Relationship between the colours of the rivers in the Amazon and the incidence of malaria.

BACKGROUND: Malaria is transmitted by different Anopheles species. In Brazil, the disease is concentrated in the Amazon region. Rivers play an important role in the life cycle of malaria since the vector reproduces in aquatic environments. The waters of the rivers in the Amazon have distinct chemical characteristics, which affect the colour of the water and therefore, the study analysed whether the colour of the waters of the rivers have an on influence the distribution of malaria. The goal of the study was to correlate the different colourations of the water (black, white and mixed water) and the malaria incidence in 50 municipalities of the Amazonas state, Brazil, and then test hypotheses about the characteristics of the colour of the rivers and disease incidence. METHODS: This study was conducted for a period of seventeen years (2003-2019) in 50 municipalities in the state of Amazonas, Brazil. A conditionally Gaussian dynamic linear model was developed to analyse the association of malaria incidence and three types of river colour: white, black and mixed. RESULTS: The analyses indicate that the distribution of malaria is related to the colouration of the rivers. The results showed that places located near black-water rivers have a higher malaria incidence when compared to places on the banks of white-water rivers. CONCLUSIONS: Historically, the hydrological regime has played an important role in the dynamics of malaria in the Amazon, but little is known about the relationship between river colours and the incidence of the disease. This research was carried out in a region with hydrographic characteristics that were heterogeneous enough to allow an analysis that contrasted different colours of the rivers and covered almost the whole of the state of Amazonas. The results help to identify the places with the highest risk of malaria transmission and it is believed that they will be able to contribute to more precise planning of actions aimed at controlling the disease in the region.

Population Pharmacokinetic Modeling and Determination of Individual Exposure to Avalglucosidase Alfa in Adolescent and Adult Patients With Late-Onset Pompe Disease: Analysis of Pooled Data From Phase I to III Clinical Trials.

BACKGROUND: Pompe disease is a rare genetic disorder caused by a deficiency of a lysosomal enzyme called acid alpha-glucosidase and is classified into infantile and late-onset forms. Since 2006, an enzyme replacement therapy involving alglucosidase alfa has been available. In 2021, a new enzyme replacement therapy involving avalglucosidase alfa demonstrated improved clinical benefits. In this article, the authors describe the pharmacokinetics of avalglucosidase alfa using a population pharmacokinetic approach. METHODS: The population pharmacokinetic model was developed using a data set that included 75 patients and 2042 plasma drug concentrations determined through enzymatic activity assay from 3 studies (phases I/II and III) and involved 3 dose levels (5, 10, and 20 mg/kg). The analysis was performed using NONMEM software. RESULTS: Two sequences were observed in the plasma drug concentration profile: the first kinetic driving exposure, and after 12 hours postdose, a slight rebound addressing very low concentrations that lasted up to 2 weeks. Following model screening, a model with a central compartment with parallel linear and nonlinear elimination and 2 concatenated peripheral compartments was proposed. A putative back-redistribution of a marginal fraction of the drug from the second peripheral compartment to the central compartment may explain the slight rebound in concentration. The final model's mean bias and precision for individual predictions were -2.66% and 30.7%, respectively, and -0.433% and 38.9%, respectively, for population predictions. CONCLUSIONS: A concatenated 3-compartment model was developed to describe the avalglucosidase alfa concentrations in patients with late-onset Pompe disease. None of the covariates tested could explain the interindividual variability.

Population pharmacokinetic modeling and dosing simulation of avalglucosidase alfa for selecting alternative dosing regimen in pediatric patients with late-onset pompe disease.

Avalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from three clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1-12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1-17 years) and adult patients. Corresponding simulated individual exposures (maximal concentration, Cmax and area under the curve in the 2-week dosing interval, AUC2W), and distributions were calculated. It was found that dosing of 40 mg/kg and 20 mg/kg in pediatric patients < 30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC2W) to adult patients receiving 20 mg/kg. PK simulations conducted on the basis of this model provided supporting data for the currently approved US labelling for dosing adapted bodyweight in LOPD patients ≥ 1 year by USFDA.

