Organic Synthesis and Catalysis Enable Facile Access to Bioactive Compounds and Drugs DOI Creative Commons
Svetlana B. Tsogoeva, Kirk S. Schanze

ACS Central Science, Journal Year: 2024, Volume and Issue: 11(1), P. 1 - 5

Published: Dec. 16, 2024

InfoMetricsFiguresRef. ACS Central ScienceASAPArticle This publication is Open Access under the license indicated. Learn More CiteCitationCitation and abstractCitation referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse EditorialDecember 16, 2024Organic Synthesis Catalysis Enable Facile to Bioactive Compounds DrugsClick copy article linkArticle link copied!Svetlana B. TsogoevaSvetlana TsogoevaMore by Svetlana Tsogoevahttps://orcid.org/0000-0003-4845-0951Kirk S. Schanze*Kirk Schanze*Email: [email protected]More Kirk Schanzehttps://orcid.org/0000-0003-3342-4080Open PDFACS ScienceCite this: Cent. Sci. 2024, XXXX, XXX, XXX-XXXClick citationCitation copied!https://pubs.acs.org/doi/10.1021/acscentsci.4c02041https://doi.org/10.1021/acscentsci.4c02041Published December 2024 Publication History Published online 16 2024editorial© American Chemical Society. licensed CC-BY 4.0 . License Summary*You are free share (copy redistribute) this in any medium or format adapt (remix, transform, build upon) material for purpose, even commercially within parameters below:Creative Commons (CC): a Creative license.Attribution (BY): Credit must be given creator.View full license*DisclaimerThis summary highlights only some of key features terms actual license. It not has no legal value. Carefully review before using these materials. underCC-BY share(copy adapt(remix, below: Attribution *DisclaimerThis creator. View Publications© SocietyThe process drug discovery development inherently complex, resource-intensive, multidisciplinary. Organic synthesis catalysis play roles transforming enabling efficient construction bioactive compounds pharmaceuticals.Total organic remains fundamental aspect chemistry, allowing generation complex natural molecules while driving development. Recent advancements field have demonstrated innovative new strategies synthesizing novel therapeutics, e.g., anti-inflammatory compounds, treatments osteoporosis, antiviral agents with enhanced efficacy. (1−6) Cutting-edge approaches include enzyme-, transition metal-, photo-, organocatalysis, which instrumental accelerating candidates. advances enzyme enabled substrate-selective chemoenzymatic methods, facilitating products pharmaceuticals regio- stereoselectivity. These recent developments demonstrate growing importance enzyme-catalyzed transformations medicinal providing green, scalable routes therapeutic compounds. (7−12) Catalytic techniques, such as significantly broadened further scope bond forming reactions. Key stereoselective metal-catalyzed additions C–H functionalizations, organo- photocatalyzed transformations, boron-centered radical reactions, all advanced synthetic applications. functional group transfer late-stage diversification, creating valuable demonstrating high impact on chemistry. (13−20)Figure 1Figure 1. Collective efforts toward facile access drugs.High Resolution ImageDownload MS PowerPoint SlideThis Collection latest that been published recently Science, selective pharmaceutically relevant products, drugs. Emphasizing impactful work total synthesis, biocatalysis, catalytic methodologies─including organocatalyzed reactions─this reflects cutting-edge research chemistry related chemistry.Total SynthesisClick section linkSection copied!The cornerstone means but also opportunity explore chemical scaffolds potential role optimization targeting variety diseases. In context, Wang, Gao, co-workers reported two phthalides, falcarinphthalides A B, from Angelica sinensis, falcarinphthalide showing potent antiosteoporotic activity inhibiting NF-κB c-Fos signaling. (1) They successfully achieved bioinspired gram-scale A, offering promising scaffold osteoporosis treatment. structural modification cannabinoid receptor type 2 (CB2R) ligands inverse agonists our understanding their managing inflammatory conditions. Frank, Grether, Carreira, teams presented structure-based design agonists, derived agonist HU-308 modifying side chain introduce phenyl group. (2) The lead compound exhibits affinity CB2R serves versatile platform fluorescent probes retain activity, stabilizing its inactive state without activating signaling pathways. Furthermore, innovations methodology, concise route salvinorin analogs kappa-opioid (KOR), were reported. Bohn, Shenvi, an elegant short asymmetric analogs, leveraging sterically confined organocatalyst cobalt-catalyzed cycloaddition focused library (3) resulting potency, selectivity, bias at surpassing properties next-generation analgesics other field, candidates scalability environmental considerations crucial large-scale generation. Along line, Kawajiri outlined scalable, manufacturing SARS-CoV-2 candidate Ensitrelvir, focusing convergent indazole, 1,2,4-triazole, 1,3,5-triazinone fragments. (4) optimized improved yield 7-fold, intermediate