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Abstract The eukaryotic helicase MCM2-7, is loaded by ORC, Cdc6 and Cdt1 as a double-hexamer onto replication origins. The insertion of DNA into the helicase leads to partial MCM2-7 ring closure, while ATP hydrolysis is essential for consecutive steps in pre-replicative complex (pre-RC) assembly. Currently it is unknown how MCM2-7 ring closure and ATP-hydrolysis are controlled. A cryo-EM structure of an ORC-Cdc6-Cdt1-MCM2-7 intermediate shows a remodelled, fully-closed Mcm2/Mcm5 interface. The Mcm5 C-terminus (C5) contacts Orc3 and specifically recognises this closed ring. Interestingly, we found that normal helicase loading triggers Mcm4 ATP-hydrolysis, which in turn leads to reorganisation of the MCM2-7 complex and Cdt1 release. However, defective MCM2-7 ring closure, due to mutations at the Mcm2/Mcm5 interface, leads to MCM2-7 ring splitting and complex disassembly. As such we identify Mcm4 as the key ATPase in regulating pre-RC formation. Crucially, a stable Mcm2/Mcm5 interface is essential for productive ATP-hydrolysis-dependent remodelling of the helicase.

The equistoichiometric three-component reaction of an acid chloride, an alkyne, and an ortho -amino- or ortho -hydroxyphenylboronic ester proceeds smoothly to give phenanthridines or benzo[ c ]chromenes, respectively, with good to quantitative yields in the sense of a Sonogashira–Suzuki–Michael cyclization sequence. In the coupling of ortho -amidophenylboronates, interestingly, after ring closure a subsequent an acyl migration occurs to give 6-(2-(acyloxy)vinyl)phenanthridines. [ABSTRACT FROM AUTHOR]

A series of R-[1,2,5]oxadiazolo[3,4-c]cinnoline 5-mono- and 1,5-dioxides containing substituents (R = CH3, F, Br, CF3) at different positions were synthesized by an N-nitration–annulation process occurring upon treatment of 3-amino-4-(R-aryl)furazans and 4-amino-3-(R-aryl)furoxans with the HNO3–H2SO4–Ac2O system. The regioselectivity of the ring closure step was determined for the unsymmetrically substituted R-aryl precursors. Unexpected acylation at position 6 of 7-bromo-[1,2,5]oxadiazolo[3,4-c]cinnoline 5-oxide occurred as a result of the increased duration of the synthesis. The crystal structures of five new compounds were determined by X-ray diffraction analysis, and their crystal packings were compared with each other and with those of previously studied molecules, revealing common motifs regardless of the type or position of the substituent. Specifically, the fluorine derivative forms layers isostructural with those in unsubstituted mono- and dioxides, differing only in their arrangement within the P21 and P21/c space groups. Two methyl derivatives, on the other hand, exhibit a structure with flat layers. While the crystal environments of different R-substituents are generally distinct, the unsubstituted part of the heterocyclic core tends to form repeating isostructural motifs, such as dimers, chains, and layers. Although substituents disrupt the crystal packing, they still allow for the combination of these motifs in different crystal structures. [ABSTRACT FROM AUTHOR]

Many bacteriophages modulate host transcription to favor expression of their own genomes. Phage satellite P4 polarity suppression protein, Psu, a building block of the viral capsid, inhibits hexameric transcription termination factor, ρ, by presently unknown mechanisms. Our cryogenic electron microscopy structures of ρ-Psu complexes show that Psu dimers clamp two inactive, open ρ rings and promote their expansion to higher-oligomeric states. ATPase, nucleotide binding and nucleic acid binding studies revealed that Psu hinders ρ ring closure and traps nucleotides in their binding pockets on ρ. Structure-guided mutagenesis in combination with growth, pull-down, and termination assays further delineated the functional ρ-Psu interfaces in vivo. Bioinformatic analyses revealed that Psu is associated with a wide variety of phage defense systems across Enterobacteriaceae, suggesting that Psu may regulate expression of anti-phage genes. Our findings show that modulation of the ρ oligomeric state via diverse strategies is a pervasive gene regulatory principle in bacteria. Many bacteriophages can modulate host transcription. Here, the authors uncover the anti-termination mechanism of phage satellite P4 protein, Psu. Psu dimers clamp two open rings of the termination factor ρ, promote ρ hyper-oligomerization, and trap nucleotides in ρ's binding pockets. [ABSTRACT FROM AUTHOR]

