited absorbance in the visible region, we have demonstrated that, independently from their structure, α-diazoketones all undergo a very efficient Wolff rearrangement. Contrarily to the same UV-mediated reaction, where photons can give rise to side processes, in this case, almost all absorbed photons are selective and effective, and the quantum yield is close to 100%. If the rearrangement is carried out in the presence of isocyanides and carboxylic acids/silanols, the photoreactivity is not affected, and the resulting ketenes can afford α-acyloxy- and α-silyloxyacrylamides through two distinct multicomponent reactions, performed both in batch and under continuous flow, with improved selectivity and broader scope. These photoinduced multicomponent reactions can be coupled with other visible-light-mediated transformations, thus increasing the diversity of the molecules obtainable by this approach.

Transcriptional profiling of embryo cryotolerance.

The cryosurvival of embryos is a complex process involving dynamic and integrated morphological, functional, and molecular changes. Here, we evaluated the transcriptional profiling of bovine embryos possessing high and low cryotolerance (HC and LC, respectively) by assessing the resumption of development. Embryos were produced in vitro (N = 1137) and cryopreserved (N = 894). Blastocysts samples possessed pronounced group individualization at RNA sequencing. A total of 114 genes were differentially expressed, and 27 and 84 genes were upregulated in HC and LC, respectively. Among the over-represented biological functions, cellular growth and proliferation, cell death and survival, and organismal survival were predicted to be activated, while cellular movement and cell-to-cell signaling were predicted to be inhibited in HC embryos. Enriched canonical pathways and upstream regulators related to cellular proliferation and survival (HC), inflammatory processes, and cell death (LC) were predicted to represent two embryonic molecular profiles present during the resumption of development after cryopreservation. The marked contrast in transcriptional profiles between HC and LC strongly suggests the influence of embryonic competence after cryopreservation on its respective transcriptome and indicated that HC and LC presented two different molecular strategies to overcome cryopreservation-related stress and resume postcryopreservation development.

Synthesis of Polyoxygenated Heterocycles by Diastereoselective Functionalization of a Bio-Based Chiral Aldehyde Exploiting the Passerini Reaction.

A chiral bio-based building block, prepared by the lipase-mediated desymmetrization of an erythritol derivative, was further functionalized and then submitted to stereoselective Passerini reactions, allowing the synthesis of a small library of new molecules. Thanks to the presence of different functional groups, further cyclizations were performed providing bicyclic polyoxygenated heterocycles.

Multicomponent Synthesis of Polyphenols and their in vitro Evaluation as Potential ß-Amyloid Aggregation Inhibitors.

While plant polyphenols possess a variety of biological properties, exploration of chemical diversity around them is still problematic. Here, an example of application of the Ugi multicomponent reaction to the combinatorial assembly of artificial, yet "natural-like", polyphenols is presented. The synthesized compounds represent a second-generation library directed to the inhibition of ß-amyloid protein aggregation. Chiral enantiopure compounds, and polyphenol-ß-lactam hybrids have been prepared too. The biochemical assays have highlighted the importance of the key pharmacophores in these compounds. A lead for inhibition of aggregation of truncated protein AßpE3-42 was selected.

Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence.

Tocotrienols (T3) have been shown to represent a very important part of the vitamin E family since they have opened new opportunities to prevent or treat a multitude of age-related chronic diseases. The beneficial effects of T3 include the amelioration of lipid profile, the promotion of Nrf2 mediated cytoprotective activity and the suppression of inflammation. All these effects may be the consequence of the ability of T3 to target multiple pathways. We here propose that these effects may be the result of a single target of T3, namely senescent cells. Indeed, T3 may act by a direct suppression of the senescence-associated secretory phenotype (SASP) produced by senescent cells, mediated by inhibition of NF-kB and mTOR, or may potentially remove the origin of the SASP trough senolysis (selective death of senescent cells). Further studies addressed to investigate the impact of T3 on cellular senescence "in vitro" as well as in experimental models of age-related diseases "in vivo" are clearly encouraged.

Discovery of a highly potent orally bioavailable imidazo-[1, 2-a]pyrazine Aurora inhibitor.

Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.

Integrating biocatalysis and multicomponent reactions.

While often multicomponent reactions (MCR) are used for the diversity-oriented synthesis of racemic (or achiral) molecular entities, this short review describes two alternative approaches for accessing enantiopure products exploiting the power of biocatalysis. Enzymes or microorganisms may be used for preparing enantiopure MCR inputs or for resolving racemic (or achiral) MCR adducts.

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy.

The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

To each his own: isonitriles for all flavors. Functionalized isocyanides as valuable tools in organic synthesis.

The term functionalized isocyanides refers to all those isocyanides in which a neighbouring functional group can finely tune the reactivity of the isocyano group or can be exploited in post-functionalization processes. In this manuscript, we have reviewed all the isocyanides in which the pendant functional group causes either deviation from or reinforces the normal reactivity of the isocyano group and categorized them to highlight their common features and differences. An analysis of their synthetic potential and the possible unexplored directions for future research studies is also addressed.

Multi-Gram Synthesis of Enantiopure 1,5-Disubstituted Tetrazoles Via Ugi-Azide 3-Component Reaction.

Tetrazoles have been widely studied for their biological properties. An efficient route for large-scale synthesis of 1,5-disubstituted tetrazoles (1,5-DTs) is presented. The strategy exploits a reductive approach to synthetize a cyclic chiral imine substrate which is then converted into the target product through an Ugi-azide three-component reaction (UA-3CR). The final products are equipped with additional functionalities which can be further elaborated for the generation of combinatorial libraries of enantiopure heterocycles.

A total evidence phylogeny for the processionary moths of the genus Thaumetopoea (Lepidoptera: Notodontidae: Thaumetopoeinae).

Processionary moths belong to a group of about 100 species well known for their social behaviour and their urticating systems. The genus Thaumetopoea s.l. includes about 15 species and has been divided into three genera (Helianthocampa, Thaumetopoea s.s., and Traumatocampa) in the last revision, based on key morphological features of the adults and on the host plants of the larvae. We performed a total evidence approach to resolve the phylogeny of the genus Thaumetopoea s.l., analysing all valid taxa included in this group, plus a broad array of close relatives. Thaumetopoea was monophyletic and supported by several apomorphies. Further subclades corroborated by synapomorphies were identified. Our phylogeny suggests that Thaumetopoea must be regarded as a single genus. The mapping of key life history traits on the total evidence tree allowed us to sketch a plausible identikit of the Thaumetopoea ancestor and to track the evolution of the genus. The ancestor originated in the eastern Mediterranean area, and used broadleaved host plants. Subsequently, a switch to conifers occurred, just once, in a large subclade. The ancestor pupated in the soil, like several current species, but in a few taxa this trait was lost, together with the related morphological adaptations.

Different transcriptional profiling between senescent and non-senescent human coronary artery endothelial cells (HCAECs) by Omeprazole and Lansoprazole treatment.

Recent evidence suggests that high dose and/or long term use of proton pump inhibitors (PPIs) may increase the risk of adverse cardiovascular events in older patients, but mechanisms underlying these detrimental effects are not known. Taking into account that the senescent endothelial cells have been implicated in the genesis or promotion of age-related cardiovascular disease, we hypothesized an active role of PPIs in senescent cells. The aim of this study is to investigate the changes in gene expression occurring in senescent and non-senescent human coronary artery endothelial cells (HCAECs) following Omeprazole (OPZ) or Lansoprazole (LPZ) treatment. Here, we show that atherogenic response is among the most regulated processes in PPI-treated HCAECs. PPIs induced down-regulation of anti-atherogenic chemokines (CXCL11, CXCL12 and CX3CL1) in senescent but not in non-senescent cells, while the same chemokines were up-regulated in untreated senescent cells. These findings support the hypothesis that up-regulated anti-atherogenic chemokines may represent a defensive mechanism against atherosclerosis during cellular senescence, and suggest that PPIs could activate pro-atherogenic pathways by changing the secretory phenotype of senescent HCAECs. Moreover, the genes coding for fatty acid binding protein 4 (FABP4) and piezo-type mechanosensitive ion channel component 2 (PIEZO2) were modulated by PPIs treatment with respect to untreated cells. In conclusions, our results show that long-term and high dose use of PPI could change the secretory phenotype of senescent cells, suggesting one of the potential mechanisms by which use of PPI can increase adverse outcomes in older subjects.