stability meta-cresolyl moiety, minimized direct crystallization isolation, reducing solvent reagent waste. Additionally, biomimetic approaches, macrocyclization strategies, employed products. Hong first chejuenolides A–C, based hypothetical Mannich macrocyclization, lactone-based precursor constructed via aldol–Julia–aldol (5) revealed stereochemical insights, β-oxo-δ-lactone unit easily converts C2/C18 diastereoisomers, information about stereoselectivity proposed enzymatic biosynthetic pathway. Finally, Li, Patil, structure–activity relationship exploration laterocidine, cyclic lipodepsipeptide against multidrug-resistant Gram-negative pathogens. (6) identified responsible antimicrobial action led engineered peptide efficacy, including complete inhibition polymyxin-resistant Pseudomonas aeruginosa. Together, remarkable examples illustrate continued power advancing development.Biocatalyzed ReactionsClick copied!Biocatalysis emerged highly useful approach diverse interest technology. Enzyme can serve step enhance efficiency minimizing use harsh reagents. lines, Narayan final cyclization intermediates, azaphilone linear angular tricyclic cores. (7) By utilizing flavin-dependent monooxygenase (FDMO) acyl transferase (AT) sequence, method five several unnatural derivatives single reaction vessel. Recently, Li tumor-associated glycolipid disialosyl globopentaosylceramide (DSGb5) approach. (8) Through sialylation, challenging α2,6-linked sialoside was installed, binding studies DSGb5 higher Siglec-7 than oligosaccharide highlighting ceramide enhancing multivalent interactions recognition. encapsulation metal frameworks directed evolution variants biocatalysis constructing intricate chiral cancer therapeutics. Yuan, Zhang, Cheng, green strategy encapsulating enzymes azolate (MAFs) micelles, like BCL larger molecules. (9) optimizing pore sizes surfactants, BCL@MAF-6-SDS catalyst showed 420 times ZIF-8, achieving 94–99% enantioselectivity near-quantitative yields synthesis. Biocatalytic platforms N-heterocycles underscore study, Arnold biocatalytic N-heterocycles, specifically pyrrolidines indolines, intramolecular C(sp3)–H amination azides. (10) applying cytochrome P411 variants, they developed capable selectively inserting alkyl nitrenes into bonds, enantioselective important building blocks new-to-nature molecule construction.Enzymes leveraged cascades produce scaffolds. Flitsch protecting-group-free cascade iminosugars, steps over 70% product yield. (11) galactose oxidase promiscuous bacterial shikimate dehydrogenases, offers one-pot producing polar iminosugar scaffolds, pharmaceutical targets. Another synthesize cepafungin I analogues, aiming better understand proteasome inhibitors treatment potential, Adibekian, Renata, co-workers. (12) 13 analogues chemoproteomic studies, found more product, one analogue exhibiting 7-fold greater β5 subunit, multiple myeloma mantle cell lymphoma compared clinical bortezomib. enzyme-based methods biologically active applications.Transition Metal-, Photo-, Organocatalyzed copied!Catalytic plays pivotal modern efficient, selective, sustainable molecular architectures. catalysis, opened avenues formation, previously inert groups expanding Zhang 1,4-syn-addition 1,3-dienes hybrid palladium broad substrate tolerance mild (13) enables molecules, TRPV6 inhibitor CFTR modulator, radical-polar crossover mechanism (dr > 20:1). Lu introduced Cu/Cr system functionalization bonds converting them nucleophilic alkyl–Cr(III) species room temperature. (14) facilitates carbonyl addition reactions 1,1-difunctionalization aldehydes conditions, aryl alcohols notable radicals. Wang unveiled generating radicals tetraarylborate salts simple activation reagent. (15) formation C–B, C–C, C–X visible light, broadening applications boron transformations. Similarly, advent Pd-catalyzed glycosylation provided pathways C-glycosides. Yu, Lei, C-glycosides coupling native carboxylic acids glycals, external directing groups. (16) approach, applied different substrates, SGLT-2 antidiabetic manifesting utility diversification. breakthrough involves transformation methyl Hartwig terpenoids functionalization, substitution, elimination, integration skeleton through C–C cleavage. (17) expands groups, architectures relevance Hu nickel-catalyzed enantio- diastereoselective fluorinated vicinal stereogenic centers, need (18) enantioenriched organofluorine difluorides. Dai skeletal recasting editing pyrroles, pyrroles fully substituted phosphoric acid-promoted reaction. (19) tetrasubstituted N–N axial chirality, anticancer Sutent, heterocycles. Qi, three-component synergistic photoredox Brønsted acid α-amino (20) reaction, involving addition, ring-opening, radical–radical coupling, supported mechanistic quantum calculations.Overall, transformative smoothly aligns overarching covers range topics across sciences, focus high-impact, multidisciplinary connects various fields. set articles provides outstanding leading biology Science past three years. between progress bio- evident, making papers excellent fit Science. editors journal enthusiastic represent interdisciplinary sciences allied fields, authors working areas encouraged submit manuscripts journal.In closing, we hope you enjoy reading special covering exemplify dynamic tools structures precision contributing discovery, broader chemistry.Author InformationClick copied!Corresponding AuthorKirk Schanze, Department Chemistry, University Texas San Antonio, https://orcid.org/0000-0003-3342-4080, Email: protected]AuthorSvetlana Tsogoeva, Chemistry Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, https://orcid.org/0000-0003-4845-0951NotesViews expressed editorial those necessarily views ACS.ReferencesClick copied! references 20 publications. 