Ruthenium-based catalysts were prepared through a deposition–precipitation approach, taking beta zeolites with Si/Al ratios of 12.5, 18.5, and 150, respectively, as supports, and 1–3 wt% loadings of metal. Their activation was performed in the presence of either H2 or NaBH4. The dispersion of the Ru species and the acid–base properties were influenced by both the preparation method and the activation protocol. The catalysts reduced under H2 flow presented well-dispersed Ru(0) and RuOx nanoparticles, while the reduction with NaBH4 led to larger RuOx crystallites and highly dispersed Ru(0). These characteristics exerted an important role in the hydrogenation of levulinic acid (LA) to γ-valerolactone (GVL). The H2 dissociation occurred via a heterolytic mechanism involving Lewis acid–base pairs associated with RuOx and the framework oxygen (Si-O-Al) located near the zeolite pore edge. The Ru(0) nanoparticles activated the –C=O bond of the LA substrate, while the presence of the carrier zeolite Brønsted acid sites promoted the ring-closure esterification of the 4-hydroxyvaleric acid (4-HVA) intermediate to GVL. An optimal combination of these features was achieved for the catalyst with 3 wt% Ru and a Si/Al ratio of 150, which selectively converted LA (XLA = 96.5%) to GVL (SGVL = 97.8%) at 130 °C and 10 bars of H2. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Indolizine is a nitrogen‐containing heterocycle with strong aromaticity, possessing a delocalized 10π‐electron system. Based on the indolizine scaffolds, numerous molecules with biological activity and organic functional materials have been synthesized. Since 2016, over 110 papers have been published on the synthesis of indolizine scaffolds, but the reviews on synthesizing indolizine scaffolds have been incomplete and not up‐to‐date. Herein, from the perspective of the structure of indolizine with the combination of pyrrole and pyridine ring, we focus on the construction of indolizine scaffolds through the diversity of starting substrates, including pyridine derivatives (N1‐substituted pyridinium salt derivatives, C2‐substituted pyridine derivatives, N1‐ and C2‐free substituted pyridine derivatives), pyrrole derivatives and unoriginal ring substrates. Furthermore, the corresponding reaction mechanisms of synthetic methodologies are also elaborated. Therefore, this review not only paves the way for indolizine synthesis but also provides insight into exploring new reaction modes for constructing nitrogen‐containing heterocycles. Key Scientists: Indolizine was discovered by Angeli in 1890 and first prepared by Scholtz in 1912 from α‐picoline and acetic anhydride. A general approach was developed by Chichibabin in 1927, that is of practical value for the preparation of 2‐alkyl‐ or 2‐arylindolizines. The Chichibabin reaction was the ring closure of quaternary pyridinium halides. At the begining of the 21st century, Basavaiah introduced a new dimension in the Baylis‐Hillman chemistry leading to a novel facile convenient methodology for synthesis of indolizine scaffolds in one‐pot operation. In 2010, Barluenga reported Cu(I)‐catalyzed regioselective [3+2] cyclization of unsubstituted pyridines toward alkenyldiazoacetates leading to functionalized indolizine derivatives, that was the first successful example of metal‐catalyzed cyclization of a π‐deficient heterocyclic system with alkenyldiazo compounds. In 2019 and 2022, Xi and Liu exploited the methods of non‐pyridine derivatives as starting materials to synthesize indolizines, respectively. In 2022, Guo developed an environmentally benign electrooxidative approach for constructing formyl‐ and acyl‐substituted indolizines. [ABSTRACT FROM AUTHOR]

• A new route for the synthesis of [1,3]oxazine-piperazine derivatives. • Ga(NO 3) 3 as an effective catalyst for the synthesis of [1,3]oxazine-piperazine compounds. • Role of tert -butyl groups in promoting the ring closure of the [1,3]oxazine-piperazine ring. The oxazines bearing piperazinyl moieties namely 2-(tert- butyl)-6-((4-(2-(8-(tert -butyl)-6-methyl- 2H -benzo[ e ][1,3]oxazin-3(4H)-yl)ethyl)piperazin-1-yl)methyl)-4-methylphenol (1) and its corresponding 2,4-di- tert -butyl-6-((4-(2-(6,8-di- tert -butyl- 2H -benzo[ e ]-[1,3]oxazin-3(4H)-yl)ethyl)piperazin-1-yl)methyl)phenol (2), which was previously isolated were described. The transformation of the piperazinyl tri- tert -butyl-phenol derivatives 6,6′-(((2-(4-(3-(tert -butyl)-2-hydroxy-5-methylbenzyl)piperazin-1-yl)ethyl)-azanediyl)bis-(methylene))bis-(2-(tert- butyl)-4-methylphenol) 3 and 6,6′-(((2-(4-(3,5-di- tert -butyl-2-hydroxybenzyl)piperazin-1-yl)ethyl)-azanediyl)-bis(methylene))bis(2,4-di- tert -butyl-phenol) 4 into 1 and 2, respectively was achieved in high yield by heating and stirring a methanolic solution containing Et 3 N and Ga(NO 3) 3 ·6H 2 O in the stochiometric ratio 1:3:1 for 30 min. The novel oxazine-piperazine 1 together with its triphenol-piperazine 3 (H 3 L4) were structurally characterized by spectroscopic and single crystal X-ray crystallography. A simple novel methoud for the synthesis of the synthesis of [1,3]oxazine-piperazine derivatives using Ga(NO 3) 3 is described. [Display omitted] [ABSTRACT FROM AUTHOR]