Gene Expression, Oxidative Stress, and Senescence of Primary Coronary Endothelial Cells Exposed to Postprandial Serum of Healthy Adult and Elderly Volunteers after Oven-Cooked Meat Meals.

Epidemiological studies have linked high consumption of meat with major age-related diseases including cardiovascular diseases. Abnormal postprandial increases in plasma lipids after a meat meal have been hypothesized among the pathogenetic mechanisms. However, it is still unknown if the postprandial serum derived after a normal meat meal is able to affect endothelial function, and if the type of meat and the age of the donors are critical factors. Here, we show the effects of postprandial sera derived from healthy adults and elderly volunteers who consumed meat meals on human coronary artery endothelial cell (HCAEC) oxidative stress, gene expression, DNA damage, and cellular senescence. We observed that a single exposure to postprandial serum induces a slight increase in ROS that is associated with modulation of gene expression pathways related to oxidative stress response and metabolism. The postprandial-induced increase in ROS is not associated with a measurable DNA oxidative damage. However, repeated exposure to postprandial serum induces an acceleration of cellular senescence. Taking into account the deleterious role of cellular senescence in age-related vascular diseases, the results suggest a new mechanism by which excessive meat consumption and time spent in postprandial state may affect health status during aging.

Photocatalyzed synthesis of isochromanones and isobenzofuranones under batch and flow conditions.

Photocatalyzed reactions of 2-(alkoxycarbonyl)benzenediazonium tetrafluoroborates with various alkenes afforded isochromanones in good yields, according to a mechanism that was investigated. The advantage of using highly soluble esters rather than carboxylic acids as starting compounds became evident when the reactions were performed under flow conditions. On the other hand, when 2-vinylbenzoic acid derivatives were employed as reagents, isobenzofuranones were obtained together with unprecedented benzo[e][1,3]oxazepin-1(5H)-ones, with the latter derived from incorporation of the solvent (acetonitrile).

Circadian rhythms of body temperature and locomotor activity in aging BALB/c mice: early and late life span predictors.

Impairment of one or more parameters of circadian rhythms (CR) of body temperature (BT) and locomotor activity (LMA) are considered among the hallmarks of mammalian aging. These alterations are frequently used as markers for imminent death in laboratory mice. However, there are still contradictory data for particular strains and it is also uncertain which changes might predict senescence changes later in life, including the force of mortality. In the present paper we use telemetry to study LMA and CR of BT during aging of BALB/c mice. At our knowledge this is the first time that CR of BT and LMA are investigated in this strain in a range of age covering the whole lifespan, from young adult up to very old age. CR of BT was analyzed with a cosine model using a cross sectional approach and follow-up measurements. The results show that BT, LMA, amplitude, goodness-of-fit (GoF) to circadian cycle of temperature decrease with different shapes during chronological age. Moreover, we found that the % change of amplitude and BT in early life (5-19 months) can predict the remaining lifespan of the mice. Later in life (22-32 months), best predictors are single measurements of LMA and GoF. The results of this study also offer potential measures to rapidly identifying freely unrestrained mice with the worst longitudinal outcome and against which existing or novel biomarkers and treatments may be assessed.

Passerini Reactions on Biocatalytically Derived Chiral Azetidines.

The purpose of this study was to explore a series of Passerini reactions on a biocatalytically derived enantiopure azetidine-2-carboxyaldehyde in order to obtain, in a diastereoselective manner, polyfunctionalised derivatives having the potential to be cyclized to chiral bridged bicyclic nitrogen heterocycles. While diastereoselectivity was poor under classical Passerini conditions, a significant increase of diastereoselectivity (up to 76:24) was gained by the use of zinc bromide as promoter. The methodology has a broad scope and yields are always good.