Molecular Skeleton Editing for New Drug Discovery
2024; American Chemical Society; Volume: 67; Issue: 16 Linguagem: Inglês
10.1021/acs.jmedchem.4c01841
ISSN1520-4804
AutoresEr‐Qing Li, Craig W. Lindsley, Junbiao Chang, Bin Yu,
Tópico(s)Biochemical and Molecular Research
ResumoInfoMetricsFiguresRef. Journal of Medicinal ChemistryVol 67/Issue 16Article This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation and referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse EditorialAugust 12, 2024Molecular Skeleton Editing for New Drug DiscoveryClick to copy article linkArticle link copied!Er-Qing LiEr-Qing LiCollege of Chemistry, Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou University, Zhengzhou 450001, ChinaMore by Er-Qing Lihttps://orcid.org/0000-0003-1286-6832Craig W. Lindsley*Craig W. LindsleyVanderbilt University Medical Center, Franklin, Tennessee 37027, United States*[email protected]More by Craig W. Lindsleyhttps://orcid.org/0000-0003-0168-1445Junbiao Chang*Junbiao ChangCollege of Chemistry, Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou University, Zhengzhou 450001, ChinaTianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China*[email protected]More by Junbiao ChangBin Yu*Bin YuCollege of Chemistry, Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou University, Zhengzhou 450001, ChinaTianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China*[email protected]More by Bin Yuhttps://orcid.org/0000-0002-7207-643XOpen PDFJournal of Medicinal ChemistryCite this: J. Med. Chem. 2024, 67, 16, 13509–13511Click to copy citationCitation copied!https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01841https://doi.org/10.1021/acs.jmedchem.4c01841Published August 12, 2024 Publication History Received 5 August 2024Published online 12 August 2024Published in issue 22 August 2024editorialCopyright © Published 2024 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsThis publication is licensed for personal use by The American Chemical Society. ACS PublicationsCopyright © Published 2024 by American Chemical SocietySubjectswhat are subjectsArticle subjects are automatically applied from the ACS Subject Taxonomy and describe the scientific concepts and themes of the article.Drug discoveryMoleculesNitrogenPharmaceuticalsPyridinesIn general, most drug molecules are structurally complex and possess multiple heterocyclic skeletons; as a result, multistep synthesis is usually required for the preparation of highly functionalized compounds. The development of new synthetic methods that provide rapid access to biologically active compounds has witnessed increasing interest, and many state-of-the-art synthetic methods, such as cross-coupling reactions, C–H bond functionalization reactions, selective cycloadditions, etc., have been widely applied in drug discovery and development. Changes to the core skeleton and the appended substituents always cause potency discrepancies, potential safety issues, varied drug-like properties, etc. In terms of chemistry, the above-mentioned structural changes, particularly the skeleton variations, often necessitate designing new synthetic routes that depend heavily on using different reagents, starting materials, or reaction conditions. In order to satisfy the growing demand of the medicinal chemistry community, methods that directly modify the complex molecules (e.g., pharmaceuticals, natural products) have been highly pursued. Modern synthetic organic chemistries have enriched the synthetic toolkits and serve as the foundation of the current pharmaceutical industry. The pursuit of novel biologically active molecules in turn significantly advances contemporary chemistries. Nevertheless, only several reactions like amide bond formation, Suzuki–Miyaura coupling, and SNAr reactions are commonly used in medicinal chemistry practice, resulting in an excess of certain molecular shapes and limited chemical diversity. Therefore, the development of new molecular editing toolkits, particularly those tailored for modifying intricate molecules like natural products and drugs, could streamline the design of new compound libraries and enable late-stage diversification as well as access to new drug-like regions beyond conventional chemical space.Molecular skeleton editing refers to structural remodeling and represents an appealing editing strategy due to the capability of rapidly building onto, changing, or pruning molecules (Figure 1A). In this aspect, the Baeyer–Villiger oxidation, Ciamician–Dennstedt rearrangement, and Hofmann rearrangement, which involve inserting or deleting atoms of a given molecule, represent the earliest known examples of molecular editing. Nonetheless, accessible single-step molecular skeletal transformations remain limited. In 2006, Wilson and Danishefsky proposed the concept of "molecular editing