Rich Motif Research Articles

Photoredox-catalysed amidyl radical insertion to bicyclo[1.1.0]butanes

AbstractReplacing planar aromatic rings in drug molecules with C(sp3)-rich isosteric mimetics, such as bicyclo[n.1.1]alkanes, can significantly alter their physicochemical and pharmacokinetic properties, often leading to higher clinical success rates. However, unlike a benzene ring, the structurally rigid C(sp3)-rich isosteric mimetics of heteroaromatic rings are rare. Heterobicyclo[n.1.1]alkanes are promising in this regard, but the lack of modular synthetic methods has currently hindered their exploration. We envisioned that the strategic and selective insertion of different heteroatomic units to bicyclo[1.1.0]butanes could offer a highly modular platform to access diverse heterobicyclo[n.1.1]alkanes. Herein we report a photoredox-catalysed highly regioselective and chemoselective insertion of amidyl radicals to bicyclo[1.1.0]butanes, providing direct access to 2-oxa-4-azabicyclo[3.1.1]hept-3-enes. The exit vector analysis shows a geometric resemblance of these C(sp3)-rich heterobicyclic motifs with pyridine and pyrimidine derivatives, suggesting their potential as isosteric mimetics of such medicinally important heterocycles. Additionally, various downstream transformations demonstrate their utility as versatile building blocks in synthetic chemistry.

Dual transcriptional characterization of spinach and Peronospora effusa during resistant and susceptible race-cultivar interactions

BackgroundSpinach downy mildew, caused by the obligate oomycete pathogen, Peronospora effusa remains a major concern for spinach production. Disease control is predominantly based on development of resistant spinach cultivars. However, new races and novel isolates of the pathogen continue to emerge and overcome cultivar resistance. Currently there are 20 known races of P. effusa. Here we characterized the transcriptomes of spinach, Spinacia oleracea, and P. effusa during disease progression using the spinach cultivar Viroflay, the near isogenic lines NIL1 and NIL3, and P. effusa races, R13 and R19, at 24 h post inoculation and 6 days post inoculation. A total of 54 samples were collected and subjected to sequencing and transcriptomic analysis.ResultsDifferentially expressed gene (DEG) analysis in resistant spinach interactions of R13-NIL1 and R19-NIL3 revealed spinach DEGs from protein kinase-like and P-loop containing families, which have roles in plant defense. The homologous plant defense genes included but were not limited to, receptor-like protein kinases (Spiol0281C06495, Spiol06Chr21559 and Spiol06Chr24027), a BAK1 homolog (Spiol0223C05961), genes with leucine rich repeat motifs (Spiol04Chr08771, Spiol04Chr01972, Spiol05Chr26812, Spiol04Chr11049, Spiol0084S08137, Spiol03Chr20299) and ABC-transporters (Spiol02Chr28975, Spiol06Chr22112, Spiol06Chr03998 and Spiol04Chr09723). Additionally, analysis of the expression of eight homologous to previously reported downy mildew resistance genes revealed that some are differentially expressed during resistant reactions but not during susceptible reactions. Examination of P. effusa gene expression during infection of susceptible cultivars identified expressed genes present in R19 or R13 including predicted RxLR and Crinkler effector genes that may be responsible for race-specific virulence on NIL1 or NIL3 spinach hosts, respectively.ConclusionsThese findings deliver foundational insight to gene expression in both spinach and P. effusa during susceptible and resistant interactions and provide a library of candidate genes for further exploration and functional analysis. Such resources will be beneficial to spinach breeding efforts for disease resistance in addition to better understanding the virulence mechanisms of this obligate pathogen.

Phase-Matching Second-Harmonic Generation and Enhanced Laser-Induced Damage Threshold Induced by Cs Substitution: Cu3PSe4 vs Cs2CuP3S9.

