Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors Full article

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2021, Volume: 26, Number: 7, Article number : 1945, Pages count : DOI: 10.3390/molecules26071945

Tags

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

Authors

Gladkova Elizaveta D. ^1,2 , Chepanova Arina A. ³ , Ilina Ekaterina S. ³ , Zakharenko Alexandra L. ³ , Reynisson Jóhannes ⁴ , Luzina Olga A. ¹ , Volcho Konstantin P. ¹ , Lavrik Olga I. ³ , Salakhutdinov Nariman F. ¹

Affiliations

1	N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
2	Department of Natural Sciences, Novosibirsk State University, Pirogova str. 1, Novosibirsk, 630090, Russian Federation
3	Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
4	School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire, ST5 5BG, United Kingdom

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.

Gladkova E.D. , Chepanova A.A. , Ilina E.S. , Zakharenko A.L. , Reynisson J. , Luzina O.A. , Volcho K.P. , Lavrik O.I. , Salakhutdinov N.F.
Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

Molecules. 2021. V.26. N7. 1945 . DOI: 10.3390/molecules26071945 WOS Scopus РИНЦ

Full text from publisher

Published print:	Mar 30, 2021
Published online:	Mar 30, 2021

Web of science	WOS:000638747200001
Scopus	2-s2.0-85103862885
Elibrary	46764600
OpenAlex	W3151289162