through divergent total synthesis". (1) Up to now, the molecular skeleton editing strategy has been increasingly used to remove unnecessary or undesirable structural features of natural products and drugs. In 2021, Antonchick and co-workers developed a nitrogen extrusion strategy to stereospecifically turn pyrrolidines into multisubstituted cyclobutanes using iodonitrene chemistry and also achieved the formal total synthesis of piperarborenine B (Figure 1B). (2) Mechanistic studies suggested that the in situ-generated iodonitrene acted as an electrophilic nitrogen transfer reagent to a secondary amine, the 1-diazene produced a biradical structure through nitrogen extrusion, resulting in the formation of the cyclobutane. The atom-deletion editing strategy has shown potential applications in drug discovery. For instance, it allows for converting polar cyclic pyrrolidines into nonpolar linear dienes and editing the skeletons of estrone, stigmasterol, amitifadine, and belaperidone. Additionally, removing nitrogen from saturated linear secondary amines yields carbon–carbon coupling counterparts.Figure 1Figure 1. Molecular skeleton editing for new drug discovery. (A) The classification of molecular skeleton editing. (B) Stereoselective synthesis of cyclobutanes by contraction of pyrrolidines. (C) Carbon-to-nitrogen single-atom transmutation of azaarenes. (D) Skeletal editing of pyridines through atom-pair swap from CN to CC. (E) Synthesis of polysubstituted azepanes by dearomative ring expansion of nitroarenes.High Resolution ImageDownload MS PowerPoint SlideSingle-atom skeleton editing, particularly the carbon-to-nitrogen transmutation in an aromatic ring, has proven to be a more challenging approach for modifying the molecular core structure. In 2023, Levin and co-workers reported a straightforward carbon-to-nitrogen single-atom transmutation strategy for the synthesis of quinazolines from quinolines, in which nitrogen insertion and carbon deletion proceeded simultaneously in a skeletal reconstruction (Figure 1C). (3) This approach addressed site-selectivity innately and avoided extra appendages to the skeleton. The selective oxidation of a "quinoline-type" rather than an "isoquinoline-type" nitrogen demonstrated potential for synthesizing pharmaceuticals. This transmutation method enabled the synthesis of belumosudil (DHODH inhibitor, approved by the FDA in 2021) on a gram scale, talnetant (the FDA-approved TACR3 receptor antagonist), and brequinar (the dihydroorotate dehydrogenase inhibitor).The pyridine ring is a ubiquitous core skeleton in pharmaceuticals─the skeleton editing of pyridines is thus of high interest in the field of drug development. However, direct skeletal editing of pyridines is rarely explored because of their inherent electron deficiency in the π-system and the nitrogen atom's σ-donating ability. In 2023, Studer and co-workers disclosed an atom-pair swap strategy from CN to CC for the synthesis of benzenes and naphthalenes from pyridines by direct skeletal editing (Figure 1D). (4) This precise skeletal editing of pyridines involved a one-pot sequence comprising sequential dearomatization, cycloaddition, and rearomatizing retro-cycloaddition processes. In this study, the authors also applied the pyridine editing strategy to achieve the late-stage modifications of drugs. For example, acyl-protected tropicamide, a mydriatic drug, was precisely edited to generate its benzene and naphthalene derivatives by using different dienophiles. Besides, the authors also finished late-stage skeletal modification of loratadine (an antihistamine), probenecid (an antigout drug), and indomethacin (an anti-inflammatory agent). It is worth noting that this one-pot pyridine editing strategy realized efficient hybridization of two drug molecules (stanolone/probenecid, estrone/(+)-δ-tocopherol) on a gram scale.Another representative strategy for molecular skeleton editing is one-atom insertion. This method avoids complex multistep synthesis and simplifies the production of high-value molecules that are difficult to create using traditional methods. In 2023, Leonori and co-workers reported a photochemical dearomative ring expansion (nitrogen insertion) strategy, followed by hydrogenolysis, to prepare complex polyfunctionalized seven-membered azepanes from nitroarenes (Figure 1E). (5) This approach achieved precise introduction of multiple substituents on the azepane core and high diastereoselectivity in multifunctionalized azepanes and may have potential applications in scaffold hopping for new lead generation. Compared to prevalent six- and five-membered piperidine and pyrrolidine in compound libraries, the seven-membered azepane is rare, and compounds with azepane may occupy new three-dimensional chemical space. In this study, the authors further demonstrated the