Altemicidin and related Streptomyces-derived monoterpene alkaloids possess dense, highly polar azaindane cores as well as potent cytotoxic and tRNA synthetase inhibitory properties. The congested ...α-amino acid motif decorating their presumed iridoid-like core structure has proven to be both a synthetic challenge and a biosynthetic mystery to date. Herein, we report a distinct, abiotic strategy to these alkaloids resulting in a concise synthesis of altemicidin from simple chemical feedstocks. Key chemical findings include the exploitation of a dearomative pyridinium addition and dipolar cycloaddition sequence to stereospecifically install the quaternary amine moiety, and a chemoselective molybdenum-mediated double reduction to establish the fully functionalized azaindane nucleus with minimal redox manipulations.
Many traditional drugs inhibit enzyme function; in contrast, some naturally "sticky" small molecules can stabilize protein-protein interactions. In this issue of Cell Chemical Biology, Kaplan et al. ...(2020) explore regulation of the 14-3-3 interactome by a small-molecule molecular glue leading to neurite outgrowth through a polypharmacological mechanism.
•We modelled five scenarios of plastic waste management.•Scenarios P1–P4 include a certain amount of plastic sent to recycling.•The evaluation was performed using the life cycle assessment ...methodology.•We made a sensitivity analysis about the marginal energy.•None of the examined scenarios emerged as the best option for all impact categories.
The management of the plastic fraction is one of the most debated issues in the discussion on integrated municipal solid waste systems. Both material and energy recovery can be performed on such a waste stream, and different separate collection schemes can be implemented. The aim of the paper is to contribute to the debate, based on the analysis of different plastic waste recovery routes. Five scenarios were defined and modelled with a life cycle assessment approach using the EASEWASTE model. In the baseline scenario (P0) the plastic is treated as residual waste and routed partly to incineration with energy recovery and partly to mechanical biological treatment. A range of potential improvements in plastic management is introduced in the other four scenarios (P1–P4). P1 includes a source separation of clean plastic fractions for material recycling, whereas P2 a source separation of mixed plastic fraction for mechanical upgrading and separation into specific polymer types, with the residual plastic fraction being down-cycled and used for “wood items”. In P3 a mixed plastic fraction is source separated together with metals in a “dry bin”. In P4 plastic is mechanically separated from residual waste prior to incineration.
A sensitivity analysis on the marginal energy was carried out. Scenarios were modelled as a first step assuming that marginal electricity and heat were based on coal and on a mix of fuels and then, in the sensitivity analysis, the marginal energy was based on natural gas.
The study confirmed the difficulty to clearly identify an optimal strategy for plastic waste management. In fact none of the examined scenarios emerged univocally as the best option for all impact categories. When moving from the P0 treatment strategy to the other scenarios, substantial improvements can be obtained for “Global Warming”. For the other impact categories, results are affected by the assumption about the substituted marginal energy. Nevertheless, irrespective of the assumptions on marginal energy, scenario P4, which implies the highest quantities of specific polymer types sent to recycling, resulted the best option in most impact categories.
Conspectus From structure elucidation and biogenesis to synthetic methodology and total synthesis, terpene natural products have profoundly influenced the development of organic chemistry. Moreover, ...their myriad functional attributes range from fragrance to pharmaceuticals and have had great societal impact. Ruzicka’s formulation of the “biogenetic isoprene rule,” a Nobel Prize winning discovery now over 80 years old, allowed for identification of higher order terpene (aka “isoprenoid”) structures from simple five-carbon isoprene fragments. Notably, the isoprene rule still holds pedagogical value to students of organic chemistry today. Our laboratory has completed syntheses of over two dozen terpene and meroterpene structures to date, and the isoprene rule has served as a key pattern recognition tool for our synthetic planning purposes. At the strategic level, great opportunity exists in finding unique and synthetically simplifying ways to connect the formal C5 isoprene fragments embedded in terpenes. Biomimetic cationic polyene cyclizations represent the earliest incarnation of this idea, which has facilitated expedient routes to certain terpene polycycle classes. Nonetheless, a large swath of terpene chemical space remains inaccessible using this approach. In this Account, we describe strategic insight into our endeavors in terpene synthesis published over the last five years. We show how biosynthetic understanding, combined with a desire to utilize abundant and inexpensive C5 n building blocks, has led to efficient, abiotic syntheses of multiple complex terpenes with disparate ring systems. Informed by nature, but unconstrained by its processes, our synthetic assembly exploits chemical reactivity across diverse reaction typesincluding radical, anionic, pericyclic, and metal-mediated transformations. First, we detail an eight-step synthesis of the cembrane diterpene chatancin from dihydrofarnesal using a bioinspiredbut not -mimeticcycloaddition. Next, we describe the assembly of the antimalarial cardamom peroxide using a polyoxygenation cascade to fuse multiple units of molecular oxygen onto a dimeric skeleton. This three-to-four-step synthesis arises from (−)-myrtenal, an inexpensive pinene oxidation product. We then show how a radical cyclization cascade can forge the hallmark cyclooctane ring system of the complex sesterterpene 6-epi-ophiobolin N from two simple polyprenyl precursors, (−)-linalool and farnesol. To access the related, more complex metabolite 6-epi-ophiobolin A, we exploited the plasticity of our synthetic route and found that use of geraniol (C10) rather than farnesol (C15) gave us the flexibility needed to address the additional oxidation found in this congener. Following this work, we describe two strategies to access several guaianolide sesquiterpenes. Retrosynthetic disconnection to monoterpenes, carvone or (−)-linalool, coupled with a powerful allylation strategy allowed us to address guaianolides with disparate stereochemical motifs. Finally, we examine a semisynthetic approach to the illicium sesquiterpenes from the abundant 15-carbon feedstock terpene (+)-cedrol using an abiotic ring shift and multiple C–H oxidation reactions inspired by a postulated biosynthesis of this natural product class.