Chalcophosphates are an important type of infrared nonlinear optical (NLO) candidates in view of their rich anionic motifs. Here, two copper chalcophosphates Cu3PSe4 (CPSe) and Cs2CuP3S9 (CCPS) were synthesized and studied as IR NLO materials. They both feature three-dimensional polyanionic frameworks constructed by similar T2-supertetrahedra, and the structure of CCPS can be derived from CPSe via introducing Cs and substituting Se with S. This structural evolution results in phase-matchable NLO behavior, enlarged optical band gap, and enhanced laser-induced damage threshold for CCPS. These results are elucidated by structure analysis and theoretical calculations, and the increased structural anisotropy contributes to the phase matchable behavior of CCPS. This work presents a case on how to adjust NLO properties via certain structure considerations, which may be extended to more systems for obtaining high-performance NLO materials.

Inorganic Polyphosphate Is in the Surface of Trypanosoma cruzi but Is Not Significantly Secreted.

Trypanosoma cruzi is the etiologic agent of Chagas disease, an infection that can lead to the development of cardiac fibrosis, which is characterized by the deposition of extracellular matrix (ECM) components in the interstitial region of the myocardium. The parasite itself can induce myofibroblast differentiation of cardiac fibroblast in vitro, leading to increased expression of ECM. Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate that can also induce myofibroblast differentiation and deposition of ECM components and is highly abundant in T. cruzi. PolyP can modify proteins post-translationally by non-enzymatic polyphosphorylation of lysine residues of poly-acidic, serine-(S) and lysine (K)-rich (PASK) motifs. In this work, we used a bioinformatics screen and identified the presence of PASK domains in several surface proteins of T. cruzi. We also detected polyP in the external surface of its different life cycle stages and confirmed the stimulation of host cell fibrosis by trypomastigote infection. However, we were not able to detect significant secretion of the polymer or activation of transforming growth factor beta (TGF-β), an important factor for the generation of fibrosis by inorganic polyP- or trypomastigote-conditioned medium.

Colibactin leads to a bacteria-specific mutation pattern and self-inflicted DNA damage.

Colibactin produced primarily by Escherichia coli strains of the B2 phylogroup cross-links DNA and can promote colon cancer in human hosts. Here, we investigate the toxin's impact on colibactin producers and on bacteria cocultured with producing cells. Using genome-wide genetic screens and mutation accumulation experiments, we uncover the cellular pathways that mitigate colibactin damage and reveal the specific mutations it induces. We discover that although colibactin targets A/T-rich motifs, as observed in human colon cells, it induces a bacteria-unique mutation pattern. Based on this pattern, we predict that long-term colibactin exposure will culminate in a genomic bias in trinucleotide composition. We test this prediction by analyzing thousands of E. coli genomes and find that colibactin-producing strains indeed show the predicted skewness in trinucleotide composition. Our work reveals a bacteria-specific mutation pattern and suggests that the resistance protein encoded on the colibactin pathogenicity island is insufficient in preventing self-inflicted DNA damage.

Altered nucleocytoplasmic export of adenosine-rich circRNAs by PABPC1 contributes to neuronal function

Circular RNAs (circRNAs) are upregulated during neurogenesis. Where and how circRNAs are localized and what roles they play during this process have remained elusive. Comparing the nuclear and cytoplasmic circRNAs between H9 cells and H9-derived forebrain (FB) neurons, we identify that a subset of adenosine (A)-rich circRNAs are restricted in H9 nuclei but exported to cytosols upon differentiation. Such a subcellular relocation of circRNAs is modulated by the poly(A)-binding protein PABPC1. In the H9 nucleus, newly produced (A)-rich circRNAs are bound by PABPC1 and trapped by the nuclear basket protein TPR to prevent their export. Modulating (A)-rich motifs in circRNAs alters their subcellular localization, and introducing (A)-rich circRNAs in H9 cytosols results in mRNA translation suppression. Moreover, decreased nuclear PABPC1 upon neuronal differentiation enables the export of (A)-rich circRNAs, including circRTN4(2,3), which is required for neurite outgrowth. These findings uncover subcellular localization features of circRNAs, linking their processing and function during neurogenesis.