utility of their approach by synthesizing various azepane analogs of piperidine drugs, including melperone (an atypical antipsychotic), ifenprodil (an N-methyl-d-aspartate inhibitor), pirodavir (a picornavirus inhibitor), and fentanyl (a synthetic opioid analgesic).In recent years, there have been many efforts to develop molecular skeleton editing toolkits. These tools have supported the advancement of different drug discovery techniques like macrocyclization and late-stage functionalization. Specifically, due to the notable alteration in molecular shape between macrocycles and linear U-shaped structures, along with their exploration of new chemical space, we herein categorize macrocyclization as a novel strategy for molecular skeleton editing, and this macrocyclization strategy has witnessed great success. In this case, our previously proposed structure-guided rational molecular editing (SGRME) strategy would be highly appealing. (6) This SGRME approach has been used to effectively modify the heavily patented pyrimidine-based scaffold, resulting in the development of pacritinib, a macrocyclic drug approved for treating myelofibrosis patients.While progress has been made in molecular editing, there are still some inherent limitations in scaffold editing that need to be effectively addressed, particularly regarding substrate scope and functional group tolerance. Most molecular skeleton editing approaches can only achieve the transformation of one scaffold into another (A→B editing)─diversity-oriented skeleton editing (DOSE) is rarely reported and represents a promising direction in this field. Fully understanding the rearrangement reaction mechanisms and trapping the reactive intermediates with various reagents can aid in achieving DOSE. Furthermore, the molecular skeleton editing strategies primarily focus on simple substrates and struggle to efficiently modify highly functionalized complex molecules like drugs and natural products. Editing the core structures of highly functionalized complex molecules directly is a persistent challenge. Developing new molecular editing toolkits would help address these challenges to some extent, at least in synthesizing structurally simple yet diverse starting materials that can be used to realize skeleton diversity of the target molecules. When it comes to editing complex molecules at a molecular level, we here propose a new strategy called Partially Diverse Molecular Skeleton Editing (PDMSE). As its name implies, this strategy involves skillfully modifying a specific site on complex molecules to diversify the partial skeleton (similar to but different from scaffold hopping) without altering the overall molecular shape significantly. In drug discovery, this strategy can benefit from having information on protein–ligand binding. The editing site mentioned above is typically exposed to the solvent region or refers to those that can be modified without significantly affecting its binding to the target molecules of interest. This PDMSE approach may offer a direct way to edit complex molecules and shows promise for applications in drug discovery. Drug discovery practices using the PDMSE approach are expected to experience a significant increase in the near future.With the advancement of artificial intelligence (AI) and machine learning (ML) in chemistry (e.g., for designing new chemistries and analyzing the reactive sites, etc.) and drug discovery (e.g., for predicting the ADMET profiles, etc.), integrating AI and ML into molecular skeleton editing is an attractive direction in new drug discovery. Finally, we believe that a paradigm shift from random molecular editing (chemistry-driven editing) to rational editing (drug development-oriented editing) will revolutionize drug discovery practices.Author InformationClick to copy section linkSection link copied!Corresponding AuthorsCraig W. Lindsley, Vanderbilt University Medical Center, Franklin, Tennessee 37027, United States, https://orcid.org/0000-0003-0168-1445, Email: [email protected]Junbiao Chang, College of Chemistry, Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou University, Zhengzhou 450001, China; Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China, Email: [email protected]Bin Yu, College of Chemistry, Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou University, Zhengzhou 450001, China; Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China, https://orcid.org/0000-0002-7207-643X, Email: [email protected]AuthorEr-Qing Li, College of Chemistry, Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou University, Zhengzhou 450001, China, https://orcid.org/0000-0003-1286-6832NotesViews expressed in this editorial are those of the authors and not necessarily the views of the ACS.AcknowledgmentsClick to copy section linkSection link copied!This work was supported by the National Natural Science Foundation of China (no. 22277110) and Tianjian Laboratory of Advanced Biomedical Sciences.ReferencesClick to copy section linkSection link copied! This article references 6 other publications. 