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Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors. / Salomatina, Oksana V.; Popadyuk, Irina I.; Zakharenko, Alexandra L. et al.

In: Molecules, Vol. 23, No. 3, 679, 17.03.2018.

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

Harvard

Salomatina, OV, Popadyuk, II, Zakharenko, AL, Zakharova, OD, Fadeev, DS, Komarova, NI, Reynisson, J, Arabshahi, HJ, Chand, R, Volcho, KP, Salakhutdinov, NF & Lavrik, OI 2018, 'Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors', Molecules, vol. 23, no. 3, 679. https://doi.org/10.3390/molecules23030679

APA

Salomatina, O. V., Popadyuk, I. I., Zakharenko, A. L., Zakharova, O. D., Fadeev, D. S., Komarova, N. I., Reynisson, J., Arabshahi, H. J., Chand, R., Volcho, K. P., Salakhutdinov, N. F., & Lavrik, O. I. (2018). Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors. Molecules, 23(3), [679]. https://doi.org/10.3390/molecules23030679

Vancouver

Salomatina OV, Popadyuk II, Zakharenko AL, Zakharova OD, Fadeev DS, Komarova NI et al. Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors. Molecules. 2018 Mar 17;23(3):679. doi: 10.3390/molecules23030679

Author

Salomatina, Oksana V. ; Popadyuk, Irina I. ; Zakharenko, Alexandra L. et al. / Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors. In: Molecules. 2018 ; Vol. 23, No. 3.

BibTeX

@article{6d93146c9de64e8f8c6338e90e21c37b,
title = "Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors",
abstract = "An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC50 up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme.",
keywords = "Amide, Cancer, Chenodeoxycholic acid, Deoxycholic acid, Molecular modelling, Tdp1 inhibitor, Tumor, Ursodeoxycholic acid, Virtual screening, HCT116 Cells, Humans, Bile Acids and Salts/chemical synthesis, Phosphodiesterase Inhibitors/chemical synthesis, Phosphoric Diester Hydrolases/metabolism, MCF-7 Cells, Molecular Docking Simulation, Drug Evaluation, Preclinical, Binding Sites, Niacinamide/analogs & derivatives, Tryptamines/chemical synthesis, STRAND BREAK REPAIR, virtual screening, HUMAN-CELLS, TOPOISOMERASE-I, deoxycholic acid, ursodeoxycholic acid, CAMPTOTHECIN, BIOLOGICAL EVALUATION, CHEMISTRY, molecular modelling, DAMAGE, ANTICANCER, amide, TDP1, tumor, cancer, BINDING, chenodeoxycholic acid",
author = "Salomatina, {Oksana V.} and Popadyuk, {Irina I.} and Zakharenko, {Alexandra L.} and Zakharova, {Olga D.} and Fadeev, {Dmitriy S.} and Komarova, {Nina I.} and J{\'o}hannes Reynisson and Arabshahi, {H. John} and Raina Chand and Volcho, {Konstantin P.} and Salakhutdinov, {Nariman F.} and Lavrik, {Olga I.}",
year = "2018",
month = mar,
day = "17",
doi = "10.3390/molecules23030679",
language = "English",
volume = "23",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "3",

}

RIS

TY - JOUR

T1 - Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors

AU - Salomatina, Oksana V.

AU - Popadyuk, Irina I.

AU - Zakharenko, Alexandra L.

AU - Zakharova, Olga D.

AU - Fadeev, Dmitriy S.

AU - Komarova, Nina I.

AU - Reynisson, Jóhannes

AU - Arabshahi, H. John

AU - Chand, Raina

AU - Volcho, Konstantin P.

AU - Salakhutdinov, Nariman F.

AU - Lavrik, Olga I.

PY - 2018/3/17

Y1 - 2018/3/17

N2 - An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC50 up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme.

AB - An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC50 up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme.

KW - Amide

KW - Cancer

KW - Chenodeoxycholic acid

KW - Deoxycholic acid

KW - Molecular modelling

KW - Tdp1 inhibitor

KW - Tumor

KW - Ursodeoxycholic acid

KW - Virtual screening

KW - HCT116 Cells

KW - Humans

KW - Bile Acids and Salts/chemical synthesis

KW - Phosphodiesterase Inhibitors/chemical synthesis

KW - Phosphoric Diester Hydrolases/metabolism

KW - MCF-7 Cells

KW - Molecular Docking Simulation

KW - Drug Evaluation, Preclinical

KW - Binding Sites

KW - Niacinamide/analogs & derivatives

KW - Tryptamines/chemical synthesis

KW - STRAND BREAK REPAIR

KW - virtual screening

KW - HUMAN-CELLS

KW - TOPOISOMERASE-I

KW - deoxycholic acid

KW - ursodeoxycholic acid

KW - CAMPTOTHECIN

KW - BIOLOGICAL EVALUATION

KW - CHEMISTRY

KW - molecular modelling

KW - DAMAGE

KW - ANTICANCER

KW - amide

KW - TDP1

KW - tumor

KW - cancer

KW - BINDING

KW - chenodeoxycholic acid

UR - http://www.scopus.com/inward/record.url?scp=85044436142&partnerID=8YFLogxK

U2 - 10.3390/molecules23030679

DO - 10.3390/molecules23030679

M3 - Article

C2 - 29562592

AN - SCOPUS:85044436142

VL - 23

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 3

M1 - 679

ER -

ID: 12214493