1-Aminobicyclo[2.2.2]octane-2-carboxylic Acid and Derivatives As Chiral Constrained Bridged Scaffolds for Foldamers and Chiral Catalysts.

The improvement of molecular diversity is one of the major concerns of chemists since the continuous development of original synthetic molecules provides unique scaffolds usable in organic and bioorganic chemistry. The challenge is to develop versatile platforms with highly controlled chemical three-dimensional space thanks to controlled chirality and conformational restraints. In this respect, cyclic ß-amino acids are of great interest with applications in various fields of chemistry. In addition to their intrinsic biological properties, they are important precursors for the synthesis of new generations of bioactive compounds such as antibiotics, enzyme inhibitors, and antitumor agents. They have also been involved in asymmetric synthesis as efficient organo-catalysts in their free form and as derivatives. Finally, constrained cyclic ß-amino acids have been incorporated into oligomers to successfully stabilize original structures in foldamer science with recent successes in health, material science, and catalysis. Over the last ∼10 years, we focused on bicyclic ß-amino acids possessing a bicyclo[2.2.2]octane structure. This latter is a structural key element in numerous families of biologically active natural and synthetic products and is an interesting template for asymmetric synthesis. Nonetheless, reported studies on bicyclic carbo-bridged compounds are rather limited compared to those on bicyclic-fused and heterobridged derivatives. In this Account, we particularly focused on the synthesis and applications of the 1-aminobicyclo[2.2.2]octane-2-carboxylic acid, named, ABOC, and its derivatives. This highly constrained bicyclic ß-amino acid, with a sterically hindered bridgehead primary amine and an endocyclic chiral center, displays drastically reduced conformational freedom. In addition, its high bulkiness strongly impacts the spatial orientation of the appended functionalities and the conformation of adjacent building blocks. Thus, we have first expanded a fundamental synthetic work by a wide ranging study in the field of foldamers, in the design of various stable peptide/peptidomimetic helical structures incorporating the ABOC residue (11/9-, 18/16-, 12/14/14-, and 12/10-helices). In addition, such bicyclic residue was fully compatible with and stabilized the canonical oligourea helix, whereas very few cyclic ß-amino acids have been incorporated into oligoureas. In addition, we have pursued with the synthesis of some ABOC derivatives, in particular the 1,2-diaminobicyclo[2.2.2]octane chiral diamine, named DABO, and its investigation in chiral catalytic systems. Covalent organo-catalysis of the aldol reaction using ABOC-containing tripeptide catalysts provided a range of aldol products with high enantioselectivity. Moreover, the double reductive condensation of DABO with various aldehydes allowed the building of new chiral ligands that proved their efficiency in the copper-catalyzed asymmetric Henry reaction.

Continuous Monitoring of Suspended Particulate Matter in Tropical Inland Waters by High-Frequency, Above-Water Radiometry.

Water and sediment discharges can change rapidly, and low-frequency measurement devices might not be sufficient to elucidate existing dynamics. As such, above-water radiometry might enhance monitoring of suspended particulate matter (SPM) dynamics in inland waters. However, it has been barely applied for continuous monitoring, especially under partially cloudy sky conditions. In this study, an in situ, high-frequency (30 s timestep), above-water radiometric dataset, collected over 18 days in a tropical reservoir, is analyzed for the purpose of continuous monitoring of SPM concentration. Different modalities to retrieve reflectance spectra, as well as SPM inversion algorithms, were applied and evaluated. We propose a sequence of processing that achieved an average unsigned percent difference (UPD) of 10.4% during cloudy conditions and 4.6% during clear-sky conditions for Rrs (665 nm), compared to the respective UPD values of 88.23% and 13.17% when using a simple calculation approach. SPM retrieval methods were also evaluated and, depending on the methods used, we show that the coefficient of variation (CV) of the SPM concentration varied from 69.5% down to 2.7% when using a semi-analytical approach. As such, the proposed processing approach is effective at reducing unwanted variability in the resulting SPM concentration assessed from above-water radiometry, and our work paves the way towards the use of this noninvasive technique for high-frequency monitoring of SPM concentrations in streams and lakes.

