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Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors.

Reynisson

Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors. Thumbnail


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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.

Acceptance Date Mar 26, 2021
Publication Date Mar 30, 2021
Publicly Available Date Mar 29, 2024
Journal Molecules
Publisher MDPI
DOI https://doi.org/10.3390/molecules26071945
Keywords berberine, berberrubine, cancer, Tdp1 inhibitor, DNA repair enzyme, SAR, molecular modeling, sultone, sulfonate
Publisher URL https://doi.org/10.3390/molecules26071945

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