The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress.

Nicotinamide adenine dinucleotide (NAD) is a crucial compound in energy metabolism and cell signaling. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for NAD biosynthesis from nicotinamide (NAM). Here, we report that NAMPT activity is inhibited by adenosine monophosphate (AMP) in response to energy stress.

-Heterocyclic carbene-catalyzed enantioselective (dynamic) kinetic resolution for the assembly of inherently chiral macrocycles.

Heterocalixaromatics play a significant role in supramolecular chemistry and materials science. However, the absence of robust enantioselective synthetic methods has constrained their broader applications. In contrast, the construction of inherently chiral macrocycles -heterocyclic carbene (NHC) remains underexplored to date.

Research on hybrid reservoir scheduling optimization based on improved walrus optimization algorithm with coupling adaptive ε constraint and multi-strategy optimization.

Reservoir flood control scheduling is a challenging optimization task, particularly due to the complexity of various constraints. This paper proposes an innovative algorithm design approach to address this challenge. Combining the basic walrus optimization algorithm with the adaptive ε-constraint method and introducing the SPM chaotic mapping for population initialization, spiral search strategy, and local enhancement search strategy based on Cauchy mutation and reverse learning significantly enhances the algorithm's optimization performance.

Combined Computational and Experimental Study Reveals Complex Mechanistic Landscape of Brønsted Acid-Catalyzed Silane-Dependent P═O Reduction.

The reaction mechanism of Brønsted acid-catalyzed silane-dependent P═O reduction has been elucidated through combined computational and experimental methods. Due to its remarkable chemo- and stereoselective nature, the Brønsted acid/silane reduction system has been widely employed in organophosphine-catalyzed transformations involving P(V)/P(III) redox cycle. However, the full mechanistic profile of this type of P═O reduction has yet to be clearly established to date.

Chiral Bisphosphine-Catalyzed Asymmetric Staudinger/aza-Wittig Reaction: An Enantioselective Desymmetrizing Approach to Crinine-Type Alkaloids.

An unprecedented chiral bisphosphine-catalyzed asymmetric Staudinger/aza-Wittig reaction of 2,2-disubstituted cyclohexane-1,3-diones is reported, enabling the facile access of a broad range of -3a-arylhydroindoles in high yields with excellent enantioselectivities. The key to the success of this work relies on the first application of chiral bisphosphine DuanPhos to the asymmetric Staudinger/aza-Wittig reaction. An effective reductive system has been established to address the challenging P═O/P redox cycle associated with the chiral bisphosphine catalyst.

Hinokitiol protects gastric injury from ethanol exposure via its iron sequestration capacity.

Hinokitiol is a natural bioactive tropolone derivative isolated from Chamaecyparis obtusa and Thuja plicata, which exhibits promising potential in terms of antioxidant and anti-inflammatory properties and possesses potent iron-binding capacity. In this study, we aimed to investigate the potential role of hinokitiol in protecting against ethanol-induced gastric injury and elucidate the underlying mechanism. Our results demonstrated that hinokitiol effectively attenuated hemorrhagic gastric lesions, epithelial cell loss, and inflammatory response in mice with ethanol-induced gastric injury.

Total Synthesis of Carolacton and Demethylcarolactons with Potent Antiviral Activity.

Carolacton, a naturally occurring MTHFD1 inhibitor, exhibits potent inhibitory activity against various RNA viruses including SARS-CoV-2. Herein, we present a concise total synthesis of carolacton, featuring the Krische allylation, Marshall coupling, NHK coupling, and RCM reaction as key elements. Additionally, we have synthesized three simplified carolacton analogues, one of which, namely, 14-demethyl-carolacton, exhibited notable antiviral activity.

Natural Product-Oriented Photo-Induced Denitrogenative Annulations of 1-Alkenylbenzotriazoles.

The photo-induced denitrogenative annulations of a variety of 1-alkenylbenzotriazoles were investigated. By judiciously manipulating the structural variations of 1-alkenylbenzotriazoles, two characteristic polycyclic skeletons associated with monoterpene indole alkaloids were constructed through a diverted and controllable manner. The present work not only enriches the photochemistry of 1-alkenylbenzotriazoles, but also offers a unified approach to access skeletally diverse indole alkaloid scaffolds.