1Zou, J.; Qiu, Z. C.; Q. Q.; Wu, J. M.; Y. H.; Shi, K. D.; F.; He, R. R.; Qin, L.; Yao, X. Discovery Potent Antiosteoporotic Drug Molecular Scaffold Derived sinensis Its Bioinspired Total Synthesis. 10 (3), 628– 636, DOI: 10.1021/acscentsci.3c01414 Google ScholarThere corresponding record reference.2Kosar, Sarott, Sykes, D. A.; Viray, A. E. G.; Vitale, Tomasevic, N.; X.; Ganzoni, L. Z.; Kicin, B.; Reichert, Flipping GPCR Switch: Structure-Based Development Selective Cannabinoid Receptor Inverse Agonists. (5), 956– 968, 10.1021/acscentsci.3c01461 reference.3Hill, Dao, Dang, V. Stahl, Route Potent, Selective, Biased Salvinorin Space. 2023, 9 (8), 1567– 1574, 10.1021/acscentsci.3c00616 reference.4Kawajiri, T.; Kijima, Iimuro, Ohashi, E.; Yamakawa, K.; Agura, Masuda, Kouki, Kasamatsu, Yanagisawa, Manufacturing Process Convergent COVID-19 Antiviral Ensitrelvir. (4), 836– 843, 10.1021/acscentsci.2c01203 reference.5Zhang, Zheng, Hong, Biomimetic Chejuenolides A-C Cryptic Lactone-Based Macrocyclization: Stereochemical Implications Biosynthesis. (1), 84– 92, 10.1021/acscentsci.2c01096 reference.6Thombare, Swarbrick, Azad, M. Zhu, Y.; Lu, H. Wickremasinghe, Bandiatmakur, Exploring Structure-Activity Relationships Modes Action Laterocidine. (9), 1703– 1717, 10.1021/acscentsci.4c00776 reference.7Wang, Torma, Pyser, Zimmerman, P. Narayan, Substrate-Selective Enabled Azaphilone Natural Products. 708– 716, 10.1021/acscentsci.3c01405 reference.8Liu, Yan, Luo, S.; Xu, Ma, W.; Wen, T. Stereoconvergent Chemoenzymatic Tumor-Associated Glycolipid Disialosyl Globopentaosylceramide Probing Binding Affinity Siglec-7. (2), 417– 425, 10.1021/acscentsci.3c01170 reference.9Ren, W. Guo, Peng, Hu, G. Highly Enantioselective Encapsulated Metal Azolate Frameworks Micelle-Controlled Pore Sizes. 358– 366, 10.1021/acscentsci.3c01432 reference.10Qin, Zou, Liu, Houk, Arnold, F. Construction Chiral Pyrrolidines Indolines Intramolecular C(sp(3))-H Amination. (12), 2333– 2338, 10.1021/acscentsci.3c00516 reference.11Swanson, C. Ford, Mattey, P.; Gourbeyre, Flitsch, Cascades Iminosugar Scaffolds Reveal Promiscuous Activity Shikimate Dehydrogenases. 103– 108, 10.1021/acscentsci.2c01169 reference.12Amatuni, Shuster, Abegg, Comprehensive Structure–Activity Relationship Studies Cepafungin Oxidations. 239– 251, 10.1021/acscentsci.2c01219 reference.13Liang, Bian, Yadav, Zhou, Sun, 1,4-syn-Addition Cyclic 1,3-Dienes Hybrid Palladium Catalysis. (6), 1191– 1200, 10.1021/acscentsci.4c00094 reference.14Peng, Zhong, Tao, Unlocking Nucleophilicity Strong Alkyl C-H Bonds 756– 762, 10.1021/acscentsci.2c01389 reference.15Yue, Ding, Song, Formation C-B, C-C, C-X Nonstabilized Aryl Radicals Generated Diaryl Boryl Radicals. 2268– 2276, 10.1021/acscentsci.3c00993 reference.16Wang, Chen, Dong, J.-Q.; Glycosylation Native Carboxylic Acids: Antidiabetic Inhibitors. 1129– 1139, 10.1021/acscentsci.3c00201 reference.17Kang, Wetterer, Karimov, Kojima, Surke, Martín-Torres, I.; Nicolai, Elkin, Hartwig, Substitution, Elimination, Integration Methyl Groups Terpenes Initiated Bond Functionalization. 10, 2016– 2027, 10.1021/acscentsci.4c01108 reference.18Dhawa, U.; Lavrencic, Nickel-Catalyzed Enantio- Diastereoselective Fluorine-Containing Vicinal Stereogenic Centers. 1657– 1666, 10.1021/acscentsci.4c00819 reference.19Zhou, Huang, Dai, Editing Pyrroles Skeletal Recasting Strategy. 1758– 1767, 10.1021/acscentsci.3c00812 reference.20Che, Y.-N.; Fang, Zhen, G.-J.; C.-J. Asymmetric Three-Component Radical Cascade Reactions Synergistic Photoredox/Brønsted Acid Catalysis: α-Amino Derivatives. 10.1021/acscentsci.4c00970 reference.Cited Click copied!This yet cited publications.Download PDFFiguresReferences Get e-AlertsGet e-AlertsACS copied!https://doi.org/10.1021/acscentsci.4c02041Published 2024© Article Views-Altmetric-Citations-Learn metrics closeArticle Views COUNTER-compliant sum text downloads since November 2008 (both PDF HTML) institutions individuals. regularly updated reflect usage up last few days.Citations number citing article, calculated Crossref daily. Find counts.The Altmetric Attention Score quantitative measure attention received online. Clicking donut icon will load page altmetric.com additional details score social media presence article. how calculated.Recommended Articles FiguresReferencesFigure SlideReferences There reference.

