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

Oksana V. Salomatina; Irina I. Popadyuk; Alexandra L. Zakharenko; Olga D. Zakharova; Dmitriy S. Fadeev; Nina I. Komarova; Jóhannes Reynisson; H. John Arabshahi; Raina Chand; Konstantin P. Volcho; Nariman F. Salakhutdinov; Olga I. Lavrik

doi:10.3390/molecules23030679

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

Oksana V. Salomatina, Irina I. Popadyuk, Alexandra L. Zakharenko, Olga D. Zakharova, Dmitriy S. Fadeev, Nina I. Komarova, Jóhannes Reynisson, H. John Arabshahi, Raina Chand, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. Lavrik

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

19 Citations (Scopus)

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.

Original language	English
Article number	679
Number of pages	19
Journal	Molecules
Volume	23
Issue number	3
DOIs	https://doi.org/10.3390/molecules23030679
Publication status	Published - 17 Mar 2018

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

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10.3390/molecules23030679

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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

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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.",

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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.}",

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month = mar,

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doi = "10.3390/molecules23030679",

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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 -

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

Abstract

Keywords

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