Tracing the stepwise Darwinian evolution of a plant halogenase DOI
Colin Y. Kim, David W. Kastner, Andrew J. Mitchell

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 11, 2024

Abstract Halogenation chemistry is rare in plant metabolism, with the chloroalkaloid acutumine produced by Menispermaceae species being only well characterized example, involving a specialized dechloroacutumine halogenase (DAH) from iron(II)- and 2-oxoglutarate-dependent dioxygenase (2ODD) superfamily. While DAH presumed to have evolved an ancestral 2ODD enzyme, broader question of how new enzymes arise through Darwinian processes, such as birth Menispermaceae, remains fundamental challenge understanding metabolic evolution. Here, we investigate DAH’s evolutionary trajectory using chromosomal-level genome assembly Menispermum canadense . By analyzing genomic context M. syntenic regions related plants, show that tandem duplication flavonol synthase ( FLS ) gene, followed series neofunctionalization gene loss events. Through structural modeling, molecular dynamics simulations, site-directed mutagenesis, identify residue changes enabling transition DAH. This functional switch required traversing complex landscape where adaptive peaks were separated deep fitness valleys. Our work illustrates enzymatic functions can lineage-specific pathways gradually reshape active site architecture permissive mutations, ultimately mechanism-switching mutations establish novel catalytic activities.

Язык: Английский

The Electrochemical Iodination of Electron‐Deficient Arenes DOI Creative Commons
Sara Torabi, Mahdi Jamshidi, Gerhard Hilt

и другие.

Angewandte Chemie International Edition, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

Abstract The iodination of electron‐deficient arenes and heteroarenes is a long‐standing problem in organic synthesis. Herein we describe the electrochemical nitromethane with Bu 4 NI as iodine source supporting electrolyte under Lewis acid‐free conditions presence small amounts chloride anions. electrochemically generated reagent could be applied for halogenated arenes, aromatic aldehydes, acids, esters, ketones, well nitroarenes to afford products good excellent yields.

Язык: Английский

Процитировано

1
Die Elektrochemische Iodierung von Elektronenarmen Aromaten DOI Creative Commons
Sara Torabi, Mahdi Jamshidi, Gerhard Hilt

и другие.

Angewandte Chemie, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

Abstract Die direkte Iodierung von elektronenarmen Aromaten und Heteroaromaten ist ein seit langer Zeit ungelöstes Problem in der Organischen Synthese. In diesem Beitrag beschreiben wir die elektrochemische Nitromethan mit Bu 4 NI als Iodid‐Quelle Leitsalz unter Lewis‐Säure freien Bedingungen Anwesenheit katalytischen Mengen Chlorid‐Ionen. Das elektrochemisch generierte Reagenz konnte für halogenierten Aromaten, aromatischen Aldehyden, Säuren, Estern, Ketonen sowie Nitroaromaten genutzt werden, um gewünschten Produkte guten bis exzellenten Ausbeuten zu erzeugen.

Процитировано

0
CuI-Catalyzed Dearomatization/Peroxidation/Cyclization Cascade of Pyrrole-Tethered Indoles DOI

Xue Sheng,

Yang Liu,

Jiayi Han

и другие.

The Journal of Organic Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 27, 2025

A mild CuI-catalyzed dearomatization/peroxidation/cyclization cascade of pyrrole-tethered indoles has been reached, providing peroxide-incorporated indolizino[8,7-b]indole derivatives in acceptable to good yields (46–76%). Dehydrogenated peroxide can be obtained by the use a FeCl3/TBHP (tBuOOH)/2,2,2-trifluoroethanol (TFE) system at 50 °C.

Язык: Английский

Процитировано

0
Molecular Ring Remodeling through C–C Bond Cleavage DOI
Zengrui Cheng, Zhibin Hu, Ning Jiao

и другие.