Language: Английский

Investigation of the Antifungal Activity and Preliminary Mode of Action of Novel 2-(1H-Indol-2-yl)-1,3,4-oxadiazole Derivatives against Botrytis cinerea DOI
Yue Zhang, Jing Li, Kun Li

et al.

Journal of Agricultural and Food Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

The discovery of novel leads and new targets is an important approach to address the issue fungicide resistance by development. indole skeleton has been widely utilized in agrochemicals due its unique biological activity. YZK-C22 a potent pyruvate kinase inhibitor with high antifungal Several were developed based on YZK-C22. Inspired these, [1,2,4]triazino[4,5-a]indol-1(2H)-one derivatives designed using hopping strategy; however, these compounds exhibited moderate fungicidal Unexpectedly, 2-(1H-indol-2-yl)-1,3,4-oxadiazole formed under controlled reaction conditions showed significantly higher Compounds 6c, 6d, 6f, 6j excellent activity vitro, EC50 values ranging from 0.120 0.310 μg/mL against Botrytis cinerea, more than commercial pyrimethanil (EC50 = 0.990 μg/mL). In field trials at 540 720 g active ingredient (ai)/hm2, compound 6c 81.46 86.58% efficacy B. that rate ai/hm2 (70.46%). affinity constants 6d cinerea lower Higher but implies may work as prodrugs or have different mode action. Thus, are worth being further investigated.