• A diversity of novel pyrazolylquinoline and pyrimidinylquinolins were prepared. • FMOs, global reactive parameters, MEP and Fukui functions were studied. • The ADME analysis and molecular docking were carried out. • Experimental results of 1H and 13C NMR spectra were in good agreement with theoretical data. • In vitro anticancer activity was examined. A diversity of heterocyclic compounds (3, 6 – 8, 9, 11 and 12) linked 4‑hydroxy-1-methylquinoline-2(1 H)one moiety have been synthesized from ring opening ring closure reaction (RORC) of 4‑hydroxy-6-methyl-3-nitro-2 H -pyrano[3,2- c ]quinoline-2,5(6 H)‑dione (2) with various nucleophilic reagents namely hydrazine hydrate, phenylhydrazine, 3-hydrazino-5,6-diphenyl-1,2,4-triazine (4) , 7‑chloro-4-hydrazino quinoline (5), 3-amino-1,2,4-triazole, 2-aminobenzimidazole and 3-amino-4,6-dimethyl-1 H -pyrazolo[3,4- b ]pyridine (10). The biological efficiency of the synthesized compounds against hepatocellular carcinoma cell lines (HepG-2) was analyzed both experimentally and theoretically (topoisomerase IIβ protein). Compound 12 (IC 50 = 4.36 µM/L) has the highest anticancer activity against HepG-2 cell lines in comparison with the positive control (Cis-platin). The synthesized compounds were optimized by DFT/B3LYP functionality using the 6–311G++(d,p) basis set. Frontier molecular orbital analysis using global reactivity parameters indicated that compounds 1 and 12 have the largest) ∆ E = 4.268 eV) and smallest) ∆ E = 3.344 eV) energy gap, respectively. Thus, compound 1 (η= 2.134 eV) is harder than other compounds and has high stability. While compound 12 (S = 0.598eV-1) is softer than other compounds and more reactive. MEP surface and Fukui function were used to show charge distribution and show reactive zones within the molecules. For further validate of the NMR results, GIAO method was utilized to evaluation the 1HNMR and 13CNMR chemical shifts which were then correlate with the experimental spectra. Non-linear optical (NLO) behavior was further studied and compared to urea, which is a prototype substrate, and found to be greater than that of urea. Swiss-ADME (absorption, distribution, metabolism and excretion) analysis was performed to examine the drug-likeness properties of the current compounds. Finally, using the topoisomerase IIβ protein (PDB ID: 4G0U) receptor, molecular docking studies were used to examine the binding interactions of the synthesized compounds and correlated with anticancer activity. [Display omitted] [ABSTRACT FROM AUTHOR]

Gamma-valerolactone (GVL) has been converted into a mixture of methyl pentenoate isomers (MPs) in presence of methanol using Zr/SiO 2 catalysts. These isomers are valuable precursors in fine chemistry and for polymer production. The terminal alkene methyl 4-pentenoate (M4P) is bio-based intermediate to produce caprolactam in excellent yield via hydroformylation to methyl 5-formylvalerate (M5FV) with subsequent reductive amination and ring-closure. For an economic process, a high selectivity of M4P is desired. In this paper, the dependency of the product selectivities on various key reaction parameters (e.g. Zr loading, temperature, GVL/MeOH ratio etc.) is presented. In addition, a set of control experiments were performed using the products (MPs) as educts under similar reaction conditions with the aim to investigate C C double bond isomerisation. The initial ring opening of GVL leads to a mixture of M4P and methyl 3-pentenoate (M3P) with small amounts of M2P. Surprisingly, M4P can be converted back to GVL and also to M3P. However, M3P can be converted mainly to M2P and vice-versa. GVL formation is not observed from the conversion of M3P and M2P. The underlying isomerizations limit the selectivity of M4P to ≤80 %, whereas the space time yield could be remarkably improved to 35.3 kg MP /kg Cat h−1 under optimum conditions. Interestingly, the best catalyst (25Zr/SiO 2) developed through the present study exhibited an excellent long-term stability for a period of >340 h-on-stream. [Display omitted] • An efficient Zr/SiO 2 catalyst to produce bio-based nylon intermediates from GVL. • Extremely high STY of methyl pentenoates (35.3 kg MP /kg cat h−1). • Deep insights on C C bond isomerisation to enhance methyl 4-pentenoate formation. • Plausible reaction mechanism based on several control experiments. [ABSTRACT FROM AUTHOR]