G-quadruplex forming motifs in the promoter region of the B-MYB proto-oncogene

To combat cancer, a comprehensive understanding of the molecular mechanisms and behaviors involved in carcinogenesis is crucial, as tumorigenesis is a complex process influenced by various genetic events and disease hallmarks. The B-MYB gene encodes a transcription factor involved in cell cycle regulation, survival, and differentiation in normal cells. B-MYB can be transformed into an oncogene through mutations, and abnormal expression of B-MYB has been identified in various cancers, including lung cancer, and is associated with poor prognosis. Targeting this oncogene is a promising approach for anti-cancer drug design. B-MYB has been deemed undruggable in previous reports, necessitating the search for novel therapeutic options. In this study, we found that the B-MYB gene promoter contains several G/C rich motifs compatible with G-quadruplex (G4) formation. We investigated and validated the existence of G4 structures in the promoter region of B-MYB, first in vitro using a combination of bioinformatics, biophysical, and biochemical methods, then in cell with the recently developed G4access method.

Positioning of pyrimidine motifs around cassette exons defines their PTB-dependent splicing in Arabidopsis.

Alternative splicing (AS) is a complex process that generates transcript variants from a single pre-mRNA and is involved in numerous biological functions. Many RNA-binding proteins are known to regulate AS; however, little is known about the underlying mechanisms, especially outside the mammalian clade. Here, we show that polypyrimidine tract binding proteins (PTBs) from Arabidopsis thaliana regulate AS of cassette exons via pyrimidine (Py)-rich motifs close to the alternative splice sites. Mutational studies on three PTB-dependent cassette exon events revealed that only some of the Py motifs in this region are critical for AS. Moreover, in vitro binding of PTBs did not reflect a motif's impact on AS in vivo. Our mutational studies and bioinformatic investigation of all known PTB-regulated cassette exons from A. thaliana and human suggested that the binding position of PTBs relative to a cassette exon defines whether its inclusion or skipping is induced. Accordingly, exon skipping is associated with a higher frequency of Py stretches within the cassette exon, and in human also upstream of it, whereas exon inclusion is characterized by increased Py motif occurrence downstream of said exon. Enrichment of Py motifs downstream of PTB-activated 5' splice sites is also seen for PTB-dependent intron removal and alternative 5' splice site events from A. thaliana, suggesting this is a common step of exon definition. In conclusion, the position-dependent AS regulatory mechanism by PTB homologs has been conserved during the separate evolution of plants and mammals, while other critical features, in particular intron length, have considerably changed.

Abstract 2796: Colibactin mutation signatures are associated with younger age of onset in colorectal cancer

Abstract Escherichia coli (E. coli) strains carrying the polyketide synthase (pks) island produce the genotoxin colibactin associated with pathogenesis of colorectal cancer (CRC). Colibactin binds directly to DNA, causing alkylating damage leading to double stranded DNA breaks. Colibactin mutagenesis results in mutations in hexameric A-T rich DNA motifs that can be identified by whole genome sequencing (WGS) as mutation signatures SBS28 and SBS88 (SBS-pks). Since WGS is not routinely used clinically, we developed an approach to specifically identify SBS-pks using a clinical targeted exon capture assay, MSK-IMPACT. In an institutional pan-cancer clinical cohort of 78,905 tumors we identified 15,967 samples with > 20 mutations detected by MSK-IMPACT. We identified 150/1,884 samples with microsatellite stable CRC with >10% mutations attributable to SBS-pks. Examining clinicopathologic and genomic features of SBS-pks+ compared to SBS-pks- CRC tumors, we found that SBS-pks+ signatures are significantly enriched in younger age of onset compared to SBS-pks- CRC patients (median age 55 vs median age 59, p= 0.0028). SBS-pks+ CRC exhibit similar driver mutations and tumor mutational burden (TMB) compared to SBS-pks- CRC but are associated with increased fraction of genome altered (FGA). To mechanistically investigate colibactin-associated damage we developed a novel long-term human colon organoid-microbe co-culture model system that takes advantage of reversal of polarity in suspension culture. WGS of human CRC organoids co-cultured for three months with pks+ and delta-pks E. coli NC101 confirmed induction of pks+ specific SBS-pks signatures, validating the model. Leveraging this model and a biobank of normal colon organoids from donors aged </> 50 years, we are investigating the molecular mechanisms underlying the association of SBS-pks with younger age of onset CRC. Citation Format: Stefanie Gerstberger, Melissa Lumish, Saskia Hartner, Farheen Shah, Seongmin Choi, Anisha Luthra, Qingwen Jiang, Hyung Jun Woo, Ahmed Mahmoud, Henry Walch, Simran Asawa, Mark Donoghue, Andrea Cercek, Rona Yaeger, Andrew McPherson, Francisco Sanchez-Vega, Karuna Ganesh. Colibactin mutation signatures are associated with younger age of onset in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2796.