Language: Английский

Citations

0
Truce-smiles rearrangement mediated by ligand-to-iron charge transfer DOI Creative Commons

Fuyang Yue,

Ming‐Xing Li, Kangkang Yang

et al.

Green Synthesis and Catalysis, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Arylation of gold nanoclusters and insights into structure-related CO2 reduction reaction performances DOI Creative Commons

Chen Zhu,

Bo Li, Li Chen

et al.

Chemical Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

This work achieved the arylation of gold nanoclusters with maintained templates, bridging two major research areas chemistry—arylgold complexes and nanoclusters.

Language: Английский

Citations

0
Visible Light Catalyzed Reductive Cross‐Coupling of α‐CF3‐alkyl Bromide and Alkynyl Bromide† DOI

Yiqiang Tian,

Yi Li, Chun Zhang

et al.

Chinese Journal of Chemistry, Journal Year: 2024, Volume and Issue: 42(20), P. 2479 - 2484

Published: June 21, 2024

Comprehensive Summary Traditional reduction coupling reactions of two bromides typically rely on transition metal catalysis. Here, we introduce the development a visible‐light catalytic direct reaction between α ‐CF 3 ‐alkyl and alkynyl to access valuable organic frameworks. Our research confirms excellent compatibility this with various functional groups, which could be used modify substrate biologically active molecular fragments. Mechanistic investigations, including control experiments, fluorescence quenching studies, light‐switching have provided insights into mechanism. This study paves way for application catalysis in diverse synthetic transformations, offering sustainable efficient approach synthesis.

Language: Английский

Citations

3
Advances in Photoinduced Minisci-like Reactions DOI

Mario Martos,

Irene Bosque, José C. González‐Gómez

et al.

Synthesis, Journal Year: 2024, Volume and Issue: unknown

Published: July 29, 2024

Abstract The Minisci reaction, which has been around for more than five decades, is still the preferred tool straightforward alkylation of basic heteroarenes. recent developments in photocatalysis have opened novel pathways radical generation under milder and sustainable conditions. Implementing this approach into reaction renewed interest transformation, attractive per se Medicinal Chemistry. Aspects such as sacrificial oxidants, catalysts, specific conditions should be carefully examined to evaluate practicability protocol. This short review focuses on advances (2020 February 2024) photoinduced Minisci-type reactions, emphasizing sustainability. 1 Introduction 2 Using Noble-Metal-Based Photocatalysts 3 Noble-Metal-Free Methods Sacrificial Oxidants 4 Without 5 Conclusions Perspectives

Language: Английский

Citations

3
Photoredox-Catalyzed Synthesis of 3,3-Difluoro-γ-lactams via 1,5-Hydrogen Atom Transfer-Involved Alkyne Difunctionalization and C–N Cleavage DOI
Lin Tang,

Fengjuan Jia,

Ge Lv

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(46), P. 9903 - 9908

Published: Nov. 8, 2024

This manuscript describes the application of a 1,5-hydrogen atom transfer strategy in photoredox-catalyzed hydrodifluoroalkylation alkynes. The approach utilizes sequential cascade process difluoroalkylation, transfer, C(sp

Language: Английский

Citations

2
Boryl Radical-Promoted Synthesis of Biaryls and Benzylcarboxylic Acids Methyl Ester via C—C Bond Formation Reactions DOI

Wenduo Li,

Na'na Wei,

Nan Feng

et al.

Chinese Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 44(6), P. 1853 - 1853

Published: Jan. 1, 2024

Language: Английский

Citations

1
Modular Assembly of E-Selective Trisubstituted Alkenylborons via Nickel-Catalyzed Reductive Dicarbofunctionalization of Ethynylboron DOI
Yifan Ping, Jianbo Wang

ACS Catalysis, Journal Year: 2024, Volume and Issue: unknown, P. 18204 - 18215

Published: Nov. 25, 2024

While alkenylborons have emerged as powerful precursors for the stereospecific construction of substituted alkenes, efficient synthetic methods toward stereodefined trisubstituted remain limited. Herein, we report a modular and practical approach stereoselective synthesis E-trisubstituted through nickel-catalyzed three-component reductive coupling two readily available carbon electrophiles with an ethynyl-Bdan reagent. The protocol exhibits broad substrate scope good functional group tolerance, providing expedient access to variety exclusive E-selectivity. work demonstrates possibility applying type boron reagent in organic synthesis.

