Gladkova, ED, Chepanova, AA, Ilina, ES, Zakharenko, AL, Reynisson, J ORCID: https://orcid.org/0000-0003-4174-9512, Luzina, OA, Volcho, KP, Lavrik, OI and Salakhutdinov, NF (2021) Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors. Molecules, 26 (7).

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Abstract

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 C and D 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-O-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-O-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.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via MDPI AG at https://doi.org/10.3390/molecules26071945 - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: berberine, berberrubine, cancer, Tdp1 inhibitor, DNA repair enzyme, SAR, molecular modeling, sultone, sulfonate
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Related URLs:
Depositing User: Symplectic
Date Deposited: 22 Apr 2021 10:28
Last Modified: 11 Jun 2021 10:49
URI: https://eprints.keele.ac.uk/id/eprint/9412

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