EVs‐on‐a‐Bubble: Self‐Aggregated Click Bubbles Streamline Isolation and Amplified Profiling of Circulating Extracellular Vesicles

AbstractTumor‐derived circulating extracellular vesicles (EVs) provide a non‐invasive solution for cancer diagnostics, but hampered by challenges in EVs isolation and profiling. Herein, this work shows that bioorthogonal microbubbles (click bubbles) combine a panel of fluorescent aptamers for streamlined isolation and profiling of oncologic EVs in a single assay. This click bubble‐driven aptasensor (cBAS) features self‐aggregation, self‐separation and self‐enhancing in fluorescence. The facile protein phase transition renders bubble surface polyvalent with rich clickable motifs, enabling fast enrichment of EVs. Moreover, the buoyancy allows click bubbles to self‐float to the droplet apex for self‐aggregated fluorescence enhancement via a bubble lensing effect, thus achieving a sensitive profiling of EVs without requiring additional signal amplification or ultrasensitive detectors. By using cBAS to profile EVs surface proteins from a cohort (n = 45) across three cancer types, a machine learning algorithm enables cancer diagnosis and classification with an overall accuracy of 91%. This EVs‐on‐a‐bubble assay is fast, sensitive, self‐powered, and provides a promising tool to facilitate EVs‐based cancer diagnosis in clinical settings.

MIWI N-terminal RG motif promotes efficient pachytene piRNA production and spermatogenesis independent of LINE1 transposon silencing.

PIWI proteins and their associated piRNAs act to silence transposons and promote gametogenesis. Murine PIWI proteins MIWI, MILI, and MIWI2 have multiple arginine and glycine (RG)-rich motifs at their N-terminal domains. Despite being known as docking sites for the TDRD family proteins, the in vivo regulatory roles for these RG motifs in directing PIWI in piRNA biogenesis and spermatogenesis remain elusive. To investigate the functional significance of RG motifs in mammalian PIWI proteins in vivo, we genetically engineered an arginine to lysine (RK) point mutation of a conserved N-terminal RG motif in MIWI in mice. We show that this tiny MIWI RG motif is indispensable for piRNA biogenesis and male fertility. The RK mutation in the RG motif disrupts MIWI-TDRKH interaction and impairs enrichment of MIWI to the intermitochondrial cement (IMC) for efficient piRNA production. Despite significant overall piRNA level reduction, piRNA trimming and maturation are not affected by the RK mutation. Consequently, MiwiRK mutant mice show chromatoid body malformation, spermatogenic arrest, and male sterility. Surprisingly, LINE1 transposons are effectively silenced in MiwiRK mutant mice, indicating a LINE1-independent cause of germ cell arrest distinctive from Miwi knockout mice. These findings reveal a crucial function of the RG motif in directing PIWI proteins to engage in efficient piRNA production critical for germ cell progression and highlight the functional importance of the PIWI N-terminal motifs in regulating male fertility.

Abraham Lincoln in the Hollywood cinema

Abraham Lincoln is a towering figure in American popular consciousness, one who acts as a rich and complex motif and metaphor across its cinema history. This essay is broad-ranging in considering Hollywood’s Lincoln but places particular emphasis on ‘classical’ representations. Its primary aim is to consider the cinematic uses of Lincoln (Lincoln as embedded in the style and rhetoric of a range of films) but a minor thread running through is why Lincoln and which Lincoln is called upon at different points of US movie history. The essay distinguishes itself from previous accounts by combining the analysis of the flesh and blood incarnation of the president’s peculiar physicality with a consideration of the literal and metaphoric solidity of the Lincoln memorial. A final section conveys the sixteenth president’s symbolic power by, paradoxically, revealing it in films that are not even about Lincoln. Lincoln is one of the Greatest Men of Vision™ in US history. In It’s a Wonderful Life (Frank Capra, 1946) and Bigger than Life (Nicholas Ray, 1956), a portrait and a verbal invocation, respectively, connect to themes of hubris and the tensions that ensue when the visions of frustrated ordinary men go too far.

