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López-Francés A, Serna-Burgos Z, Del Corte X, de Los Santos JM, de Cózar A, Vicario J. Exploring the Reactivity of Rigid 1-Azadienes Derived from Methylene γ-Lactams. Applications to the Stereoselective Synthesis of Spiro-γ-Lactams. J Org Chem 2024; 89:9502-9515. [PMID: 38901015 PMCID: PMC11232019 DOI: 10.1021/acs.joc.4c00822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
A study on the reactivity of rigid 1-azadienes derived from methylene γ-lactams is reported. Through the functionalization of 1-amino α,β-unsaturated γ-lactam derivatives, easily available from a multicomponent reaction of amines, aldehydes, and pyruvates, it is possible to in situ generate rigid 1-azadienes locked by a γ-lactam core. The 4π-electron system of those rigid 1-azadienes can behave as both diene and dienophile species through a spontaneous cyclodimerization reaction or exclusively as dienes or dienophiles if they are trapped with imines or cyclopentadiene, respectively. The use of chiral rigid 1-azadienes as dienophiles in the cycloaddition reaction with cyclopentadiene leads to the formation of spiro-γ-lactams bearing four stereogenic centers in a highly stereospecific manner, reporting the first example of the use of methylene-γ-lactams in the synthesis of spirocycles.
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Affiliation(s)
- Adrián López-Francés
- Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, UPV/EHU. Paseo de la Universidad 7, Vitoria-Gasteiz 01006, Spain
| | - Zuriñe Serna-Burgos
- Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, UPV/EHU. Paseo de la Universidad 7, Vitoria-Gasteiz 01006, Spain
| | - Xabier Del Corte
- Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, UPV/EHU. Paseo de la Universidad 7, Vitoria-Gasteiz 01006, Spain
| | - Jesús M de Los Santos
- Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, UPV/EHU. Paseo de la Universidad 7, Vitoria-Gasteiz 01006, Spain
| | - Abel de Cózar
- Department of Organic Chemistry I, Donostia International Physics Centre (DIPC), University of the Basque Country, UPV/EHU. Paseo Manuel de Lardizabal, 3, Donostia-San Sebastián 20018, Spain
- Ikerbasque, Basque Foundation for Science, Plaza Euskadi 5, Bilbao 48009, Spain
| | - Javier Vicario
- Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, UPV/EHU. Paseo de la Universidad 7, Vitoria-Gasteiz 01006, Spain
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Pathak T, Bose A. 1,5-disubstituted 1,2,3-triazolylated carbohydrates and nucleosides. Carbohydr Res 2024; 541:109126. [PMID: 38823061 DOI: 10.1016/j.carres.2024.109126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 06/03/2024]
Abstract
In general, 1,5-disubstituted 1,2,3-triazolyl moiety is much less common in the synthesis and applications in comparison to its regioisomeric counterpart. Moreover, the synthesis of 1,5-disubstituted 1,2,3-triazoles are not so straightforward as is the case for copper catalyzed strategy of 1,4-disubstituted 1,2,3-triazoles. The preparation of 1,5-triazolylated carbohydrates and nucleosides are even more complex because of the difficulties in accessing the appropriate starting materials as well as the compatibility of reaction conditions with the various protecting groups. 1,5-Disubstitution regioisomeric triazoles of carbohydrates and nucleosides were traditionally obtained as minor products through straightforward heating of the mixture of azides and terminal alkynes. However, the separation of isomers was tedious or in some cases futile. On the other hand, regioselective synthesis using ruthenium catalysis triggered serious concern of residual metal content in therapeutically important ingredients. Therefore, serious efforts are being made by several groups to develop non-toxic metal based or completely metal-free synthesis of 1,5-disubstituted 1,2,3-triazoles. This article strives to summarize the pre-Click era as well as the post-2001 reports on the synthesis and potential applications of 1,5-disubstituted 1,2,3-triazoles in biological systems.
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Affiliation(s)
- Tanmaya Pathak
- Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721 302, West Bengal, India.
| | - Amitabha Bose
- Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721 302, West Bengal, India
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Wong XK, Ng CS, Yeong KY. Shaping the future of antiviral Treatment: Spotlight on Nucleobase-Containing drugs and their revolutionary impact. Bioorg Chem 2024; 144:107150. [PMID: 38309002 DOI: 10.1016/j.bioorg.2024.107150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/28/2023] [Accepted: 01/22/2024] [Indexed: 02/05/2024]
Abstract
Nucleobases serve as essential molecular frameworks present in both natural and synthetic compounds that exhibit notable antiviral activity. Through molecular modifications, novel nucleobase-containing drugs (NCDs) have been developed, exhibiting enhanced antiviral activity against a wide range of viruses, including the recently emerged SARS‑CoV‑2. This article provides a detailed examination of the significant advancements in NCDs from 2015 till current, encompassing various aspects concerning their mechanisms of action, pharmacology and antiviral properties. Additionally, the article discusses antiviral prodrugs relevant to the scope of this review. It fills in the knowledge gap by examining the structure-activity relationship and trend of NCDs as therapeutics against a diverse range of viral diseases, either as approved drugs, clinical candidates or as early-stage development prospects. Moreover, the article highlights on the status of this field of study and addresses the prevailing limitations encountered.