We report on our progress towards the synthesis of the exotic, delicate, and tense polyketidic macrolactam of incednine. This work constitutes a significant advancement towards the total synthesis of a family of molecules of biological and medicinal interest. Some of the key features of this synthesis required evolutions from the initially designed strategy, leading to the use of a Horner–Wadsworth–Emmons olefination to build the C2–C9 tetraene. For this purpose, a polyfunctionalized phosphonate was used that was obtained through an unprecedented Pd-catalyzed cross-coupling involving the zinc salt of diethyl methylphosphonate. The resulting desired C1–C15 fragment displays a carboxylic acid ester at C1 and a vinyl iodide at C15, both functions being ready for subsequent amide coupling with the C16–C23 fragment and final Suzuki cyclization, respectively. [ABSTRACT FROM AUTHOR]

In the past three years, bicyclo[3.1.1]heptanes and their structural analogues have emerged as useful bioisosteres of meta -substituted (hetero)arenes. To meet the increasing demand for bicyclo[3.1.1]heptanes, chemists have developed a plethora of novel methods for their synthesis. In this short review, we assess the research progress on their synthesis and functionalization, considering both the scope and mechanistic aspects. In addition, we discuss the posed challenges and the outlook for the identification of new reaction manifolds to access novel functionalized bicyclo[3.1.1]heptanes. 1 Introduction 2 Synthesis of Bicyclo[3.1.1]heptanes (BCHeps) 3 Synthesis of 3-Azabicyclo[3.1.1]heptanes (3-Aza-BCHeps) 4 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

In polymer science and technology, the distinction between thermoplastic and thermosetting materials has always been sharp, clear, and well-documented: indeed, the former can theoretically be reprocessed a potentially infinite number of times by heating, forming, and subsequent cooling. This cannot be done in the case of thermosetting polymers due to the presence of cross-links that covalently bind the macromolecular chains, giving rise to insoluble and infusible polymeric networks. In 2011, the discovery of vitrimers revolutionized the classification mentioned above, demonstrating the possibility of using new materials that consist of covalent adaptable networks (CANs): this way, they can change their topology through thermally-activated bond-exchange reactions. Recently, the increasing attention directed at green systems and circular economies has pushed the scientific community toward the synthesis and characterization of biobased materials, including vitrimers. Indeed, these latter represent a practical and reliable answer to the demanding issue of the eco sustainability of both materials and related technologies. The main advantage of using biobased vitrimers relies on their limited environmental impact as compared with the traditional systems deriving from fossil sources. Furthermore, biobased vitrimers exploit the same chemistries and plants already optimized for their fossil-based counterparts. The present work aims to review the current use of biobased vitrimers for advanced applications, highlighting their importance for designing novel, green, and sustainable materials that perfectly match the up-to-date circular economy concept. [ABSTRACT FROM AUTHOR]

In the continuing effort towards reducing reliance on fossil resources, the transition to biobased materials is of utmost importance, together with the adoption of more sustainable and safe production processes. This work focuses on the implementation of renewable resources and greener protocols for the synthesis of a bio-based amino crosslinker and its subsequent use in non-isocyanate polyurethane (NIPU) synthesis. NIPUs are a new class of materials, analogous to isocyanate derived polyurethanes (PUs), that avoid hazardous chemicals in their production process, such as phosgene and isocyanates, that raise high concern in the PU manufacturing processes. Vegetable oils and lignin are two abundant renewable feedstocks largely investigated during the last decade. In this paper, we study the synthesis of a high oleic sunflower oil derived polyamine (PA) via thiol–ene photoreaction in batch and in flow. Additionally, cyclic carbonate functionalized lignin (CCLF) was synthesized and reacted with PA to create fully bio-based NIPU networks with different lignin contents. The curing behavior as well as the characterization of the obtained thermosets is described. [ABSTRACT FROM AUTHOR]