Language: Английский

Citations

0
Organic Synthesis and Catalysis Enable Facile Access to Bioactive Compounds and Drugs DOI Creative Commons
Svetlana B. Tsogoeva, Kirk S. Schanze

ACS Central Science, Journal Year: 2024, Volume and Issue: 11(1), P. 1 - 5

Published: Dec. 16, 2024

InfoMetricsFiguresRef. ACS Central ScienceASAPArticle This publication is Open Access under the license indicated. Learn More CiteCitationCitation and abstractCitation referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse EditorialDecember 16, 2024Organic Synthesis Catalysis Enable Facile to Bioactive Compounds DrugsClick copy article linkArticle link copied!Svetlana B. TsogoevaSvetlana TsogoevaMore by Svetlana Tsogoevahttps://orcid.org/0000-0003-4845-0951Kirk S. Schanze*Kirk Schanze*Email: [email protected]More Kirk Schanzehttps://orcid.org/0000-0003-3342-4080Open PDFACS ScienceCite this: Cent. Sci. 2024, XXXX, XXX, XXX-XXXClick citationCitation copied!https://pubs.acs.org/doi/10.1021/acscentsci.4c02041https://doi.org/10.1021/acscentsci.4c02041Published December 2024 Publication History Published online 16 2024editorial© American Chemical Society. licensed CC-BY 4.0 . License Summary*You are free share (copy redistribute) this in any medium or format adapt (remix, transform, build upon) material for purpose, even commercially within parameters below:Creative Commons (CC): a Creative license.Attribution (BY): Credit must be given creator.View full license*DisclaimerThis summary highlights only some of key features terms actual license. It not has no legal value. Carefully review before using these materials. underCC-BY share(copy adapt(remix, below: Attribution *DisclaimerThis creator. View Publications© SocietyThe process drug discovery development inherently complex, resource-intensive, multidisciplinary. Organic synthesis catalysis play roles transforming enabling efficient construction bioactive compounds pharmaceuticals.Total organic remains fundamental aspect chemistry, allowing generation complex natural molecules while driving development. Recent advancements field have demonstrated innovative new strategies synthesizing novel therapeutics, e.g., anti-inflammatory compounds, treatments osteoporosis, antiviral agents with enhanced efficacy. (1−6) Cutting-edge approaches include enzyme-, transition metal-, photo-, organocatalysis, which instrumental accelerating candidates. advances enzyme enabled substrate-selective chemoenzymatic methods, facilitating products pharmaceuticals regio- stereoselectivity. These recent developments demonstrate growing importance enzyme-catalyzed transformations medicinal providing green, scalable routes therapeutic compounds. (7−12) Catalytic techniques, such as significantly broadened further scope bond forming reactions. Key stereoselective metal-catalyzed additions C–H functionalizations, organo- photocatalyzed transformations, boron-centered radical reactions, all advanced synthetic applications. functional group transfer late-stage diversification, creating valuable demonstrating high impact on chemistry. (13−20)Figure 1Figure 1. Collective efforts toward facile access drugs.High Resolution ImageDownload MS PowerPoint SlideThis Collection latest that been published recently Science, selective pharmaceutically relevant products, drugs. Emphasizing impactful work total synthesis, biocatalysis, catalytic methodologies─including organocatalyzed reactions─this reflects cutting-edge research chemistry related chemistry.Total SynthesisClick section linkSection copied!The cornerstone means but also opportunity explore chemical scaffolds potential role optimization targeting variety diseases. In context, Wang, Gao, co-workers reported two phthalides, falcarinphthalides A B, from Angelica sinensis, falcarinphthalide showing potent antiosteoporotic activity inhibiting NF-κB c-Fos signaling. (1) They successfully achieved bioinspired gram-scale A, offering promising scaffold osteoporosis treatment. structural modification cannabinoid receptor type 2 (CB2R) ligands inverse agonists our understanding their managing inflammatory conditions. Frank, Grether, Carreira, teams presented structure-based design agonists, derived agonist HU-308 modifying side chain introduce