Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

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Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors. / Gladkova, Elizaveta D.; Chepanova, Arina A.; Ilina, Ekaterina S. et al.

In: Molecules (Basel, Switzerland), Vol. 26, No. 7, 1945, 30.03.2021.

Research output: Contribution to journal › Article › peer-review

Harvard

Gladkova, ED, Chepanova, AA, Ilina, ES, Zakharenko, AL, Reynisson, J, Luzina, OA, Volcho, KP, Lavrik, OI & Salakhutdinov, NF 2021, 'Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors', Molecules (Basel, Switzerland), vol. 26, no. 7, 1945. https://doi.org/10.3390/molecules26071945

APA

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. (2021). Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors. Molecules (Basel, Switzerland), 26(7), [1945]. https://doi.org/10.3390/molecules26071945

Vancouver

Gladkova ED, Chepanova AA, Ilina ES, Zakharenko AL, Reynisson J, Luzina OA et al. Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors. Molecules (Basel, Switzerland). 2021 Mar 30;26(7):1945. doi: 10.3390/molecules26071945

Author

Gladkova, Elizaveta D. ; Chepanova, Arina A. ; Ilina, Ekaterina S. et al. / Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors. In: Molecules (Basel, Switzerland). 2021 ; Vol. 26, No. 7.

BibTeX

@article{83b293d5301845e7ad0629573e4e3602,

title = "Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors",

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.",

keywords = "berberine, berberrubine, cancer, DNA repair enzyme, molecular modeling, SAR, sulfonate, sultone, Tdp1 inhibitor, Berberine, Sultone, Sulfonate, Berberrubine, Molecular modeling, Cancer",

author = "Gladkova, {Elizaveta D.} and Chepanova, {Arina A.} and Ilina, {Ekaterina S.} and Zakharenko, {Alexandra L.} and J{\'o}hannes Reynisson and Luzina, {Olga A.} and Volcho, {Konstantin P.} and Lavrik, {Olga I.} and Salakhutdinov, {Nariman F.}",

year = "2021",

month = mar,

day = "30",

doi = "10.3390/molecules26071945",

language = "English",

volume = "26",

journal = "Molecules",

issn = "1420-3049",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "7",

}

RIS

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.

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