Background and aims
The role of overweight and obesity in the development of atrial fibrillation (AF) is well established; however, the differential effect on the occurrence and recurrence of AF ...remains uncertain. The aim of this review is to compare the effect of underweight and varying degrees of obesity on onset of AF and in recurrent post-ablation AF, and, when possible, in relation to sex.
Methods
A systematic literature search was conducted in PubMed, Embase, and Cochrane Library from inception to January 31, 2023. Studies reporting frequency of newly-diagnosed AF and of recurrent post-ablation AF in different BMI categories, were included. 3400 records were screened and 50 met the inclusion criteria. Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were extracted from the manuscripts and were analyzed using a random effect model. The outcome was the occurrence of AF in population studies and in patients undergoing ablation.
Results
Data from 50 studies were collected, of which 27 for newly-diagnosed AF and 23 for recurrent post-ablation AF, for a total of 15,134,939 patients, of which 15,115,181 in studies on newly-diagnosed AF and 19,758 in studies on recurrent post-ablation AF. Compared to normal weight, the increase in AF was significant (
p
< 0.01) for overweight, obese, and morbidly obese patients for newly-diagnosed AF, and for obese and morbidly obese patients for recurrent post-ablation AF. Newly-diagnosed AF was more frequent in obese female than obese male patients.
Conclusion
The effect of increased BMI was greater on the onset of AF, and obese women were more affected than men.
Several isotopic (
13C/
12C,
15N/
14N,
18O/
16O,
2H/
1H,
34S/
32S) and chemical–physical parameters (pH, fruit weight, juice yield, titratable acidity, total soluble solids, skin resistance, flesh ...firmness, colorimetric characteristics, weight loss after harvesting, antioxidant activity, earliness index, total nitrogen, ascorbic acid, synephrine, anthocyanins and polyphenols, citric acid, malic acid, sucrose, glucose and fructose content) were investigated as potential markers of organically cultivated oranges, clementines, strawberries and peaches produced in Italy between 2006 and 2008, in experimental fields and in certified farms. The ratio
15N/
14N, ascorbic acid and total soluble solids were shown to be the most significant variables for distinguishing between organically and conventionally cultivated fruits. It was not possible to define general threshold limits typical of organic fruits because these parameters are influenced also by fruit specie, cultivar, year and site of production. Combining isotopic and chemical markers a good discrimination between organic and conventional fruits of different species was achieved.
Stepping on ground can be evoked in human neonates, though it is rather irregular and stereotyped heel-to-toe roll-over pattern is lacking. Such investigations can provide insights into the role of ...contact- or load-related proprioceptive feedback during early development of locomotion. However, the detailed characteristics of foot placements and their association with motor patterns are still incompletely documented. We elicited stepping in 33 neonates supported on a table. Unilateral limb kinematics, bilateral plantar pressure distribution and EMG activity from up to 11 ipsilateral leg muscles were recorded. Foot placement characteristics in neonates showed a wide variation. In ~25% of steps, the swinging foot stepped onto the contralateral foot due to generally small step width. In the remaining steps with separate foot placements, the stance phase could start with forefoot (28%), midfoot (47%), or heel (25%) touchdowns. Despite forefoot or heel initial contacts, the kinematic and loading patterns markedly differed relatively to toe-walking or adult-like two-peaked vertical force profile. Furthermore, while the general stepping parameters (cycle duration, step length, range of motion of proximal joints) were similar, the initial foot contact was consistently associated with specific center-of-pressure excursion, range of motion in the ankle joint, and the center-of-activity of extensor muscles (being shifted by ~5% of cycle toward the end of stance in the "heel" relative to "forefoot" condition). In sum, we found a variety of footfall patterns in conjunction with associated changes in motor patterns. These findings suggest the potential contribution of load-related proprioceptive feedback and/or the expression of variations in the locomotor program already during early manifestations of stepping on ground in human babies.
Monoterpene alkaloids encompass distinct chemical diversity and wide-ranging bioactivity. Their compact complexity has made them popular as synthetic targets and has inspired many distinct strategies ...and tactics in the field of heterocyclic chemistry. This article documents the evolution of a synthetic program aimed at accessing the unusual sulfonamide-containing natural product altemicidin, which was generally believed to be a monoterpene alkaloid throughout our entire synthetic investigations but has recently been found to originate through an unexpected and quite disparate biosynthetic pathway. By leveraging a pyridine dearomatization/cycloaddition strategy, we developed a concise pathway to the 5,6-fused bicyclic azaindane core and, after significant experimentation, an ultimate synthesis of altemicidin itself. Tactics to productively manipulate the multiple functional groups present on this highly polar scaffold proved challenging but were eventually realized via several carefully orchestrated and chemoselective transformations–investments that paid dividends in the form of significantly shorter chemical synthesis. Surprisingly, the bond-forming logic between our presumed abiotic synthetic strategy to this alkaloid class and its subsequently identified biosynthetic pathway is eerily similar.
An account of synthetic work directed toward the total synthesis of the cytotoxic cephalotaxus norditerpenoid, harringtonolide, is disclosed. An initial Lewis Acid-catalyzed Diels-Alder/Ene cascade ...was designed to construct a key 6,6,5-fused tricyclic building block in a single step. While this process could not be realized in a single pot, a three-step cycloaddition/Barbier-type sequence afforded this motif, and after subsequent ring-closing metathesis, the entire 7,6,6,5-fused core of the natural product was generated. This strategy could be of use in the synthesis of various cephalotane natural products containing 7-membered rings.
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