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Affiliation(s)
- Xi Khai Wong
- School of Science, Monash University (Malaysia Campus), Jalan Lagoon Selatan, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia
| | - Chen Seng Ng
- School of Science, Monash University (Malaysia Campus), Jalan Lagoon Selatan, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia
| | - Keng Yoon Yeong
- School of Science, Monash University (Malaysia Campus), Jalan Lagoon Selatan, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia.
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Regier J, Bolshan Y. Synthesis of C,N-Glycosides via Brønsted Acid-Catalyzed Azidation of exo-Glycals. J Org Chem 2024; 89:141-151. [PMID: 38110245 DOI: 10.1021/acs.joc.3c01842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2023]
Abstract
The reaction of exo-glycals with azidotrimethylsilane in the presence of a Brønsted acid leads to the generation of the corresponding C,N-glycosyl azides. The majority of these glycosylation reactions proceed at room temperature with short reaction times. In addition, the targeted products were obtained in high yields with exclusive diastereoselectivity to the α-anomer in pyranose-based derivatives. Carbohydrate units based on mannose, galactose, arabinose, and ribose were also shown to proceed in high yields.
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Affiliation(s)
- Jeffery Regier
- TLC Pharmaceutical Standards, Newmarket, Ontario L3Y 7B6, Canada
| | - Yuri Bolshan
- Faculty of Science, Ontario Tech University, Oshawa, Ontario L1G 0C5, Canada
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Laxman Rao BSV, Mahesh M, Yacovan A, Kumar Pillai B. Brønsted Acid Mediated Annulation of α‐Hydroxy Amides with Cycloalkanones: Access to Double Spirocyclic Oxazolidin‐4‐ones. ChemistrySelect 2023. [DOI: 10.1002/slct.202204886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Affiliation(s)
- Bachu S. V. Laxman Rao
- R&D centre ADAMA India Pvt. Ltd., Genome valley Turkapally, Shameerpet Medchal-Malkajgiri district, Hyderabad, Telangana 500101 India
| | - Masna Mahesh
- R&D centre ADAMA India Pvt. Ltd., Genome valley Turkapally, Shameerpet Medchal-Malkajgiri district, Hyderabad, Telangana 500101 India
| | - Avihai Yacovan
- R&D centre ADAMA India Pvt. Ltd., Genome valley Turkapally, Shameerpet Medchal-Malkajgiri district, Hyderabad, Telangana 500101 India
| | - Biju Kumar Pillai
- R&D centre ADAMA India Pvt. Ltd., Genome valley Turkapally, Shameerpet Medchal-Malkajgiri district, Hyderabad, Telangana 500101 India
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Iusupov IR, Lukyanenko ER, Altieri A, Kurkin AV. Design and Synthesis of Fsp3-Enriched Spirocyclic-Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling. ChemMedChem 2022; 17:e202200394. [PMID: 36193863 DOI: 10.1002/cmdc.202200394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/26/2022] [Indexed: 01/14/2023]
Abstract
Medicinal chemists are keen to explore tridimensional compounds, especially when it comes to small molecules. It has already been stressed that the majority of known drugs tend to be flat, whereas natural products tend to be more tridimensional and represent a good source of active compounds. 3D metrics have been implemented and computational descriptors are available to evaluate and prioritize compounds based on their 3D geometry. This is usually done by comparing the saturated carbon atoms in a molecule with the total number of its non-hydrogen atoms (the Fsp3 value). While this aspect is clear, still there are not enough synthetic tools that support the realization of novel chemotypes that conform to these criteria. Herein we describe a diversity oriented synthesis (DOS) synthetic cascade technology that starts from two simple reagents, and generates highly enriched Fsp3 novel and diverse spiro-scaffolds with pragmatic synthetic handles (points of diversity). The spiro nature of these scaffolds not only ensures high Fsp3 values but renders the compounds more rigid and therefore more effective in forming precise stereo-interactions with their potential biological targets. These compounds were also profiled for their drug-like properties and as potential modulators of the NNMT enzyme.