Since the first reports of their isolation, penaresidins A and B together with penazetidine A and related analogues have attracted interest from the synthetic community for their unique structural features, specifically the highly functionalized azetidine core. This review provides a comprehensive overview of the biological activity of the penaresidins, penazetidine, and their analogues together with reported synthetic strategies developed since their isolation. 1 Introduction 2 Biological Activity of Penaresidin A, Penaresidin B, and Penazetidine A and Related Analogues 3 Retrosynthetic Analysis 4 Penaresidin A Analogue (Kamikawa, 1995) 5 15- epi -Penaresidin A (Mori, 1995) 6 16- epi -Penazetidine A (Mori, 1996) 7 Penaresidin B (Yoda, 1997) 8 15- epi -Penaresidin B and Penaresidin B (Mori, 1997) 9 Penaresidin A and 16- nor -Penazetidine A (Knapp, 1997) 10 Substituted Penaresidin Core (Beauhaire and Ducrot, 1998) 11 Substituted Penaresidin Core (Ducrot, 1999) 12 Penaresidin A (Lin, 1999) 13 Penaresidin B (Yoda, 2003) 14 Penaresidin Structure-Reactivity Relationship (Kobayashi, 2007) 15 Penaresidin A (Raghavan, 2010) 16 Penaresidin A (Reddy, 2014) 17 Penaresidin B (Liu, 2015) 18 Penaresidin B (Yakura, 2018) 19 Penaresidin B (DuBois, 2020) 20 Penaresidin Analogues (Bodnár, 2021) [ABSTRACT FROM AUTHOR]

The practical, rapid development of chemical leads for drug discovery depends strongly on scalable building block synthesis procedures. N-Heterocyclic moieties, especially unsaturated ones, remain essential tools in the hands of screening and medicinal chemists. Here, we report four novel chemical block families and the interconversions between them. The synthesis of 4,4-disubstituted 3-oxopyrrolidones was an essential milestone in the diversity-oriented production of 3-aminopyrrolidones, 3-hydroxypyrrolidones, and 3,3′-difluoropyrrolidines. These compounds can be functionalized with conformationally flexible spirocyclic substituents. We developed a multigram procedure to access 4,4-disubstituted 3-oxopyrrolidones from commercially accessible and cost-saving reagents via a short three-step procedure. Here, we report the robust conversion of 3-oxopyrrolidones into 3-aminopyrrolidones, 3,3′-difluoropyrrolidones, and 3-hydroxypyrrolidones, involving a minimal number of steps. We demonstrate the scope and limitations and further perspectives for such synthetic approaches. [ABSTRACT FROM AUTHOR]

Many 4- and 5-oxocarboxylic acids show open-cyclic solution racemization/tautomerism including the dehydration-resistant arylpyran pseudoacid 3-hydroxy-4,4-dimethylisobenzopyran-1-one. The crystal and molecular structures of nine α-anomeric derivatives (including 11 distinct molecular structures) of this pseudoacid (or close analogs) have been determined, including pseudoacyl chlorides, normal, pseudoanhydrides, a dipseudoanhydride, and a tertiary pseudoamide. The basicity of the implied exocyclic leaving groups span 40 pK units. Together with seven closely related pseudoacid molecular structures previously determined, a data set containing 18 compounds was generated. Exocyclic C–O bonds shortened as endocyclic C–O bonds lengthened in linear functions of exocyclic leaving group basicity with l(xC-O, Å) = 1.4426 − 0.00400 * pKa, N = 13, R2 = 0.969; l(nC-O, Å) = 1.4204 + 0.00205 * pKa, N = 18, R2 = 0.951. These correlations were compared with results for other α-anomeric pyranoid systems, tetrahydropyran and dihydropyran, and an arylfuran pseudoacyl system. Exocyclic substituents effectively modified endocyclic C–O bond polarities over a considerable range. [ABSTRACT FROM AUTHOR]

The significance of fluorine-mediated weak intermolecular interactions in crystal lattices has been debated over the past few decades. Structural, computational, and theoretical insights on such interactions have resulted in controversies on them. Therefore, to demonstrate the pivotal role of "organic fluorine" in guiding crystal structures, multipole modelling based experimental and theoretical charge density analyses were performed in 1-(2,3-difluorophenyl)-2-(2,5-difluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline. Further, a search on C–F⋯F–C interactions using the Cambridge structural database revealed that type I interactions are generally preferred, followed by type II and quasi-type I/II. The search highlighted the significance of C–F⋯F–C interactions in the presence and absence of strong hydrogen bonds. However, the major intermolecular interactions involving the F atoms in the title compound are found to be C–F⋯H–C and type II C–F⋯F–C. The directional nature and the sigma hole on the F atoms were depicted in terms of the deformation of the electron density maps. The topological analyses of electron densities illustrated that "organic fluorine" mediated intermolecular interactions have a closed shell type. The analysis of electrostatic potentials brought out the attractive nature of the C–F⋯F–C interaction. Thus, the salient features of weak but significant type II C–F⋯F–C interaction and C–H⋯F–C hydrogen bonds were characterized based on the quantitative and qualitative analyses of electron densities. [ABSTRACT FROM AUTHOR]