1,3-Diazepine: A privileged scaffold in medicinal chemistry.

Privileged structures have been widely used as effective templates for drug discovery. While benzo-1,4-diazepine constitutes the first historical example of such a structure, the 1,3 analogue is just as rich in terms of applications in medicinal chemistry. The 1,3-diazepine moiety is present in numerous biological active compounds including natural products, and is used to design compounds displaying a large range of biological activities. It is present in the clinically used anticancer compound pentostatin, in several recent FDA approved ß-lactamase inhibitors (e.g., avibactam) and also in coformycin, a natural product known as a ring-expanded purine analogue displaying antiviral and anticancer activities. Several other 1,3-diazepine containing compounds have entered into clinical trials. This heterocyclic structure has been and is still widely used in medicinal chemistry to design enzyme inhibitors, GPCR ligands, and so forth. This review endeavours to highlight the main use of the 1,3-diazepine scaffold and its derivatives, and their applications in medicinal chemistry, drug design, and therapy. We will focus more particularly on the development of enzyme inhibitors incorporating this scaffold, with a strong emphasis on the molecular interactions involved in the inhibition mechanism.

Alternative Technologies That Facilitate Access to Discrete Metal Complexes.

Organometallic complexes: these two words jump to the mind of the chemist and are directly associated with their utility in catalysis or as a pharmaceutical. Nevertheless, to be able to use them, it is necessary to synthesize them, and it is not always a small matter. Typically, synthesis is via solution chemistry, using a round-bottom flask and a magnetic or mechanical stirrer. This review takes stock of alternative technologies currently available in laboratories that facilitate the synthesis of such complexes. We highlight five such technologies: mechanochemistry, also known as solvent-free chemistry, uses a mortar and pestle or a ball mill; microwave activation can drastically reduce reaction times; ultrasonic activation promotes chemical reactions because of cavitation phenomena; photochemistry, which uses light radiation to initiate reactions; and continuous flow chemistry, which is increasingly used to simplify scale-up. While facilitating the synthesis of organometallic compounds, these enabling technologies also allow access to compounds that cannot be obtained in any other way. This shows how the paradigm is changing and evolving toward new technologies, without necessarily abandoning the round-bottom flask. A bright future is ahead of the organometallic chemist, thanks to these novel technologies.

Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide.

The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT6R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Non-physiological activation of mTOR kinase by constitutively active 5-HT6R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT6R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT6R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats.

GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation.

The growth hormone secretagogue receptor (GHSR) and dopamine receptor (D2R) have been shown to oligomerize in hypothalamic neurons with a significant effect on dopamine signaling, but the molecular processes underlying this effect are still obscure. We used here the purified GHSR and D2R to establish that these two receptors assemble in a lipid environment as a tetrameric complex composed of two each of the receptors. This complex further recruits G proteins to give rise to an assembly with only two G protein trimers bound to a receptor tetramer. We further demonstrate that receptor heteromerization directly impacts on dopamine-mediated Gi protein activation by modulating the conformation of its α-subunit. Indeed, association to the purified GHSR:D2R heteromer triggers a different active conformation of Gαi that is linked to a higher rate of GTP binding and a faster dissociation from the heteromeric receptor. This is an additional mechanism to expand the repertoire of GPCR signaling modulation that could have implications for the control of dopamine signaling in normal and physiopathological conditions.

A beat-by-beat cardiovascular index, CARDEAN, to titrate opioid administration in the setting of orthopaedic surgery: a prospective randomized trial.