Enantioselective Total Synthesis of Dysiherbols A, C, and D.

Herein, we report the enantioselective total synthesis of dysiherbols A, C, and D, a unique group of 6/6/5/6/6 pentacyclic quinone/hydroquinone sesquiterpenes, featuring a photo-induced quinone-alkene [2 + 2] cycloaddition and a tandem [1,2]-anionic rearrangement/cyclopropane fragmentation as key elements. Based on our total synthesis, the originally proposed structures of dysiherbols C and D have been revised. Detailed computational studies were carried out to gain deep insight into the unprecedented [1,2]-anionic rearrangement, which revealed that the transformation, albeit a symmetry-forbidden process, proceeded through a concerted manner owing to the release of high ring-strain energy and the evolution of local aromaticity in the transition state.

Bridgehead Alkene-Enabled Strain-Driven Bioorthogonal Reaction.

Herein, we report a novel bioorthogonal reaction that hinges on a bridgehead alkene (BHA)-enabled inverse-electron-demand Diels-Alder (IEDDA) cycloaddition. Readily accessible from natural product β-caryophyllene, the strained BHA displays high reactivity toward the IEDDA reaction while maintaining excellent biocompatibility. The developed IEDDA reaction has been applied to protein labeling and pretargeted live cell imaging.

Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity.

The decline of nicotinamide adenine dinucleotide (NAD) occurs in a variety of human pathologies including neurodegeneration. NAD-boosting agents can provide neuroprotective benefits. Here, we report the discovery and development of a class of potent activators (NATs) of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway.

Optimization of NAMPT activators to achieve in vivo neuroprotective efficacy.

NAMPT is the rate-limiting enzyme in the NAD salvage pathway, which makes it an attractive target for the treatment of many diseases associated with NAD exhaustion such as neurodegenerative diseases. Herein, we present the systematic optimization of NAT, an initial hit of NAMPT activator discovered by us through high-throughput screening, based on the co-crystal structure of the NAMPT-NAT complex. Over 80 NAT derivatives have been designed and synthesized, among which compound 72 showed notably improved potency as NAMPT activator and effectively protected cultured cells from FK866-mediated toxicity.

Investigate Natural Product Indolmycin and the Synthetically Improved Analogue Toward Antimycobacterial Agents.

Indolmycin (IND) is a microbial natural product that selectively inhibits bacterial tryptophanyl-tRNA synthetase (TrpRS). The tryptophan biosynthesis pathway was recently shown to be an important target for developing new antibacterial agents against (Mtb). We investigated the antibacterial activity of IND against several mycobacterial model strains.

Unified Biomimetic Approach to (+)-Hippolachnin A: In-Depth Insights into Its Biosynthetic Origin.

A formal biomimetic synthesis of (+)-hippolachnin A has been achieved under the guidance of its plausible biosynthetic pathway. Pivotal transformations include an intriguing O-mediated [4 + 2] cycloaddition and a tandem Kornblum-DeLaMare rearrangement/hemiketalization/dehydration reaction. The current work not only offers a unified approach to access skeletally diverse plakortin-type polyketides but also provides convincing evidence to elucidate their underlying biosynthetic network.

Biomimetic Synthesis of Natural Products: A Journey To Learn, To Mimic, and To Be Better.

Total synthesis of natural products has been one of the most exciting and dynamic areas in synthetic organic chemistry. Nowadays, the major challenge in this field is not whether a given target of interest can be synthesized but how to make it with commendable efficiency and practicality. To meet this grand challenge, a wise way is to learn from Mother Nature who is recognized for her superb capability of forging complicated and sometimes beyond-imagination molecules in her own delicate way.

Orthogonal genome-wide screens of bat cells identify MTHFD1 as a target of broad antiviral therapy.

Bats are responsible for the zoonotic transmission of several major viral diseases, including those leading to the 2003 SARS outbreak and likely the ongoing COVID-19 pandemic. While comparative genomics studies have revealed characteristic adaptations of the bat innate immune system, functional genomic studies are urgently needed to provide a foundation for the molecular dissection of the viral tolerance in bats. Here we report the establishment of genome-wide RNA interference (RNAi) and CRISPR libraries for the screening of the model megabat, We used the complementary RNAi and CRISPR libraries to interrogate cells for infection with two different viruses: mumps virus and influenza A virus, respectively.