1Wilson, R. M.; Danishefsky, S. J. Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. J. Org. Chem. 2006, 71, 8329– 8351, DOI: 10.1021/jo0610053 Google Scholar1Small Molecule Natural Products in the Discovery of Therapeutic Agents: The Synthesis ConnectionWilson, Rebecca M.; Danishefsky, Samuel J.Journal of Organic Chemistry (2006), 71 (22), 8329-8351CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society) A review. Natural products have been a rich source of agents of value in medicine. They have also inspired, at various levels, the fashioning of nonnatural agents of pharmaceutical import. Hitherto, these nonnatural derivs. have been primarily synthesized by manipulating the natural product. As a consequence of major innovations in the subscience of synthetic methodol., the capacity of synthesis to deal with mols. of considerable complexity has increased dramatically. In this paper, the authors show by example some total syntheses which draw from strategy-enabling advances in methodol. Moreover, the authors show how these capabilities can be used to discover and develop new agents of potential pharmaceutical value without recourse to the natural product itself. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xns1ajs78%253D&md5=8909c38718babb69e083e495467050ba2Hui, C.; Brieger, L.; Strohmann, C. Stereoselective synthesis of cyclobutanes by contraction of pyrrolidines. J. Am. Chem. Soc. 2021, 143, 18864– 18870, DOI: 10.1021/jacs.1c10175 Google Scholar2Stereoselective Synthesis of Cyclobutanes by Contraction of PyrrolidinesHui, Chunngai; Brieger, Lukas; Strohmann, Carsten; Antonchick, Andrey P.Journal of the American Chemical Society (2021), 143 (45), 18864-18870CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society) Here authors report a contractive synthesis of multisubstituted cyclobutanes contg. multiple stereocenters from readily accessible pyrrolidines using iodonitrene chem. Mediated by a nitrogen extrusion process, the stereospecific synthesis of cyclobutanes involves a radical pathway. Unprecedented unsym. spirocyclobutanes were prepd. successfully, and a concise, formal synthesis of the cytotoxic natural product piperarborenine B is reported. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVeisbzN&md5=b8ae578328ade6f0c5a82c17581101c13Woo, J.; Stein, C.; Christian, A. H. Carbon-to-nitrogen single-atom transmutation of azaarenes. Nature 2023, 623, 77– 82, DOI: 10.1038/s41586-023-06613-4 Google Scholar3Carbon-to-nitrogen single-atom transmutation of azaarenesWoo, Jisoo; Stein, Colin; Christian, Alec H.; Levin, Mark D.Nature (London, United Kingdom) (2023), 623 (7985), 77-82CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio) When searching for the ideal mol. to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom1. Replacing an arom. carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines2, but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis3. Here, authors report a transformation that enables the direct conversion of a heteroarom. carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a 'sticky end' approach subverts existing atom insertion-deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. Authors show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic expts. support the crit. role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXit1Kks7zM&md5=97428c57ddfc8e65d0553906f33a32234Cheng, Q.; Bhattacharya, D.; Haring, M. Skeletal editing of pyridines through atom-pair swap from CN to CC. Nat. Chem. 2024, 16, 741– 748, DOI: 10.1038/s41557-023-01428-2 Google ScholarThere is no corresponding record for this reference.5Mykura, R.; Sánchez-Bento, R.; Matador, E. Synthesis of polysubstituted azepanes by dearomative ring expansion of nitroarenes. Nat. Chem. 2024, 16, 771– 779, DOI: 10.1038/s41557-023-01429-1 Google ScholarThere is no corresponding record for this reference.6Ma, C.; Lindsley, C. W.; Chang, J. Rational Molecular Editing: A New Paradigm in Drug Discovery. J. Med. Chem. 2024, 67, 11459– 11466, DOI: 10.1021/acs.jmedchem.4c01347 Google ScholarThere is no corresponding record for this reference.Cited By Click to copy section linkSection link copied!This article has not yet been cited by other publications.Download PDFFiguresReferencesOpen PDF Get e-AlertsGet e-AlertsJournal of Medicinal ChemistryCite this: J. Med. Chem. 2024, 67, 16, 13509–13511Click to copy citationCitation copied!https://doi.org/10.1021/acs.jmedchem.4c01841Published August 12, 2024 Publication History Received 5 August 2024Published online 12 August 2024Published in issue 22 August 2024Copyright © Published 