To determine whether a beat-by-beat cardiovascular index (CARDEAN: cardiovascular depth of analgesia, Alpha-2 Ltd, Lyon, France) reduces the incidence of tachycardia in ASA I-III patients undergoing orthopaedic surgery. A total of 76 patients were prospectively randomized into (1) a control group or (2) the CARDEAN group, in which the nurse anaesthetist was blinded to CARDEAN application. In addition to conventional signs, an external observer instructed the nurse anaesthetist to administer sufentanil 0.1 µg kg-1 when the CARDEAN crossed a threshold (≥ 60). The primary outcome was the incidence of tachycardia (> 120% of reference heart rate, HR). Non-invasive blood pressure (BP), electrocardiogram (ECG), O2 saturation-photoplethysmography and the bispectral index (40 < BIS < 60) were monitored. HR and an estimation of beat-by-beat BP changes acquired from photoplethysmography and ECG were combined in an algorithm that detected hypertension followed by tachycardia (index scaled 0-100). Sufentanil 0.1 µg kg-1 was administered when tachycardia, hypertension or movement ("conventional signs") was observed. Data for 66 patients (27 with known hypertension) were analysed. In the CARDEAN group, (a) the dose of sufentanil was higher (control: 0.46 µg kg-1 100 min-1, CARDEAN: 0.57 µg kg-1 100 min-1, p = 0.016), (b) the incidence rates of tachycardia and untoward events were lower (respectively: - 44%; control: 2.52 events 100 min-1 [1.98-3.22]; CARDEAN: 1.42 [1.03-1.96], p = 0.005, hazard ratio: 0.56; movement, muscular contraction, or coughing: control: 0.74 events 100 min-1 [0.47-1.16]; CARDEAN: 0.31 [0.15-0.62], p = 0.038), and (c) extubation occurred more often in the operating room (control: 76.5%, CARDEAN: 97%, p = 0.016). CARDEAN-titrated opioid administration was associated with a higher dose of sufentanil, a reduction in tachycardia and earlier emergence in ASA I-III patients undergoing major orthopaedic surgery.

Direct Synthesis of Peptide-Containing Silicones: A New Way to Bioactive Materials.

A simple and efficient way to synthesize peptide-containing silicone materials is described. Silicone oils containing a chosen ratio of bioactive peptide sequences were prepared by acid-catalyzed copolymerization of dichlorodimethylsilane, hybrid dichloromethyl peptidosilane, and Si(vinyl)- or SiH-functionalized monomers. Functionalized silicone oils were first obtained and then, after hydrosilylation cross-linking, bioactive polydimethylsiloxane (PDMS)-based materials were straightforwardly obtained. The introduction of an antibacterial peptide yielded PDMS materials showing activity against Staphylococcus aureus. PDMS containing RGD ligands showed improved cell-adhesion properties. This generic method was fully compatible with the stability of peptides and thus opened the way to the synthesis of a wide range of biologically active silicones.

Amazon River carbon dioxide outgassing fuelled by wetlands.

River systems connect the terrestrial biosphere, the atmosphere and the ocean in the global carbon cycle. A recent estimate suggests that up to 3 petagrams of carbon per year could be emitted as carbon dioxide (CO2) from global inland waters, offsetting the carbon uptake by terrestrial ecosystems. It is generally assumed that inland waters emit carbon that has been previously fixed upstream by land plant photosynthesis, then transferred to soils, and subsequently transported downstream in run-off. But at the scale of entire drainage basins, the lateral carbon fluxes carried by small rivers upstream do not account for all of the CO2 emitted from inundated areas downstream. Three-quarters of the world's flooded land consists of temporary wetlands, but the contribution of these productive ecosystems to the inland water carbon budget has been largely overlooked. Here we show that wetlands pump large amounts of atmospheric CO2 into river waters in the floodplains of the central Amazon. Flooded forests and floating vegetation export large amounts of carbon to river waters and the dissolved CO2 can be transported dozens to hundreds of kilometres downstream before being emitted. We estimate that Amazonian wetlands export half of their gross primary production to river waters as dissolved CO2 and organic carbon, compared with only a few per cent of gross primary production exported in upland (not flooded) ecosystems. Moreover, we suggest that wetland carbon export is potentially large enough to account for at least the 0.21 petagrams of carbon emitted per year as CO2 from the central Amazon River and its floodplains. Global carbon budgets should explicitly address temporary or vegetated flooded areas, because these ecosystems combine high aerial primary production with large, fast carbon export, potentially supporting a substantial fraction of CO2 evasion from inland waters.

Chemical insights into bioinks for 3D printing.