An mTRAN-mRNA interaction mediates mitochondrial translation initiation in plants.

Plant mitochondria represent the largest group of respiring organelles on the planet. Plant mitochondrial messenger RNAs (mRNAs) lack Shine-Dalgarno-like ribosome-binding sites, so it is unknown how plant mitoribosomes recognize mRNA. We show that "mitochondrial translation factors" mTRAN1 and mTRAN2 are land plant-specific proteins, required for normal mitochondrial respiration chain biogenesis. Our studies suggest that mTRANs are noncanonical pentatricopeptide repeat (PPR)-like RNA binding proteins of the mitoribosomal "small" subunit. We identified conserved Adenosine (A)/Uridine (U)-rich motifs in the 5' regions of plant mitochondrial mRNAs. mTRAN1 binds this motif, suggesting that it is a mitoribosome homing factor to identify mRNAs. We demonstrate that mTRANs are likely required for translation of all plant mitochondrial mRNAs. Plant mitochondrial translation initiation thus appears to use a protein-mRNA interaction that is divergent from bacteria or mammalian mitochondria.

Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation.

The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss. RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3'-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets' steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression. Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells.

Isolation and molecular characterization of an FSK2-type dehydrin from Atriplex halimus

Dehydrins form the group II LEA protein family and are known to play multiple roles in plant stress tolerance and enzyme protection. They harbor a variable number of conserved lysine rich motifs (K-segments) and may also contain three additional conserved motifs (Y-, F- and S-segments). In this work, we report the isolation and characterization of an FSK2-type dehydrin from the halophytic species Atriplex halimus, which we designate as AhDHN1. In silico analysis of the protein sequence revealed that AhDHN1 contains large number of hydrophilic residues, and is predicted to be intrinsically disordered. In addition, it has an FSK2 architecture with one F-segment, one S-segment, and two K-segments. The expression analysis showed that the AhDHN1 transcript is induced by salt and water stress treatments in the leaves of Atriplex seedlings. Moreover, circular dichroism spectrum performed on recombinant AhDHN1 showed that the dehydrin lacks any secondary structure, confirming its intrinsic disorder nature. However, there is a gain of α-helicity in the presence of membrane-like SDS micelles. In vitro assays revealed that AhDHN1 is able to effectively protect enzymatic activity of the lactate dehydrogenase against cold, heat and dehydration stresses. Our findings strongly suggest that AhDHN1 can be involved in the adaptation mechanisms of halophytes to adverse environments.

Circular RNAs arising from synaptic host genes during human neuronal differentiation are modulated by SFPQ RNA-binding protein

BackgroundCircular RNA (circRNA) molecules, generated through non-canonical back-splicing of exon-exon junctions, have recently been implicated in diverse biological functions including transcriptional regulation and modulation of protein interactions. CircRNAs are emerging as a key component of the complex neural transcriptome implicated in brain development. However, the specific expression patterns and functions of circRNAs in human neuronal differentiation have not been explored.ResultsUsing total RNA sequencing analysis, we identified expressed circRNAs during the differentiation of human neuroepithelial stem (NES) cells into developing neurons and discovered that many circRNAs originated from host genes associated with synaptic function. Interestingly, when assessing population data, exons giving rise to circRNAs in our dataset had a higher frequency of genetic variants. Additionally, screening for RNA-binding protein sites identified enrichment of Splicing Factor Proline and Glutamine Rich (SFPQ) motifs in increased circRNAs, several of which were reduced by SFPQ knockdown and enriched in SFPQ ribonucleoprotein complexes.ConclusionsOur study provides an in-depth characterisation of circRNAs in a human neuronal differentiation model and highlights SFPQ as both a regulator and binding partner of circRNAs elevated during neuronal maturation.

