Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction
The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final...
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MDPI AG
2022-09-01
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| Series: | Molecules |
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| author | Natalia A. Danilkina Ekaterina A. Khmelevskaya Anna G. Lyapunova Alexander S. D’yachenko Alexander S. Bunev Rovshan E. Gasanov Maxim A. Gureev Irina A. Balova |
| author_facet | Natalia A. Danilkina Ekaterina A. Khmelevskaya Anna G. Lyapunova Alexander S. D’yachenko Alexander S. Bunev Rovshan E. Gasanov Maxim A. Gureev Irina A. Balova |
| author_sort | Natalia A. Danilkina |
| collection | DOAJ |
| description | The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable under storage. Among the N-type Nicholas reactions, cyclization via an arenesulfonamide functional group followed by mild Co-deprotection was found to be the most promising, yielding 10-membered azaendiynes in high overall yields. By contrast, the Nicholas cyclization through the acylated nitrogen atom did not give the desired 10-membered cycle. It resulted in the formation of a pyrroline ring, whereas cyclization via an alkylated amino group resulted in a poor yield of the target 10-membered enediyne. The acylated 4-aminobenzenesulfonamide nucleophilic group was found to be the most convenient for the synthesis of functionalized 10-membered enediynes bearing a clickable function, such as a terminal triple bond. All the synthesized cyclic enediynes exhibited moderate activity against lung carcinoma NCI-H460 cells and had a minimal effect on lung epithelial-like WI-26 VA4 cells and are therefore promising compounds in the search for novel antitumor agents that can be converted into conjugates with tumor-targeting ligands. |
| first_indexed | 2024-03-09T22:59:53Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T22:59:53Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-418e404c8d404aa5abefedcc37995ca32023-11-23T18:03:53ZengMDPI AGMolecules1420-30492022-09-012718607110.3390/molecules27186071Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas ReactionNatalia A. Danilkina0Ekaterina A. Khmelevskaya1Anna G. Lyapunova2Alexander S. D’yachenko3Alexander S. Bunev4Rovshan E. Gasanov5Maxim A. Gureev6Irina A. Balova7Institute of Chemistry, Saint Petersburg State University (SPbU), Universitetskaya nab. 7/9, 199034 Saint Petersburg, RussiaInstitute of Chemistry, Saint Petersburg State University (SPbU), Universitetskaya nab. 7/9, 199034 Saint Petersburg, RussiaInstitute of Chemistry, Saint Petersburg State University (SPbU), Universitetskaya nab. 7/9, 199034 Saint Petersburg, RussiaInstitute of Chemistry, Saint Petersburg State University (SPbU), Universitetskaya nab. 7/9, 199034 Saint Petersburg, RussiaMedicinal Chemistry Center, Tolyatti State University, 445020 Tolyatti, RussiaMedicinal Chemistry Center, Tolyatti State University, 445020 Tolyatti, RussiaCenter of Chemo- and Bioinformatics, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, RussiaInstitute of Chemistry, Saint Petersburg State University (SPbU), Universitetskaya nab. 7/9, 199034 Saint Petersburg, RussiaThe scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable under storage. Among the N-type Nicholas reactions, cyclization via an arenesulfonamide functional group followed by mild Co-deprotection was found to be the most promising, yielding 10-membered azaendiynes in high overall yields. By contrast, the Nicholas cyclization through the acylated nitrogen atom did not give the desired 10-membered cycle. It resulted in the formation of a pyrroline ring, whereas cyclization via an alkylated amino group resulted in a poor yield of the target 10-membered enediyne. The acylated 4-aminobenzenesulfonamide nucleophilic group was found to be the most convenient for the synthesis of functionalized 10-membered enediynes bearing a clickable function, such as a terminal triple bond. All the synthesized cyclic enediynes exhibited moderate activity against lung carcinoma NCI-H460 cells and had a minimal effect on lung epithelial-like WI-26 VA4 cells and are therefore promising compounds in the search for novel antitumor agents that can be converted into conjugates with tumor-targeting ligands.https://www.mdpi.com/1420-3049/27/18/6071alkynesenediynesheterocyclesbenzo[<i>b</i>]thiopheneBergman cyclizationNicholas reaction |
| spellingShingle | Natalia A. Danilkina Ekaterina A. Khmelevskaya Anna G. Lyapunova Alexander S. D’yachenko Alexander S. Bunev Rovshan E. Gasanov Maxim A. Gureev Irina A. Balova Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction Molecules alkynes enediynes heterocycles benzo[<i>b</i>]thiophene Bergman cyclization Nicholas reaction |
| title | Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction |
| title_full | Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction |
| title_fullStr | Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction |
| title_full_unstemmed | Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction |
| title_short | Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction |
| title_sort | functionalized 10 membered aza and oxaenediynes through the nicholas reaction |
| topic | alkynes enediynes heterocycles benzo[<i>b</i>]thiophene Bergman cyclization Nicholas reaction |
| url | https://www.mdpi.com/1420-3049/27/18/6071 |
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