Chemical trigger-enabled bioconjugation reaction.

Development of conceptually novel and practically useful bioconjugation reactions has been an intense pursuit of chemical biology research. Herein, we report an unprecedented bioconjugation reaction that hinges on a chemical trigger-enabled inverse-electron-demand Diels-Alder (IEDDA) cycloaddition of -cycloheptene (TCH) with tetrazine. Unlike the conventional strain-promoted bioconjugation reactions that utilize built-in strained alkenes as reactants, the current one features a "trigger-release-conjugate" reaction model, in which a highly strained TCH species is released from a bench-stable bicyclic -nitrosourea (BNU) derivative upon treatment with an external stimulus.

Tailored Synthesis of Skeletally Diverse Stemona Alkaloids through Chemoselective Dyotropic Rearrangements of β-Lactones.

The collective synthesis of skeletally diverse Stemona alkaloids featuring tailored dyotropic rearrangements of β-lactones as key elements is described. Specifically, three typical 5/7/5 tricyclic skeletons associated with stemoamide, tuberostemospiroline and parvistemonine were first accessed through chemoselective dyotropic rearrangements of β-lactones involving alkyl, hydrogen, and aryl migration, respectively. By the rational manipulation of substrate structures and reaction conditions, these dyotropic rearrangements proceeded with excellent efficiency, good chemoselectivity and high stereospecificity.

A Yeast-Based Drug Discovery Platform To Identify Plasmodium falciparum Type II NADH Dehydrogenase Inhibitors.

Conventional methods utilizing protein activity assay or parasite survival to screen for malaria inhibitors suffer from high experimental background and/or inconvenience. Here, we introduce a yeast-based system to facilitate chemical screening for specific protein or pathway inhibitors. The platform comprises several isogeneic strains that differ only in the target of interest, so that a compound which inhibits one strain but not the other is implicated in working specifically against the target.

A Global Review on Short Peptides: Frontiers and Perspectives.

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life.

Recent advances in the synthesis of plakortin-type polyketides.

Plakortin-type polyketides represent a growing family of sponge-derived marine natural products that display notable structural and biological diversity. In particular, a series of polycyclic plakortin polyketides, namely hippolachnin A and gracilioethers, have been identified in recent years, which attract immense interest from the synthetic community owing to their unique molecular architectures and promising biomedical potential. A number of elegant total syntheses of these targets and some synthetic studies have been performed through either bio-inspired or rationally designed strategies.

Strain-Driven Dyotropic Rearrangement: A Unified Ring-Expansion Approach to α-Methylene-γ-butyrolactones.

An unprecedented strain-driven dyotropic rearrangement of α-methylene-β-lactones has been realized, which enables the efficient access of a wide range of α-methylene-γ-butyrolactones displaying remarkable structural diversity. Several appealing features of the reaction, including excellent efficiency, high stereospecificity, predictable chemoselectivity and broad substrate scope, render it a powerful tool for the synthesis of MBL-containing molecules of either natural or synthetic origin. Both experimental and computational evidences suggest that the new variant of dyotropic rearrangements proceed in a dualistic pattern: while an asynchronous concerted mechanism most likely accounts for the reactions featuring hydrogen migration, a stepwise process involving a phenonium ion intermediate is favored in the cases of aryl migration.

Renaissance of Ring-Opening Chemistry of Benzotriazoles: New Wine in an Old Bottle.

1,2,3-Benzotriazoles could undergo ring cleavage to form ortho-amino arenediazonium or α-diazo-imine species via a Dimroth-type equilibrium. Historically, the synthetic potential of this unique reactivity had remained underdeveloped. Recently, some new strategies have been developed to effect the ring-opening chemistry of benzotriazoles in more practical manners.

Advances in the Total Synthesis of Xanthanolide-Type Sesquiterpenoids.

Xanthanolide-type sesquiterpenoids are a diverse family of natural products isolated primarily from the genus Xanthium (Compositae). The intriguing molecular architectures and biological profiles of these natural products have rendered them attractive targets for total synthesis. This focus review aims to provide an up-to-date summary of progress in the chemical synthesis of xanthanolide-type sesquiterpenoids.