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Affiliation(s)
- Ildar R Iusupov
- Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, Moscow, 119991, Russia
| | - Evgeny R Lukyanenko
- Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, Moscow, 119991, Russia
| | - Andrea Altieri
- Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, Moscow, 119991, Russia.,EDASA Scientific Srls, Via Stingi, 3, 66050, San Salvo, Italy
| | - Alexander V Kurkin
- Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, Moscow, 119991, Russia
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Kánya N, Kun S, Somsák L. Glycopyranosylidene-Spiro-Morpholinones: Evaluation of the Synthetic Possibilities Based on Glyculosonamide Derivatives and a New Method for the Construction of the Morpholine Ring. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27227785. [PMID: 36431884 PMCID: PMC9698030 DOI: 10.3390/molecules27227785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/07/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022]
Abstract
Glycosylidene-spiro-morpholin(on)es are scarcely described skeletons in the literature. In this work, we have systematically explored the synthetic routes towards such morpholinones based on the reactions of O-peracylated hept-2-ulopyranosonamide derivatives of D-gluco and D-galacto configuration. Koenigs-Knorr type glycosylation of 2-chloroethanol, allylic and propargylic alcohols by (glyculosylbromide)onamides furnished the expected glycosides. The 2-chloroethyl glycosides were ring closed to the corresponding spiro-morpholinones by treatment with K2CO3. The (allyl glyculosid)onamides gave diastereomeric mixtures of spiro-5-hydroxymorpholinones by ozonolysis and 5-iodomethylmorpholinones under iodonium ion mediated conditions. The ozonolytic method has not yet been known for the construction of morpholine rings, therefore, it was also extended to O-allyl mandelamide. The 5-hydroxymorpholinones were subjected to oxidation and acid catalyzed elimination reactions to give the corresponding morpholine-3,5-dions and 5,6-didehydro-morpholin-3-ones, respectively. Base induced elimination of the 5-iodomethylmorpholinones gave 5-methyl-2H-1,4-oxazin-3(4H)-ones. O-Acyl protecting groups of all of the above compounds were removed under Zemplén conditions. Some of the D-gluco configured unprotected compounds were tested as inhibitors of glycogen phosphorylase, but showed no significant effect.
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Unveiling the synthesis of spirocyclic, tricyclic, and bicyclic triazolooxazines from intramolecular [3 + 2] azide-alkyne cycloadditions with a molecular electron density theory perspective. Struct Chem 2022. [DOI: 10.1007/s11224-021-01870-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Perrone D, Marchesi E, Preti L, Navacchia ML. Modified Nucleosides, Nucleotides and Nucleic Acids via Click Azide-Alkyne Cycloaddition for Pharmacological Applications. Molecules 2021; 26:3100. [PMID: 34067312 PMCID: PMC8196910 DOI: 10.3390/molecules26113100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 11/17/2022] Open
Abstract
The click azide = alkyne 1,3-dipolar cycloaddition (click chemistry) has become the approach of choice for bioconjugations in medicinal chemistry, providing facile reaction conditions amenable to both small and biological molecules. Many nucleoside analogs are known for their marked impact in cancer therapy and for the treatment of virus diseases and new targeted oligonucleotides have been developed for different purposes. The click chemistry allowing the tolerated union between units with a wide diversity of functional groups represents a robust means of designing new hybrid compounds with an extraordinary diversity of applications. This review provides an overview of the most recent works related to the use of click chemistry methodology in the field of nucleosides, nucleotides and nucleic acids for pharmacological applications.
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Affiliation(s)
- Daniela Perrone
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy; (E.M.); (L.P.)
| | - Elena Marchesi
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy; (E.M.); (L.P.)
| | - Lorenzo Preti
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy; (E.M.); (L.P.)
| | - Maria Luisa Navacchia
- Institute of Organic Synthesis and Photoreactivity National Research Council, 40129 Bologna, Italy
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Rungta P, Kumar M, Mangla P, Kumar S, Prasad AK. Chemo-enzymatic access to C-4′-hydroxyl-tetrahydrofurano-spironucleosides. NEW J CHEM 2021. [DOI: 10.1039/d0nj03253k] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The biocatalytic synthesis of C-4′-hydroxyl-tetrahydrofurano-spironucleosides where the tetrahydrofuranospirocyclic ring at C-4′ position locks the furanose ring of nucleosides in the NE-conformation (C4′-exo).
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Affiliation(s)
- Pallavi Rungta
- Bioorganic Laboratory
- Department of Chemistry
- University of Delhi
- Delhi
- India
| | - Manish Kumar
- Bioorganic Laboratory
- Department of Chemistry
- University of Delhi
- Delhi
- India
| | - Priyanka Mangla
- Bioorganic Laboratory
- Department of Chemistry
- University of Delhi
- Delhi
- India
| | - Sandeep Kumar
- Bioorganic Laboratory
- Department of Chemistry
- University of Delhi
- Delhi
- India
| | - Ashok K. Prasad
- Bioorganic Laboratory
- Department of Chemistry
- University of Delhi
- Delhi
- India
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Affiliation(s)
- Manoj Dhameja
- Department of Chemistry School Of Physical & Decision SciencesBabasaheb Bhimrao Ambedkar University (A Central University) Rae barelli Road Lucknow 226025 (U. P.) India
| | - Hariom Kumar
- Department of Chemistry School Of Physical & Decision SciencesBabasaheb Bhimrao Ambedkar University (A Central University) Rae barelli Road Lucknow 226025 (U. P.) India
| | - Preeti Gupta
- Department of Chemistry School Of Physical & Decision SciencesBabasaheb Bhimrao Ambedkar University (A Central University) Rae barelli Road Lucknow 226025 (U. P.) India
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