Flow chemistry has many advantages over batch synthesis of organic small-molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, we report the 10-step chemo-biocatalytic continuous flow asymmetric synthesis of cyproterone acetate (4) in which 10 transformations are combined into a telescoped flow linear sequence from commercially available 4-androstene-3, 17-dione (11). This integrated one-flow synthesis features an engineered 3-ketosteroid-Δ1-dehydrogenase (ReM2)-catalyzed Δ1-dehydrogenation to form the C1, C2-double bond of A ring, a substrate-controlled Co-catalyzed Mukaiyama hydration of 9 to forge the crucial chiral C17α-OH group of D ring with excellent stereoselectivity, and a rapid flow Corey-Chaykovsky cyclopropanation of 7 to build the cyclopropyl core of A ring. By strategic use of these three key reactions and fully continuous-flow operations, cyproterone acetate (4) is produced in an overall yield of 9.6% in 3 h of total reaction time, this is the highest total number of chemical transformation performance in any other continuous-flow synthesis reported to date. Flow chemistry has many advantages over batch synthesis of organic small molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, the authors report a 10-step chemobiocatalytic, continuous-flow asymmetric synthesis of cyproterone acetate in which 10 transformations are combined into a telescoped flow linear sequence from commercially available 4-androstene-3,17-dione. [ABSTRACT FROM AUTHOR]

Cytokinesis physically separates daughter cells at the end of cell division. This step is particularly challenging for epithelial cells, which are connected to their neighbors and to the extracellular matrix by transmembrane protein complexes. To systematically evaluate the impact of the cell adhesion machinery on epithelial cytokinesis efficiency, we performed an RNAi-based modifier screen in the Drosophila follicular epithelium. Strikingly, this unveiled adhesion molecules and transmembrane receptors that facilitate cytokinesis completion. Among these is Dystroglycan, which connects the extracellular matrix to the cytoskeleton via Dystrophin. Live imaging revealed that Dystrophin and Dystroglycan become enriched in the ingressing membrane, below the cytokinetic ring, during and after ring constriction. Using multiple alleles, including Dystrophin isoform-specific mutants, we show that Dystrophin/Dystroglycan localization is linked with unanticipated roles in regulating cytokinetic ring contraction and in preventing membrane regression during the abscission period. Altogether, we provide evidence that, rather than opposing cytokinesis completion, the machinery involved in cell–cell and cell–matrix interactions has also evolved functions to ensure cytokinesis efficiency in epithelial tissues. Synopsis: Building on a Drosophila RNAi modifier screen, this study identifies regulators of cell-cell and cell-matrix interactions that enhance cytokinesis efficiency in epithelial tissues, revealing new roles for the Dystrophin-associated protein complex. A Drosophila RNAi modifier screen identifies regulators of cell-cell and cell-matrix interactions that impact epithelial cytokinesis efficiency. The Dystrophin-associated protein complex promotes cytokinesis efficiency. Dystrophin and Dystroglycan show dynamic cortical redistribution during and post cytokinetic ring constriction. Dys and Dg are required for normal ring contraction and contribute to prevent membrane regression during the abscission period. Building on a Drosophila RNAi modifier screen, this study identifies regulators of cell-cell and cell-matrix interactions that enhance cytokinesis efficiency in epithelial tissues, revealing new roles for the Dystrophin-associated protein complex. [ABSTRACT FROM AUTHOR]

Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well-characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki-values of 3.3 ± 0.5 nM (CB2) and 1.0 ± 0.2 μM (CB1) for AAT-015. AAT-778 showed similar Ki-values of 4.3 ± 0.7 nM (CB2) and 1.1 ± 0.1 μM (CB1). Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 and 449 GBq/μmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2-positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of [11C]AAT-015, and [11C]AAT-778 could not be demonstrated. [ABSTRACT FROM AUTHOR]

α-Alkylidene cyclic carbonates (αCCs) are gaining interest as building blocks in organic and polymer chemistry. To date, their synthesis via the coupling of CO2 to propargylic alcohols has been restricted to batch processes, with extensive efforts devoted to improving catalytic systems. Herein, utilizing a refined, homogeneous silver–carbene–organobase catalytic system, we optimized batch conditions to achieve, for the first time, complete conversion of tertiary propargylic alcohols within minutes instead of hours. Building on this, we introduce a continuous flow methodology to produce a library of αCCs, achieving the highest space–time yields reported, with quantitative conversions in less than 20 minutes and outputs up to 111 grams per day. This approach reduces CO2 usage to 1 or 2 equivalents, improves parameter control, and is expected to facilitate scalability. In addition, "plug-and-play" lab-scale continuous flow modules enable seamless integration of subsequent αCC transformations without intermediate purification, as illustrated by the aminolysis of αCCs into oxazolidones with good conversion (91%). Furthermore, supporting the silver–carbene catalyst on a polymer matrix eliminates silver contamination and even suppresses the need for a base co-catalyst. This work advances the scalable synthesis of αCCs via continuous flow, marking a significant step toward greener, CO2-based cyclic carbonates and derivatives. [ABSTRACT FROM AUTHOR]

