Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 7; p. 1945
• Main Authors: Gladkova, Elizaveta D., Chepanova, Arina A., Ilina, Ekaterina S., Zakharenko, Alexandra L., Reynisson, Jóhannes, Luzina, Olga A., Volcho, Konstantin P., Lavrik, Olga I., Salakhutdinov, Nariman F.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.03.2021; MDPI
• Subjects: berberine; berberrubine; Cancer; Chloride; Crystal structure; DNA repair enzyme; Enzymes; Investigations; Ligands; Liquor; SAR; Tdp1 inhibitor; sulfonate; Tdp1 inhibitor; SAR; molecular modeling; berberrubine; sultone; DNA repair enzyme; cancer; berberine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26071945

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.