phenyl group. (2) The lead compound exhibits affinity CB2R serves versatile platform fluorescent probes retain activity, stabilizing its inactive state without activating signaling pathways. Furthermore, innovations methodology, concise route salvinorin analogs kappa-opioid (KOR), were reported. Bohn, Shenvi, an elegant short asymmetric analogs, leveraging sterically confined organocatalyst cobalt-catalyzed cycloaddition focused library (3) resulting potency, selectivity, bias at surpassing properties next-generation analgesics other field, candidates scalability environmental considerations crucial large-scale generation. Along line, Kawajiri outlined scalable, manufacturing SARS-CoV-2 candidate Ensitrelvir, focusing convergent indazole, 1,2,4-triazole, 1,3,5-triazinone fragments. (4) optimized improved yield 7-fold, intermediate stability meta-cresolyl moiety, minimized direct crystallization isolation, reducing solvent reagent waste. Additionally, biomimetic approaches, macrocyclization strategies, employed products. Hong first chejuenolides A–C, based hypothetical Mannich macrocyclization, lactone-based precursor constructed via aldol–Julia–aldol (5) revealed stereochemical insights, β-oxo-δ-lactone unit easily converts C2/C18 diastereoisomers, information about stereoselectivity proposed enzymatic biosynthetic pathway. Finally, Li, Patil, structure–activity relationship exploration laterocidine, cyclic lipodepsipeptide against multidrug-resistant Gram-negative pathogens. (6) identified responsible antimicrobial action led engineered peptide efficacy, including complete inhibition polymyxin-resistant Pseudomonas aeruginosa. Together, remarkable examples illustrate continued power advancing development.Biocatalyzed ReactionsClick copied!Biocatalysis emerged highly useful approach diverse interest technology. Enzyme can serve step enhance efficiency minimizing use harsh reagents. lines, Narayan final cyclization intermediates, azaphilone linear angular tricyclic cores. (7) By utilizing flavin-dependent monooxygenase (FDMO) acyl transferase (AT) sequence, method five several unnatural derivatives single reaction vessel. Recently, Li tumor-associated glycolipid disialosyl globopentaosylceramide (DSGb5) approach. (8) Through sialylation, challenging α2,6-linked sialoside was installed, binding studies DSGb5 higher Siglec-7 than oligosaccharide highlighting ceramide enhancing multivalent interactions recognition. encapsulation metal frameworks directed evolution variants biocatalysis constructing intricate chiral cancer therapeutics. Yuan, Zhang, Cheng, green strategy encapsulating enzymes azolate (MAFs) micelles, like BCL larger molecules. (9) optimizing pore sizes surfactants, BCL@MAF-6-SDS catalyst showed 420 times ZIF-8, achieving 94–99% enantioselectivity near-quantitative yields synthesis. Biocatalytic platforms N-heterocycles underscore study, Arnold biocatalytic N-heterocycles, specifically pyrrolidines indolines, intramolecular C(sp3)–H amination azides. (10) applying cytochrome P411 variants, they developed capable selectively inserting alkyl nitrenes into bonds, enantioselective important building blocks new-to-nature molecule construction.Enzymes leveraged cascades produce scaffolds. Flitsch protecting-group-free cascade iminosugars, steps over 70% product yield. (11) galactose oxidase promiscuous bacterial shikimate dehydrogenases, offers one-pot producing polar iminosugar scaffolds, pharmaceutical targets. Another synthesize cepafungin I analogues, aiming better understand proteasome inhibitors treatment potential, Adibekian, Renata, co-workers. (12) 13 analogues chemoproteomic studies, found more product, one analogue exhibiting 7-fold greater β5 subunit, multiple myeloma mantle cell lymphoma compared clinical bortezomib. enzyme-based methods biologically active applications.Transition Metal-, Photo-, Organocatalyzed copied!Catalytic plays pivotal modern efficient, selective, sustainable molecular architectures. catalysis, opened avenues formation, previously inert groups expanding Zhang 1,4-syn-addition 1,3-dienes hybrid palladium broad substrate tolerance mild (13) enables molecules, TRPV6 inhibitor CFTR modulator, radical-polar crossover mechanism (dr > 