Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors
A new type of berberine derivatives was obtained by the reaction of berberrubine with aliphatic sulfonyl chlorides. The new polycyclic compounds have a sultone ring condensed to <i>C</i> and <i>D</i> rings of a protoberberine core. The reaction conditions were developed to fa...
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| Format: | Article |
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MDPI AG
2021-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/7/1945 |
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| author | Elizaveta D. Gladkova Arina A. Chepanova Ekaterina S. Ilina Alexandra L. Zakharenko Jóhannes Reynisson Olga A. Luzina Konstantin P. Volcho Olga I. Lavrik Nariman F. Salakhutdinov |
| author_facet | Elizaveta D. Gladkova Arina A. Chepanova Ekaterina S. Ilina Alexandra L. Zakharenko Jóhannes Reynisson Olga A. Luzina Konstantin P. Volcho Olga I. Lavrik Nariman F. Salakhutdinov |
| author_sort | Elizaveta D. Gladkova |
| collection | DOAJ |
| description | A new type of berberine derivatives was obtained by the reaction of berberrubine with aliphatic sulfonyl chlorides. The new polycyclic compounds have a sultone ring condensed to <i>C</i> and <i>D</i> rings of a protoberberine core. The reaction conditions were developed to facilitate the formation of sultones with high yields without by-product formation. Thus, it was shown that the order of addition of reagents affects the composition of the reaction products: when sulfochlorides are added to berberrubine, their corresponding 9-<i>O</i>-sulfonates are predominantly formed; when berberrubine is added to pre-generated sulfenes, sultones are the only products. The reaction was shown to proceed stereo-selectively and the cycle configuration was confirmed by 2D NMR spectroscopy. The inhibitory activity of the synthesized sultones and their 12-brominated analogs against the DNA-repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1), an important target for a potential antitumor therapy, was studied. All derivatives were active in the micromolar and submicromolar range, in contrast to the acyclic analogs and 9-<i>O</i>-sulfonates, which were inactive. The significance of the sultone cycle and bromine substituent in binding with the enzyme was confirmed using molecular modeling. The active inhibitors are mostly non-toxic to the HeLa cancer cell line, and several ligands show synergy with topotecan, a topoisomerase 1 poison in clinical use. Thus, novel berberine derivatives can be considered as candidates for adjuvant therapy against cancer. |
| first_indexed | 2024-03-10T12:46:08Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T12:46:08Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-10f36ade672b4e59b0bd017b94eedeef2023-11-21T13:27:34ZengMDPI AGMolecules1420-30492021-03-01267194510.3390/molecules26071945Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 InhibitorsElizaveta D. Gladkova0Arina A. Chepanova1Ekaterina S. Ilina2Alexandra L. Zakharenko3Jóhannes Reynisson4Olga A. Luzina5Konstantin P. Volcho6Olga I. Lavrik7Nariman F. Salakhutdinov8N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaNovosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaNovosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaNovosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaSchool of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, UKN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaNovosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, RussiaA new type of berberine derivatives was obtained by the reaction of berberrubine with aliphatic sulfonyl chlorides. The new polycyclic compounds have a sultone ring condensed to <i>C</i> and <i>D</i> rings of a protoberberine core. The reaction conditions were developed to facilitate the formation of sultones with high yields without by-product formation. Thus, it was shown that the order of addition of reagents affects the composition of the reaction products: when sulfochlorides are added to berberrubine, their corresponding 9-<i>O</i>-sulfonates are predominantly formed; when berberrubine is added to pre-generated sulfenes, sultones are the only products. The reaction was shown to proceed stereo-selectively and the cycle configuration was confirmed by 2D NMR spectroscopy. The inhibitory activity of the synthesized sultones and their 12-brominated analogs against the DNA-repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1), an important target for a potential antitumor therapy, was studied. All derivatives were active in the micromolar and submicromolar range, in contrast to the acyclic analogs and 9-<i>O</i>-sulfonates, which were inactive. The significance of the sultone cycle and bromine substituent in binding with the enzyme was confirmed using molecular modeling. The active inhibitors are mostly non-toxic to the HeLa cancer cell line, and several ligands show synergy with topotecan, a topoisomerase 1 poison in clinical use. Thus, novel berberine derivatives can be considered as candidates for adjuvant therapy against cancer.https://www.mdpi.com/1420-3049/26/7/1945berberineberberrubinecancerTdp1 inhibitorDNA repair enzymeSAR |
| spellingShingle | Elizaveta D. Gladkova Arina A. Chepanova Ekaterina S. Ilina Alexandra L. Zakharenko Jóhannes Reynisson Olga A. Luzina Konstantin P. Volcho Olga I. Lavrik Nariman F. Salakhutdinov Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors Molecules berberine berberrubine cancer Tdp1 inhibitor DNA repair enzyme SAR |
| title | Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors |
| title_full | Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors |
| title_fullStr | Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors |
| title_full_unstemmed | Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors |
| title_short | Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors |
| title_sort | discovery of novel sultone fused berberine derivatives as promising tdp1 inhibitors |
| topic | berberine berberrubine cancer Tdp1 inhibitor DNA repair enzyme SAR |
| url | https://www.mdpi.com/1420-3049/26/7/1945 |
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