Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

Molecules. 2021 Mar 30;26(7):1945. 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.

Keywords: DNA repair enzyme; SAR; Tdp1 inhibitor; berberine; berberrubine; cancer; molecular modeling; sulfonate; sultone.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Berberine / analogs & derivatives*
  • Berberine / chemistry
  • Drug Design
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphoric Diester Hydrolases / chemistry*
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Phosphodiesterase Inhibitors
  • Berberine
  • berberrubine
  • Phosphoric Diester Hydrolases
  • TDP1 protein, human