Iterative Synthesis Research Articles

Catalytic Thioglycoside Activation with Diazo-Derived Copper Carbenes.

Traditional glycosylation methods using thioglycosides often require harsh conditions or expensive metal catalysts. This study presents a more sustainable alternative by employing copper, an earth-abundant catalyst. We developed diazo-based thioglycoside donors that, through copper catalysis, undergo intramolecular activation to form glycosyl sulfonium ions, leading to the generation of oxocarbenium ions. This versatile approach efficiently accommodates a variety of O-nucleophiles, including primary, secondary, and tertiary, as well as complex bioactive molecules. It is compatible with various glycosyl donors and protecting groups, including superarmed, armed, and disarmed systems. Notably, the methodology operates orthogonally to traditional thioglycoside and alkyne donors and has been successfully applied to the orthogonal iterative synthesis of trisaccharides. Mechanistic insights were gained by studying the electronic effects of electron-donating (OMe) and electron-withdrawing (NO2) groups on the donors, offering a valuable understanding of the intramolecular reaction pathway.

Recent Progress in the Synthesis and Glycosylation of Rare Sugars

AbstractOut of 42 naturally occurring monosaccharides, only seven are abundant in Nature (glucose, galactose, mannose, fructose, xylose, ribose, and l-arabinose), while the others have been classified as ‘rare sugars’. Fungi and bacteria use a wide range of monosaccharides, in contrast to mammals, reflected in their glycosylated metabolites, as well as the cellular machineries that are involved in their sugar metabolism. Recognition of the microbiome’s impact on human health has led to increased interest in microbial glycans, as they often mediate interaction between host and microbes. Efficient access to rare sugars and oligosaccharides is necessary to study their roles in Nature, which can provide new pharmacological leads. Furthermore, it enables the synthesis of bioactive glycosylated natural products and congeners. This short review highlights recent progress in the synthesis and the efficient, site- and stereoselective glycosylation of rare sugars. Finally, it provides a recent example where synthetic access to rare sugars has enabled biochemical studies to better understand and interfere with processes in Nature.1 Introduction2 Synthesis of Rare Sugars2.1 Syntheses from Renewable Feedstock2.2 De Novo Syntheses3 Glycosylation3.1 Catalyst-Controlled Glycosylation3.2 One-Pot Iterative Oligosaccharide Synthesis in Solution4 Application in Biochemical Research5 Conclusion

Research on factors that activate university students’ research work using the iterative examination process

Introduction. Many issues related to the activation of research work of university students remain insufficiently studied and are an urgent problem of higher professional education. Aim. The present research aimed to identify the main factors influencing the processes of activating students’ research work and to develop recommendations for increasing the activity of students’ participation in this activity. Methodology and research methods. The authors used iterative examination, analysis, comparison, synthesis, and systematisation methods to analyse the results obtained through empirical methods such as questionnaires and sociological surveys. Data collection was conducted through an online survey using the Google Forms Internet service and offline surveys at 16 universities in the Republic of Kazakhstan and the Russian Federation in 2023. A total of 351 scientific experts participated in the survey. The survey results were processed using the IBM SPSS statistical package. Results and scientific novelty. It has been established that a significant contribution to attracting students to research activities is made by the expansion of the use of information technologies in the research process and a system of incentives aimed at increasing the importance of students’ research work in the educational process. The scientific novelty lies in identifying and systematising the main factors that influence the activation of students’ research work in the learning process through the iterative examination process. Practical significance. The results of the conducted research can be used in the practical research work of university students.

Unified, Biosynthesis-Inspired, Completely Stereocontrolled Total Synthesis of All Highest-Order [n + 1] Oligocyclotryptamine Alkaloids.

We describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Inspired by our hypothesis for the biogenesis of these alkaloids via an iterative concatenative addition of homochiral cyclotryptamines to a meso-chimonanthine headcap, we leverage the modular, diazene-directed assembly of stereodefined cyclotryptamines to introduce successive C3a-C7' quaternary stereocenters on a heterodimeric meso-chimonanthine surrogate with full stereochemical control at each quaternary linkage. We developed a new strategy for iterative aryl-alkyl diazene synthesis using increasingly complex oligomeric hydrazide nucleophiles and a bifunctional cyclotryptamine bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of this strategy is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Enabled by our completely stereoselective total syntheses and expanded characterization data sets, we provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C, provide evidence that it is identical to the alkaloid known as (+)-isopsychotridine B, and report that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I, resolving longstanding questions about the structures of the highest-order [n + 1] oligocyclotryptamine alkaloids.

Disrupting TSLP–TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases

Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein–protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and IL-13, IL-4, TSLP, and periostin secretion, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases.