3D printing has triggered the acceleration of numerous research areas in health sciences, which traditionally used cells as starting materials, in particular tissue engineering, regenerative medicine and also in the design of more relevant bioassays for drug discovery and development. While cells can be successfully printed in 2D layers without the help of any supporting biomaterial, the obtainment of more complex 3D architectures requires a specific bioink, i.e. a material in which the cells are embedded during and after the printing process helping to support them while they are arranged in superimposed layers. The bioink plays a critical role in bioprinting: first, it must be adapted to the 3D printing technology; then, it must fulfil the physicochemical and mechanical characteristics of the target construct (e.g. stiffness, elasticity, robustness, transparency); finally it should guarantee cell viability and eventually induce a desired behaviour. This review focuses on the nature of bioink components of natural or synthetic origin, and highlights the chemistry required for the establishment of the 3D network in conditions compatible with the selected 3D printing technique and cell survival.

Parvimico materdei gen. et sp. nov.: A new platyrrhine from the Early Miocene of the Amazon Basin, Peru.

Three field seasons of exploration along the Río Alto Madre de Dios in Peruvian Amazonia have yielded a fauna of micromammals from a new locality AMD-45, at ∼12.8°S. So far we have identified the new primate described here as well as small caviomorph rodents, cenolestoid marsupials, interatheriid notoungulates, xenarthrans, fish, lizards and invertebrates. The site is in the Bala Formation as exposed where the river transects a syncline. U-Pb dates on detrital zircons constrain the locality's age at between 17.1 ± 0.7 Ma and 18.9 ± 0.7 Ma, making the fauna age-equivalent to that from the Pinturas Formation and the older parts of the Santa Cruz Formation of Patagonian Argentina (Santacrucian). The primate specimen is an unworn M1 of exceptionally small size (equivalent in size to the extant callitrichine, Callithrix jacchus, among the smallest living platyrrhines and the smallest Eocene-Early Miocene platyrrhine yet recorded). Despite its small size it is unlike extant callitrichines in having a prominent cingulum hypocone. Based on the moderate development of the buccal crests, this animal likely had a diet similar to that of frugivorous callitrichines, and distinctly different from the more similarly-sized gummivores, Cebuella and C. jacchus. The phyletic position of the new taxon is uncertain, especially given the autapomorphic character of the tooth as a whole. Nevertheless, its unusual morphology hints at a wholly original and hitherto unknown Amazonian fauna, and reinforces the impression of the geographic separation of the Amazonian tropics from the more geographically isolated southerly parts of the continent in Early Miocene times.

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold.

The review highlights the hydantoin syntheses presented from the point of view of the preparation methods. Novel synthetic routes to various hydantoin structures, the advances brought to the classical methods in the aim of producing more sustainable and environmentally friendly procedures for the preparation of these biomolecules, and a critical comparison of the different synthetic approaches developed in the last twelve years are also described. The review is composed of 95 schemes, 8 figures and 528 references for the last 12 years and includes the description of the hydantoin-based marketed drugs and clinical candidates.

Beyond Ideology: Epistemological Foundations of Vladimir Fock's approach to Quantum Theory.

Vladimir Fock was a Soviet theoretical physicist who, from the 1930s, worked to prove that modern physics was compatible with the Marxist philosophy of dialectical materialism. In 1957, he went to Copenhagen, and a dispute over the interpretation of quantum mechanics began with Niels Bohr. Fock later claimed that he had found points of convergence with his Danish colleague, most of them concerning issues of wording and recognition of the reality of the world independently of our mind. It led to a specific narrative among historians of physics on Fock and his interpretation of quantum mechanics: The Soviet physicist is often described as a member of the Copenhagen school that contributed to the rapprochement of the Soviet philosophy of physics with the ideas of complementarity in stripping away the positivism in its formulation. Our contribution aims to show that this ideological dimension was only one aspect of reality. Returning to the foundations of Fock's epistemology of physics, we argue that he relied on the principles of antireductionism and scientific realism to develop an interpretation of the theory that sought to overcome Bohr's approach and that the differences between the two men cannot be reduced to mere questions of formulation.