Accounts of Chemical Research, Год журнала: 2025, Номер unknown

Опубликована: Фев. 27, 2025

ConspectusStable and inert C-C bonds form the fundamental framework of organic compounds. Consequently, direct transformations involving bond cleavage present an innovative approach for rapid modification remodeling molecular skeletons. In recent years, concept skeletal editing has garnered widespread attention been significantly developed, providing new opportunities late-stage bioactive molecules, high-value transformation bulk chemicals, a revolution in traditional fragment coupling strategies chemical synthesis. Notable advancements this field have focused on cyclic including ring expansion, contraction, ring-opening reactions, thereby enriching synthetic toolbox available to chemists. However, selective remains formidable challenge, especially complex due high dissociation energy difficulty achieving precise selectivity control. Over past few our group made efforts address these challenges. We demonstrated potential molecule reactions as efficient strategy synthesis molecules.Herein, we two major thematic achieved by group, utilizing cascade activation entropy-driven reconstruction via cleavage. These are characterized mild conditions, accessibility catalysts reagents, exceptional functional compatibility, emerging novel approaches through atom-incorporation mainly nitrogenation, oxygenation, halogenation synthesize pharmaceuticals, natural products, material molecules. (1) Ring expansion reactions: developed that enable insertion C-, N-, O-containing units into rings. methodologies offer practical routes synthesizing amides, amines, lactones, nitrogen-containing heterocycles. (2) Ring-opening enables construction distally difunctionalized frameworks. By transition metal catalysis radical-mediated process, successfully both single C═C double within Furthermore, tackled highly challenging arene (ARO) reaction, enabling stereoselective conjugated systems unsaturation liberation aromatic systems. Mechanistic studies DFT calculations provided critical insights processes. also identified key intermediates involved cleavage, benzyl azide, O-acetyl hydroxylamine, β-azido peroxyl radical, copper bisnitrene, 2-nitrene indazole. findings deepened understanding mechanisms strategy, which further promoted discovery related acyclic substrates.

Язык: Английский

Процитировано

0
Lewis Base-Catalyzed Interhalogenation of Terminal Allenes: Selective Strategy for Accessing Vicinal Vinylic, Allylic Heterodihalides DOI

Alexandra E. Lubaev,

Favour Eze,

Manjula D. Rathnayake

и другие.

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Though precedent remains limited, the selective interhalogenation of allenes offers a valuable synthetic strategy to access products where each halide exhibits orthogonal reactivity. Here, we describe Lewis base-catalyzed approach for dihalogenation (bromochlorination, iodochlorination, iodobromination, and dibromination) terminal allenes. By employing just 1 mol % triphenylphosphine oxide or hexamethylphosphoramide activate thionyl halides in presence electrophilic halogenation reagents, achieve conversion monosubstituted vicinal allylic, vinylic dihalides with up 93% yield >20:1 regioisomeric ratio, favoring branched dihalogenated product. A range functional groups is tolerated, including nitrile, ester, phosphate, sulfonamide, silyl groups, reaction proved be scalable. The utility various dihalide was investigated substitution cross-coupling chemistry, highlighting distinct reactivity among different classes.

Язык: Английский

Процитировано

0
Recent Advances in Augmenting the Therapeutic Efficacy of Peptide–Drug Conjugates DOI Creative Commons
Jiahui Ma, Xuedan Wang, Yong-hua Hu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 23, 2025

There is an urgent need for the development of safe and effective modalities treatment diseases owing to drug resistance, undesired side effects, poor clinical outcomes. Combining cell-targeting efficient cell-killing properties, peptide-drug conjugates (PDCs) have demonstrated superior efficacy compared with peptides payloads alone. However, innovative molecular designs PDCs are essential further improving targeting precision, protease resistance stability, cell permeability, overall efficacy. Several strategies been developed address these challenges, such as multivalency approaches, bispecific targeting, long-acting PDCs. Other novel strategies, including overcoming biological barriers, conjugating functional payloads, macropinocytosis, also shown promise. This perspective compiles most recent enhancing PDC efficacy, highlights key advancements in PDC, provides insights on future directions

Язык: Английский

Процитировано

0
Tracing the stepwise Darwinian evolution of a plant halogenase DOI
Colin Y. Kim, David W. Kastner, Andrew J. Mitchell

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 11, 2024

Abstract Halogenation chemistry is rare in plant metabolism, with the chloroalkaloid acutumine produced by Menispermaceae species being only well characterized example, involving a specialized dechloroacutumine halogenase (DAH) from iron(II)- and 2-oxoglutarate-dependent dioxygenase (2ODD) superfamily. While DAH presumed to have evolved an ancestral 2ODD enzyme, broader question of how new enzymes arise through Darwinian processes, such as birth Menispermaceae, remains fundamental challenge understanding metabolic evolution. Here, we investigate DAH’s evolutionary trajectory using chromosomal-level genome assembly Menispermum canadense . By analyzing genomic context M. syntenic regions related plants, show that tandem duplication flavonol synthase ( FLS ) gene, followed series neofunctionalization gene loss events. Through structural modeling, molecular dynamics simulations, site-directed mutagenesis, identify residue changes enabling transition DAH. This functional switch required traversing complex landscape where adaptive peaks were separated deep fitness valleys. Our work illustrates enzymatic functions can lineage-specific pathways gradually reshape active site architecture permissive mutations, ultimately mechanism-switching mutations establish novel catalytic activities.

Язык: Английский

Процитировано

1