Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

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

Результат исследования: Научные публикации в периодических изданияхстатьярецензирование

Аннотация

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.

Язык оригиналаанглийский
ЖурналMolecules (Basel, Switzerland)
Том26
Номер выпуска7
DOI
СостояниеОпубликовано - 30 мар 2021

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