Publisher Correction: Rapid automated iterative small-molecule synthesis

Publisher Correction: Rapid automated iterative small-molecule synthesis

Rapid automated iterative small-molecule synthesis

Rapid automated iterative small-molecule synthesis

Iterative synthesis of multi-grid topological nanostructures based on a stepwise friedel-crafts reaction

Covalent C–C bonded macrocycle topologies have been attracting increasing attention owing to their structural diversity and various applications. However, the methods for constructing such structures are limited, with most relying on transition metal-catalysis or requiring stringent reaction conditions, highlighting the urgent need to explore innovative synthetic approaches. Hence, we report a stepwise Friedel-Crafts gridization catalyzed by BF3·Et2O under ambient conditions and air atmosphere for the synthesis of the multi-grid topological nanostructures 2G-AG (30% yield) and 3G-AG (8% yield). Furthermore, the non-planar and structurally more complex multi-grid topologies, 2G-AG and 3G-AG, exhibit stronger excimer emission. This study provides a novel method for designing and synthesizing complex macrocyclic topological nanostructures connected by covalent bonds and with optoelectronic functionality.

Acceptability and feasibility of screening with a pediatric care provider-led social determinants of health identification tool

BackgroundComplex social determinants of health may not be easily recognized by health care providers and pose a unique challenge in the vulnerable pediatric population where patients may not be able to advocate for themselves. The goal of this study was to examine the acceptability and feasibility of health care providers using an integrated brief pediatric screening tool in primary care and hospital settings.MethodsThe framework of the Child and Adolescent Needs and Strengths (CANS) and Pediatric Intermed tools was used to inform the selection of items for the 9-item Child and Adolescent Needs and Strengths-Pediatric Complexity Indicator (CANS-PCI). The tool consisted of three domains: biological, psychological, and social. Semi-structured interviews were conducted with health care providers in pediatric medical facilities in Ottawa, Canada. A low inference and iterative thematic synthesis approach was used to analyze the qualitative interview data specific to acceptability and feasibility.ResultsThirteen health care providers participated in interviews. Six overarching themes were identified: acceptability, logistics, feasibility, pros/cons, risk, and privacy. Overall, participants agreed that a routine, trained provider-led pediatric tool for the screening of social determinants of health is important (n = 10, 76.9%), acceptable (n = 11; 84.6%), and feasible (n = 7, 53.8%).InterpretationThough the importance of social determinants of health are widely recognized, there are limited systematic methods of assessing, describing, and communicating amongst health care providers about the biomedical and psychosocial complexities of pediatric patients. Based on this study’s findings, implementation of a brief provider-led screening tool into pediatric care practices may contribute to this gap.

Iterative synthesis method for high‐directivity symmetrical stepped‐impedance microstrip parallel‐line coupler

AbstractTraditional quarter‐wavelength parallel‐line couplers (QWPLC) in microstrip form suffer heavily in low directivity because of unbalanced even‐mode and odd‐mode phase velocities. Related schemes to improve directivity lead to complex structures and large dimensions. This study derives and validates an iterative synthesis method to design a high‐directivity microstrip coupler adopting a symmetric stepped‐impedance microstrip coupled line (SSIMCL). Given that the even‐mode and odd‐mode effective dielectric constants (EDCs) vary with the characteristic impedances, the authors take the EDCs of traditional QWPLC as the initial values for an SSIMCL, and the characteristic impedances and EDCs can be computed and converged in several iterations, resulting in good phase delay balance and high coupler directivity. A 20‐dB microstrip coupler working at 1 GHz with high directivity is designed, fabricated, and measured. The obtained maximum directivity is 47 dB and approximately 1 GHz, while the relative bandwidth with a directivity higher than 20 dB and a return loss better than 20 dB is larger than 70%. The novel microstrip coupler also features a compact, simple structure shorter than λg/4.

Synthetic Population: A Reliable Framework for Analysis for Agent-Based Modeling in Mobility

This paper presents a comprehensive and innovative evaluation framework for identifying a reliable population synthesis for agent-based modeling–transportation-oriented simulations (ABM–TOS). We show, via this framework and different metrics for the analysis of the generated distribution of the individuals’ attributes, that population synthesizers may fail to correctly replicate the real population heterogeneity owing to diverse control variables, data limitations, and post-simulation computation of certain parameter distributions. To show these shortcomings, the authors propose a systematic classification of different types of distributions crucial for mobility simulations. The proposed framework aims to provide a comprehensive overview of the population and serve as a rapid ’debugging’ tool to identify and rectify any flaws in a specific population during the calibration of the activity-based mobility simulation models. To prove the effectiveness of this framework, we applied it to synthetic populations generated through MOBIUS (mobility optimization based on iterative user synthesis), a newly developed synthetic population generator, which in this case was employed to create different variants of the Luxembourg population (1%, 10%, 30%). The application of our framework to these populations not only provided an effective method for assessing their goodness of fit, but also helped highlight the distributions that are most critical to the successful implementation of the methodology.