20:1). Lu introduced Cu/Cr system functionalization bonds converting them nucleophilic alkyl–Cr(III) species room temperature. (14) facilitates carbonyl addition reactions 1,1-difunctionalization aldehydes conditions, aryl alcohols notable radicals. Wang unveiled generating radicals tetraarylborate salts simple activation reagent. (15) formation C–B, C–C, C–X visible light, broadening applications boron transformations. Similarly, advent Pd-catalyzed glycosylation provided pathways C-glycosides. Yu, Lei, C-glycosides coupling native carboxylic acids glycals, external directing groups. (16) approach, applied different substrates, SGLT-2 antidiabetic manifesting utility diversification. breakthrough involves transformation methyl Hartwig terpenoids functionalization, substitution, elimination, integration skeleton through C–C cleavage. (17) expands groups, architectures relevance Hu nickel-catalyzed enantio- diastereoselective fluorinated vicinal stereogenic centers, need (18) enantioenriched organofluorine difluorides. Dai skeletal recasting editing pyrroles, pyrroles fully substituted phosphoric acid-promoted reaction. (19) tetrasubstituted N–N axial chirality, anticancer Sutent, heterocycles. Qi, three-component synergistic photoredox Brønsted acid α-amino (20) reaction, involving addition, ring-opening, radical–radical coupling, supported mechanistic quantum calculations.Overall, transformative smoothly aligns overarching covers range topics across sciences, focus high-impact, multidisciplinary connects various fields. set articles provides outstanding leading biology Science past three years. between progress bio- evident, making papers excellent fit Science. editors journal enthusiastic represent interdisciplinary sciences allied fields, authors working areas encouraged submit manuscripts journal.In closing, we hope you enjoy reading special covering exemplify dynamic tools structures precision contributing discovery, broader chemistry.Author InformationClick copied!Corresponding AuthorKirk Schanze, Department Chemistry, University Texas San Antonio, https://orcid.org/0000-0003-3342-4080, Email: protected]AuthorSvetlana Tsogoeva, Chemistry Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, https://orcid.org/0000-0003-4845-0951NotesViews expressed editorial those necessarily views ACS.ReferencesClick copied! references 20 publications. 1Zou, J.; Qiu, Z. C.; Q. Q.; Wu, J. M.; Y. H.; Shi, K. D.; F.; He, R. R.; Qin, L.; Yao, X. Discovery Potent Antiosteoporotic Drug Molecular Scaffold Derived sinensis Its Bioinspired Total Synthesis. 10 (3), 628– 636, DOI: 10.1021/acscentsci.3c01414 Google ScholarThere corresponding record reference.2Kosar, Sarott, Sykes, D. A.; Viray, A. E. G.; Vitale, Tomasevic, N.; X.; Ganzoni, L. Z.; Kicin, B.; Reichert, Flipping GPCR Switch: Structure-Based Development Selective Cannabinoid Receptor Inverse Agonists. (5), 956– 968, 10.1021/acscentsci.3c01461 reference.3Hill, Dao, Dang, V. Stahl, Route Potent, Selective, Biased Salvinorin Space. 2023, 9 (8), 1567– 1574, 10.1021/acscentsci.3c00616 reference.4Kawajiri, T.; Kijima, Iimuro, Ohashi, E.; Yamakawa, K.; Agura, Masuda, Kouki, Kasamatsu, Yanagisawa, Manufacturing Process Convergent COVID-19 Antiviral Ensitrelvir. 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Asymmetric Three-Component Radical Cascade Reactions Synergistic Photoredox/Brønsted Acid Catalysis: α-Amino Derivatives. 10.1021/acscentsci.4c00970 reference.Cited Click copied!This yet cited publications.Download PDFFiguresReferences Get e-AlertsGet e-AlertsACS copied!https://doi.org/10.1021/acscentsci.4c02041Published 2024© Article Views-Altmetric-Citations-Learn metrics closeArticle Views COUNTER-compliant sum text downloads since November 2008 (both PDF HTML) institutions individuals. regularly updated reflect usage up last few days.Citations number citing article, calculated Crossref daily. Find counts.The Altmetric Attention Score quantitative measure attention received online. Clicking donut icon will load page altmetric.com additional details score social media presence article. how calculated.Recommended Articles FiguresReferencesFigure SlideReferences There reference.

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