Indoloazepinone-Constrained Oligomers as Cell-Penetrating and Blood-Brain-Barrier-Permeating Compounds.

Non-cationic and amphipathic indoloazepinone-constrained (Aia) oligomers have been synthesized as new vectors for intracellular delivery. The conformational preferences of the [l-Aia-Xxx]n oligomers were investigated by circular dichroism (CD) and NMR spectroscopy. Whereas Boc-[l-Aia-Gly]2,4 -OBn oligomers 12 and 13 and Boc-[l-Aia-ß3 -h-l-Ala]2,4 -OBn oligomers 16 and 17 were totally or partially disordered, Boc-[l-Aia-l-Ala]2 -OBn (14) induced a typical turn stabilized by C5 - and C7 -membered H-bond pseudo-cycles and aromatic interactions. Boc-[l-Aia-l-Ala]4 -OBn (15) exhibited a unique structure with remarkable T-shaped π-stacking interactions involving the indole rings of the four l-Aia residues forming a dense hydrophobic cluster. All of the proposed FITC-6-Ahx-[l-Aia-Xxx]4 -NH2 oligomers 19-23, with the exception of FITC-6-Ahx-[l-Aia-Gly]4 -NH2 (18), were internalized by MDA-MB-231 cells with higher efficiency than the positive references penetratin and Arg8 . In parallel, the compounds of this series were successfully explored in an in vitro blood-brain barrier (BBB) permeation assay. Although no passive diffusion permeability was observed for any of the tested Ac-[l-Aia-Xxx]4 -NH2 oligomers in the PAMPA model, Ac-[l-Aia-l-Arg]4 -NH2 (26) showed significant permeation in the in vitro cell-based human model of the BBB, suggesting an active mechanism of cell penetration.

12/10-Helix in Mixed ß-Peptides Alternating Bicyclic and Acyclic ß-Amino Acids: Probing the Relationship between Bicyclic Side Chain and Helix Stability.

12/10-Helices constitute suitable templates that can be used to design original structures. Nevertheless, they often suffer from a weak stability in polar solvents because they exhibit a mixed hydrogen-bond network resulting in a small macrodipole. In this work, stable and functionalizable 12/10-helices were developed by alternating a highly constrained ß2, 3, 3 -trisubstituted bicyclic amino acid (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid ((S)-ABOC) and an acyclic substituted ß-homologated proteinogenic amino acid (l-ß3 -hAA). Based on NMR spectroscopic analysis, it was shown that such mixed ß-peptides display well-defined right-handed 12/10-helices in polar, apolar, and chaotropic solvents; that are, CD3 OH, CDCl3 , and [D6 ]DMSO, respectively. The stability of the hydrogen bonds forming the C10 and C12 pseudocycles as well as the benefit provided by the use of the constrained bicyclic ABOC versus typical acyclic ß-amino acids sequences when designing 12/10-helix were investigated using NH/ND NMR exchange experiments and DFT calculations in various solvents. These studies showed that the ß3 -hAA/(S)-ABOC helix displayed a more stable hydrogen-bond network through specific stabilization of the C10 pseudocycles involving the bridgehead NH of the ABOC bicyclic scaffold.

How are 1,2,3-triazoles accommodated in helical secondary structures?

1,4-Disubstituted-1,2,3-triazole (Tz) is widely used in peptides as a trans-amide bond mimic, despite having hazardous effects on the native peptide activity. The impact of amide bond substitution by Tz on peptide secondary structures is scarcely documented. We performed a Tz scan, by systematically replacing peptide bonds following the Aib residues with Tz on two model peptaibols: alamethicin F50/5 and bergofungin D, which adopt stable α- and 310 helices, respectively. We observed that the Tz insertion, whatever its position in the peptide sequences, abolished their antimicrobial activity. The structural consequences of this insertion were further investigated using CD, NMR and X-ray diffraction. Importantly, five crystal structures that were incorporated with Tz were solved, showing various degrees of alteration of the helical structures, from minor structural perturbation of the helix to partial disorder. Together, these results showed that Tz insertions impair helical secondary structures.

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry.

The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their main biological activities.