In this work, a chemo-enzymatic reaction was developed to synthesize indole-3-acetic acid (IAA) in a continuous flow mode. The cascade reaction consists of the oxidative decarboxylation of L -tryptophan catalyzed by tryptophan 2-monooxygenase (TMO) and the subsequent acid-catalyzed hydrolysis. The telescoped continuous-flow reaction setup was systematically designed using design equations with empirical reaction kinetics, showcasing a flow biocatalytic development framework. Optimal conditions were selected to minimize byproducts from non-specific hydrolysis. This process gave a promising space-time yield (STY) of 11.16 g L−1 day−1 while maintaining a high overall yield of 48.50%. This work demonstrates the feasibility of combining conventional chemical and enzymatic reactions, leveraging the strengths of both methods to enhance productivity and efficiency. [ABSTRACT FROM AUTHOR]

A one-pot solvothermal, polyurea (PU) synthesis was reported using propylene carbonate (PC) and methylene-4,4′-dianiline (MDA), organocatalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene. The applied method was performed under auxiliary-free conditions (halogen-, metal-, and co-catalyst-free), avoiding the use of the toxic isocyanates. The synthesized PU served as a macro organocatalyst for the cycloaddition of epichlorohydrin (ECH) and CO2 under the optimized reaction conditions of 130 °C, 24 h and 5 bar CO2, using 0.5 mL dry DMSO and 150 mg catalyst to produce 1.4 g of 4-chloromethyl-2-oxo-1,3-dioxolane. A catalyst reusability study over five consecutive cycles proved the stability of PU, as no decomposition was detected and it could be recovered by simple washing and filtration. After a few cycles, the amine end group of the catalyst was modified by ECH, decreasing the catalytic activity. In addition, density functional theory (DFT) elucidated the cycloaddition mechanism, together with the energetics of the catalytic cycle. It confirmed the accessibility of PU for the epoxide ring activation from both terminal functionalities, with a lower energy barrier for the amine terminated end compared to the alcohol-terminated one. [ABSTRACT FROM AUTHOR]

Heterocyclic compounds, especially those containing the pyrazole moiety, are highly significant in organic chemistry and possess remarkable and diverse biological properties. The 5-aminopyrazole derivatives are key starting materials for the synthesis of numerous bioactive compounds such as pyrazolopyridine, pyrazolopyrimidine, pyrazoloquinazoline, and pyrazolotriazine derivatives. Many compounds inspired by the 5-aminopyrazole derivatives possess a wide spectrum of biological activities and medicinal applications such as antioxidants, anticancer agents, enzyme inhibitors, antimicrobials, and anti-tuberculosis activities. This review summarizes the recently reported synthesis methods and biological activities of fused pyrazole and pyrazole-based derivatives based on 5-aminopyrazole compounds within the last 5 years (2020 to present). One of the important goals of this review is to illustrate future strategies for the design, development, and utilization of pyrazole products as potent drugs. [ABSTRACT FROM AUTHOR]

The natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive trans stilbenes. In this study, we have prepared a series of 18 cis-restricted triazole analogues of combretastatin A-4 (CA-4), maintaining, in all cases, the 3,4,5-trimethoxy phenyl ring A, with the aim of investigating the substitution pattern on the B-ring in a systematic way. To this end, cytotoxic activities of the cis-restricted analogues of CA-4 prepared were determined in two tumor cell lines, namely, HT-29 and A-549, as well as in the non-tumor cell line HEK-293, to pre-evaluate the selectivity profile of the compounds for the tumor cell lines. The main conclusion was the essential presence of methoxyl or ethoxyl groups at the para position of the B-ring in order to obtain good antitumor activities. Thus, the more active compounds in our study displayed IC50 values in the nanomolar range for the tumor cell lines but not for the normal cells. Consequently, these triazole analogues of CA-4 could serve as promising alternatives to the natural product, although further studies about their biological activity are essential in order to fully determine their viability as therapeutic agents in the treatment of cancer. [ABSTRACT FROM AUTHOR]

We report the unprecedented diastereoselective synthesis of novel [6,6,6]-trioxa-fused ketals via AgOTf-catalyzed cascade annulation of 5-hexyn-1-ols (with primary or secondary hydroxyl groups) and aldehydes through a [2+2+1+1] pathway. In contrast, 5-hexyn-1-ols with tertiary hydroxyl groups yield hexahydro-2H-chromenes via a [3+1+1+1] pathway. [ABSTRACT FROM AUTHOR]