2024 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsArticle Views2627Altmetric-Citations-Learn about these metrics closeArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.Recommended Articles FiguresReferencesFigure 1Figure 1. Molecular skeleton editing for new drug discovery. (A) The classification of molecular skeleton editing. (B) Stereoselective synthesis of cyclobutanes by contraction of pyrrolidines. (C) Carbon-to-nitrogen single-atom transmutation of azaarenes. (D) Skeletal editing of pyridines through atom-pair swap from CN to CC. (E) Synthesis of polysubstituted azepanes by dearomative ring expansion of nitroarenes.High Resolution ImageDownload MS PowerPoint SlideReferences This article references 6 other publications. 1Wilson, R. M.; Danishefsky, S. J. Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. J. Org. Chem. 2006, 71, 8329– 8351, DOI: 10.1021/jo0610053 1Small Molecule Natural Products in the Discovery of Therapeutic Agents: The Synthesis ConnectionWilson, Rebecca M.; Danishefsky, Samuel J.Journal of Organic Chemistry (2006), 71 (22), 8329-8351CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society) A review. Natural products have been a rich source of agents of value in medicine. They have also inspired, at various levels, the fashioning of nonnatural agents of pharmaceutical import. Hitherto, these nonnatural derivs. have been primarily synthesized by manipulating the natural product. As a consequence of major innovations in the subscience of synthetic methodol., the capacity of synthesis to deal with mols. of considerable complexity has increased dramatically. In this paper, the authors show by example some total syntheses which draw from strategy-enabling advances in methodol. Moreover, the authors show how these capabilities can be used to discover and develop new agents of potential pharmaceutical value without recourse to the natural product itself. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xns1ajs78%253D&md5=8909c38718babb69e083e495467050ba2Hui, C.; Brieger, L.; Strohmann, C. Stereoselective synthesis of cyclobutanes by contraction of pyrrolidines. J. Am. Chem. Soc. 2021, 143, 18864– 18870, DOI: 10.1021/jacs.1c10175 2Stereoselective Synthesis of Cyclobutanes by Contraction of PyrrolidinesHui, Chunngai; Brieger, Lukas; Strohmann, Carsten; Antonchick, Andrey P.Journal of the American Chemical Society (2021), 143 (45), 18864-18870CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society) Here authors report a contractive synthesis of multisubstituted cyclobutanes contg. multiple stereocenters from readily accessible pyrrolidines using iodonitrene chem. Mediated by a nitrogen extrusion process, the stereospecific synthesis of cyclobutanes involves a radical pathway. Unprecedented unsym. spirocyclobutanes were prepd. successfully, and a concise, formal synthesis of the cytotoxic natural product piperarborenine B is reported. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVeisbzN&md5=b8ae578328ade6f0c5a82c17581101c13Woo, J.; Stein, C.; Christian, A. H. Carbon-to-nitrogen single-atom transmutation of azaarenes. Nature 2023, 623, 77– 82, DOI: 10.1038/s41586-023-06613-4 3Carbon-to-nitrogen single-atom transmutation of azaarenesWoo, Jisoo; Stein, Colin; Christian, Alec H.; Levin, Mark D.Nature (London, United Kingdom) (2023), 623 (7985), 77-82CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio) When searching for the ideal mol. to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom1. Replacing an arom. carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines2, but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis3. Here, authors report a transformation that enables the direct conversion of a heteroarom. carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a 'sticky end' approach subverts existing atom insertion-deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. Authors show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic expts. support the crit. role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXit1Kks7zM&md5=97428c57ddfc8e65d0553906f33a32234Cheng, Q.; Bhattacharya, D.; Haring, M. Skeletal editing of pyridines through atom-pair swap from CN to CC. Nat. Chem. 2024, 16, 741– 748, DOI: 10.1038/s41557-023-01428-2 There is no corresponding record for this reference.5Mykura, R.; Sánchez-Bento, R.; Matador, E. Synthesis of polysubstituted azepanes by dearomative ring expansion of nitroarenes. Nat. Chem. 2024, 16, 771– 779, DOI: 10.1038/s41557-023-01429-1 There is no corresponding record for this reference.6Ma, C.; Lindsley, C. W.; Chang, J. Rational Molecular Editing: A New Paradigm in Drug Discovery. J. Med. Chem. 2024, 67, 11459– 11466, DOI: 10.1021/acs.jmedchem.4c01347 There is no corresponding record for this reference.
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