Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors. / Gladkova, Elizaveta D.; Chepanova, Arina A.; Ilina, Ekaterina S. и др.
в: Molecules (Basel, Switzerland), Том 26, № 7, 1945, 30.03.2021.Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
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TY - JOUR
T1 - Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors
AU - Gladkova, Elizaveta D.
AU - Chepanova, Arina A.
AU - Ilina, Ekaterina S.
AU - Zakharenko, Alexandra L.
AU - Reynisson, Jóhannes
AU - Luzina, Olga A.
AU - Volcho, Konstantin P.
AU - Lavrik, Olga I.
AU - Salakhutdinov, Nariman F.
N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3/30
Y1 - 2021/3/30
N2 - 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.
AB - 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.
KW - berberine
KW - berberrubine
KW - cancer
KW - DNA repair enzyme
KW - molecular modeling
KW - SAR
KW - sulfonate
KW - sultone
KW - Tdp1 inhibitor
KW - Berberine
KW - Sultone
KW - Sulfonate
KW - Berberrubine
KW - Molecular modeling
KW - Cancer
UR - http://www.scopus.com/inward/record.url?scp=85103862885&partnerID=8YFLogxK
U2 - 10.3390/molecules26071945
DO - 10.3390/molecules26071945
M3 - Article
C2 - 33808389
AN - SCOPUS:85103862885
VL - 26
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 7
M1 - 1945
ER -
ID: 28327646