Abstract P05: Novel PROTAC-based EZH2 Degraders Effectively Target Lymphoid Malignancies by Depleting Enzyme-Independent Functions of EZH2

Abstract Overexpression or mutation of the epigenetic silencer EZH2 correlates with invasive cancer growth, resistance, and poor survival outcomes. Previously, we have established a methylation-independent role for EZH2 in the transcriptional activation of oncogenes in NKTL. As EZH2 enzymatic inhibitors have proven ineffective against NKTL, we embarked on the development of novel EZH2 Proteolysis Targeting Chimera (PROTAC) compounds. EZH2 PROTACs consist of an EZH2- and E3-ligase binding domain which promotes targeted ubiquitination of the EZH2 protein thereby marking it for proteasomal degradation. Our initial efforts focused on the iterative synthesis of EZH2 PROTAC candidates optimizing factors such as permeability, solubility and stable ternary complex formation. Through extensive screening, we identified C2911 and C1311, which successfully trigger the dose-dependent degradation of EZH2 and PRC2 components concomitant with a significant loss of survival and induction of apoptosis in both NKTL and DLBCL. These effects were rescued by pre-treatment with proteasome inhibitor Bortezomib or when E3 ligase activity was disrupted through siRNA knockdown. In NKTL, we show that EZH2 PROTAC treatment decreased JAK3 and phospho-STAT5 protein expression and identified the suppression of the JAK-STAT-MYC axis as a potential mechanism of action. EZH2 PROTAC treatment effectively reactivates transcription of canonical EZH2 target genes such as MYT1 and ANPEP and downregulates expression of oncogenes c-Myc and E2F1. Pharmacokinetic studies in vivo demonstrate that these PROTACs exhibit good plasma stability, half-life (>4h) and low clearance thereby establishing potential for future clinical development. The efficacy of EZH2 PROTACs in xenograft mice are currently being evaluated. Collectively, our data supports the discovery of novel EZH2 PROTACs and the critical role it plays in successfully targeting the oncogenic role of EZH2 in NKTL or other non-canonical EZH2-driven cancers through protein depletion where enzymatic-only inhibition was ineffective. We are further investigating the mechanisms stabilizing EZH2 protein levels to enhance PROTAC-mediated cytotoxicity. Citation Format: Nurulhuda Mustafa, Zubaida Talal Alnaseri, Darrel Tan Egk Jian, David Quach Thanh Truong, Wan Hsin Lim, Wee Joo Chng. Novel PROTAC-based EZH2 Degraders Effectively Target Lymphoid Malignancies by Depleting Enzyme-Independent Functions of EZH2 [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P05.

Catalytic Orthogonal Glycosylation Enabled by Enynal‐Derived Copper Carbenes

AbstractHerein, we present an approach for catalytic orthogonal glycosylation utilizing earth‐abundant copper carbenes. This method operates under mild conditions and employs readily accessible starting materials, including benchtop stable enynal‐derived glycosyl donors, synthesized at the gram scale. The reaction accommodates a variety of glycosyl acceptors, including primary, secondary, and tertiary alcohols. The enynal‐derived copper carbenes exhibit remarkable reactivity and selectivity, allowing for the formation of glycosidic linkages with different protecting groups and stereochemical patterns. This approach provides access to both 1,2‐cis‐ and ‐trans‐glycosidic linkages. The product stereoselectivity is independent of the anomeric configuration of the glycosyl donor, which also has orthogonal reactivity to widely used alkynes and thioglycoside donors. An iterative synthesis of a trisaccharide further demonstrates the application of this orthogonal reactivity.

Bridging the gap: Implementation science, knowledge translation, and innovation for advancing maternal health sustainable development goals