Lactams are a crucial class of compounds with broad therapeutic applications, including in the treatment of cancer, diabetes, and infectious diseases. Functionalised lactams are essential core structures in numerous alkaloids and pharmaceuticals. The introduction of fluorine-containing groups, such as a trifluoromethyl (CF3) group, into organic molecules significantly alters their physical and chemical properties. This review highlights the primary biological targets, as well as the most important synthetic pathways, associated with trifluoromethylated β-lactams (four-atom rings), γ-lactams (five-atom rings), δ-lactams (six-atom rings), and ε-lactams (seven atom rings). Furthermore, we analyze the most common lactam scaffolds, evaluating their potential for future chemical synthesis and emphasizing those that merit attention despite having limited reported analogues. This article aims to provide a comprehensive overview of the importance of trifluoromethylated lactams in drug discovery and design. [ABSTRACT FROM AUTHOR]

An efficient urease-catalyzed approach for the synthesis of highly substituted 6-amino-4 H -pyran-3-carbonitriles based on the formation of three bonds in one step is developed. This unprecedented three-component reaction between one molecule of an aromatic aldehyde and two molecules of an aroylacetonitrile proceeds by employing commercially available urease from jack bean (Canavalia ensiformis) as the catalyst in water at 65 °C to deliver the desired 4 H -pyrans in yields of up to 92%. The transformation is proposed to occur via a domino Knoevenagel condensation/1,4-addition/ O -cyclization/tautomerization sequence, providing a practical and sustainable approach to 6-amino-4 H -pyran-3-carbonitriles from commercially available substrates. Full and unambiguous structural elucidation of all the products is achieved by means of NMR spectroscopy and X-ray crystal structure analysis. [ABSTRACT FROM AUTHOR]

Fluoroalkylation serves as a pivotal strategy for chemists to precisely alter the properties of small molecules. Among the established fluoroalkylation protocols, sulfone and sulfinate reagents stand out as versatile tools for these reactions, particularly in mono-, di-, and trifluoromethylations. Their versatility lies in offering multiple pathways, encompassing electrophilic, nucleophilic, as well as radical mechanisms, thus providing diverse routes for controlled molecular modifications through a variety of very exciting mechanistic paths. 1 Introduction 2 Monofluoromethylation Strategies 2.1 Fluorobis(phenylsulfonyl)methane (FBSM) 2.2 2-Fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT) 2.3 Benzothiazole-SO2 CH2 F, NaSO2 CH2 F, and ClSO2 CH2 F 2.4 PhSO2 CH2 F 3 Difluoromethylation Strategies 3.1 PhSO2 CF2 H 3.2 Benzothiazole-SO2 CF2 H 3.3 2-PyrSO2 CF2 H 3.4 NaSO2 CF2 H 4 Trifluoromethylation Strategies 4.1 PhSO2 CF3 4.2 2-PyrSO2 CF3 4.3 Benzothiazole-SO2 CF3 4.4 NaSO2 CF3 4.4.1 Electrochemical Approaches 4.4.2 Photochemical Approaches 4.4.3 Other Noteworthy Approaches 5 Conclusion [ABSTRACT FROM AUTHOR]

Catalytic dearomative cycloaddition involving the C2–C3 bond of indoles is a powerful strategy for the synthesis of fused indoline scaffolds. Through dearomative cycloaddition/annulation, planar indole substrates can be readily transformed into rigid, three-dimensional polycyclic complex structures in one step. Molecules with architectural complexity are generally considered to have drug-like properties. Hence, annulation products have tremendous potential for discovering therapeutic properties, and this strategy has become an important part of the medicinal chemistry toolbox. Using appropriate catalyst control, desirable stereoselectivity can be achieved. Previous literature reports reveal that [3+2]-cycloadditions of indoles have been extensively studied. In contrast, the catalytic [4+2]-cycloaddition/dearomatization of indoles has been much less investigated. In this short review, we focus specifically on six-membered ring annulations via [4+2]-cycloaddition with the C2–C3 bond of indoles and discuss the various catalytic methods that have been developed toward this objective. 1 Introduction 2 [4+2]-Cycloaddition/Annulation of Indoles 2.1 Electron-Rich Indoles 2.1.1 Transition-Metal Catalysis 2.1.2 Organocatalysis 2.2 Electron-Deficient Indoles 2.2.1 Transition-Metal Catalysis 2.2.2 Organocatalysis 3 Summary and Outlook [ABSTRACT FROM AUTHOR]