Modular characterization of SARS-CoV-2 nucleocapsid protein domain functions in nucleocapsid-like assembly

SARS-CoV-2 and its variants, with the Omicron subvariant XBB currently prevailing the global infections, continue to pose threats on public health worldwide. This non-segmented positive-stranded RNA virus encodes the multi-functional nucleocapsid protein (N) that plays key roles in viral infection, replication, genome packaging and budding. N protein consists of two structural domains, NTD and CTD, and three intrinsically disordered regions (IDRs) including the NIDR, the serine/arginine rich motif (SRIDR), and the CIDR. Previous studies revealed functions of N protein in RNA binding, oligomerization, and liquid–liquid phase separation (LLPS), however, characterizations of individual domains and their dissected contributions to N protein functions remain incomplete. In particular, little is known about N protein assembly that may play essential roles in viral replication and genome packing. Here, we present a modular approach to dissect functional roles of individual domains in SARS-CoV-2 N protein that reveals inhibitory or augmented modulations of protein assembly and LLPS in the presence of viral RNAs. Intriguingly, full-length N protein (NFL) assembles into ring-like architecture whereas the truncated SRIDR-CTD-CIDR (N182-419) promotes filamentous assembly. Moreover, LLPS droplets of NFL and N182-419 are significantly enlarged in the presence of viral RNAs, and we observed filamentous structures in the N182-419 droplets using correlative light and electron microscopy (CLEM), suggesting that the formation of LLPS droplets may promote higher-order assembly of N protein for transcription, replication and packaging. Together this study expands our understanding of the multiple functions of N protein in SARS-CoV-2.

Stereoselective synthesis of trans-benzo[d]oxazolyl)phenyl substituted β-lactams decorated with C-3 thio/seleno rich motifs: synthetic intermediates for diverse heterocycles

Herein, we reported an effectual protocol for the stereoselective synthesis of novel C-3 thio/seleno substituted ortho-, meta- and para-(2-benzo[d]oxazolyl)phenyl-β-lactams 7a-i. The reaction was performed by utilizing different S/Se-alkyl/aryl substituted acids 6a-d and isomeric ortho-, meta- and para-(2-benzo[d]oxazolyl)phenyl Schiff’s bases 3a-c and afforded exclusive formation of trans-β-lactams. The trans configuration was assigned with respect to coupling constant values of C3-H and C4-H (J = 1.4 to 2.6; C3-H and C4-H). The structure elucidation of all the thio/seleno anchored β-lactams 7a-i was performed using various spectroscopic techniques viz. FT-IR, NMR (1H, 13C, and 13C DEPT–135), 2D-NMR (1H–1H COSY and 1H–13C HSQC), elemental analysis (CHN), and mass spectrometry (ESI-MS). Further, divergent substrate scope accompanied by plausible mechanistic investigation have been also described. Stereoselectivity, good functional group tolerance and excellent yield along with wider synthetic utility bestows advantages to the present protocol.

Redefining the Synthetic Logic of Medicinal Chemistry. Photoredox-Catalyzed Reactions as a General Tool for Aliphatic Core Functionalization.

C(sp3)-rich aliphatic motifs in drug molecules are strongly associated with clinical success. Historically, the availability of compound libraries based on C(sp3)-rich cores has been limited due to the challenging direct functionalization of aliphatic rings. Instead, most small molecule drug-like libraries are diversified around central aromatic rings. Herein, we present a general approach to the synthesis of diversified libraries featuring aliphatic core rings via photoredox catalysis under mild conditions.

Praga Magica: Prague as a Place of Memory and Vision in George Eliot, Anthony Trollope and George Sand

George Eliot and Anthony Trollope made short visits to Prague in the mid-19th century and were fascinated by such places as the Jewish Quarter with its old synagogue or Charles Bridge with its Baroque statues. They used these motifs in some of their works: Eliot in The Lifted Veil and Daniel Deronda and Trollope in Nina Balatka. Their portrayal of Prague, however, is very much based on the image of Praga magica, the Prague of legends, mysteries and magic. This article argues that the shift of focus from the Jewish Prague to the statue of St John of Nepomuk, which appears in The Lifted Veil and in Nina Balatka, might have been motivated not only by their admiration of the bridge decorations which they saw during their visits but also by the semantically rich motif of the saint’s statue in George Sand’s Consuelo, a novel which was very popular in Britain at that time.