Background: Maternal health remains a critical global concern, with sustainable development goal 3 aiming to reduce the maternal mortality ratio and ensure universal access to reproductive healthcare by 2030. According to a 2023 report, a woman dies from preventable causes related to pregnancy and childbirth every 2 minutes, and almost 70% of maternal deaths occur in sub-Saharan Africa. The reduction of maternal mortality and promotion of maternal health and well-being are complex tasks. Objective: To understand how a synergistic approach integrating complex interventions’ research, implementation science principles, knowledge translation, and innovative solutions can be leveraged to achieve sustainable improvements in maternal health outcomes in different contexts. Methods: This study employed sequential and iterative critical interpretive synthesis (CIS), integrative literature (ILR) review with multiscale analysis of extant literature on maternal health starting with the landmark Lancet series on “Maternal Survival” 2006 (5 papers); 2016 “Maternal Health” series (6 papers); the 2023 Series – “Maternal health in Perinatal period and Beyond” (4 papers); and health sector strategic plans. Results: Despite knowledge that healthcare is a complex adaptive system (CAS), whereas interventions for maternal health are considered complex interventions, the predominant implementation approaches assume a linear cause-effect approach, leading to the observed stagnation in maternal health. Conclusion: The effectiveness of complex interventions and their success in reaching relevant populations is critically influenced by their implementation in each context. A linear understanding of evidence translation, from ‘bench to bedside’, is naïve. This is because those who deliver, manage, and receive healthcare, negotiate multiple forms and sources of evidence, which complement and compete within a complex system of institutional logics.

Iterative Binomial Synthesis of Monodisperse Conjugated Polymers

Iterative Binomial Synthesis of Monodisperse Conjugated Polymers

An exploration of analytical tools to conduct a realist synthesis and demonstrate programme theory development: An example from a realist review

Introduction A realist literature review involves iterative processes, with searches, appraisal and synthesis occurring simultaneously. Whilst this lends itself to theory development, the synthesis process often lacks transparency. This has led to unanticipated challenges for novice realist researchers, particularly PhD candidates. Methods The aim of this paper is to contribute to the realist methodological knowledge base by outlining the analytical tools of coding, consolidating and conceptual mapping used within a realist review. Specifically, how these techniques aid the synthesis process and demonstrate the development of valid and evidence informed programme theories. Results A worked example is provided to illustrate how; (i) coding techniques using realist logic can evidence a rigorous synthesis process; (ii) the use of consolidating techniques facilitates data management and aids theory development; and (iii) conceptual mapping demonstrates programme theory development. Conclusions Recommendations for novice realist researchers include defining and documenting the analytical tools for conducting a rigorous realist synthesis to provide transparency about how valid programme theories were developed. Plus, theory development checks can be built into the structure of the review process.

Glycosyl oxazolines serve as active donors for iterative synthesis of type I oligosaccharides.

Synthesis of Galβ1 → 3GlcNAc-repeating saccharides is limited mainly by the formation of less-reactive oxazolines. We herein report an expeditious approach that requires trichloroacetyloxazolines as reactive glycosyl donors. Using only two disaccharide building blocks, the iterative oxazoline formation and glycosylation synthesized hexa- and octasaccharides with overall yields of 47% and 26% in four and six steps, respectively.

Iterative Synthesis of Dual-Band Filters With Separately Assignable Operating Bands Using Bandpass Polynomials and Prototypes

Iterative Synthesis of Dual-Band Filters With Separately Assignable Operating Bands Using Bandpass Polynomials and Prototypes

Effective Teaching Mathematics at School Level: A Perspective from Nepal

Mathematical facilitators all across the globe are using fresh approaches and making use of productive results, implementation of research-based methods to teach mathematics in the classroom. A cooperative knowledge-building approach, i.e. Iterative Best Evidence Synthesis Program, is required for classroom instruction. This study gives guidelines for effective educational techniques that promote instructors for varied learners by drawing on results from mathematics, the intuitive notions that have been utilized in the classroom, and recent research investigations. In examining the links between pedagogical practices and a range of social and academic student outcomes, this article draws on the histories, cultures, language, and practices for the Nepali context.

Self-Assembly of Discrete Oligomers of Naphthalenediimides in Bulk and on Surfaces.

Here, we report on the synthesis of discrete oligomers of alkyl-bridged naphthalenediimides (NDIs) and study their molecular nanostructures both in bulk, in solution, and at the liquid-solid interface. Via an iterative synthesis method, multiple NDI cores were bridged with short and saturated alkyl-diamines (C3 and C12 ) or long and unsaturated alkyl-diamines (u2 C33 to u8 C100 ) at their imide termini. The strong intermolecular interaction between the NDI cores was observed by probing their photophysical properties in solution. In bulk, the discrete NDI oligomers preferentially ordered in lamellar morphologies, irrespective of whether a saturated or unsaturated spacer was employed. Moreover, both the molecular architecture as well as the crystallization conditions play a significant role in the nanoscale ordering. The long unsaturated alkyl chains lead preferably to folded-chain conformations while their saturated analogues form stretched arrangements. At the solution-solid interface, well-defined lamellar regions were observed. These results show that precision in chemical structure alone is not sufficient to reach well-defined structures of discrete oligomers, but that it must be combined with precision in processing conditions.