The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

Arina A. Chepanova; Evgenii S. Mozhaitsev; Aldar A. Munkuev; Evgeniy V. Suslov; Dina V. Korchagina; Olga D. Zakharova; Alexandra L. Zakharenko; Jinal Patel; Daniel M. Ayine-Tora; Jóhannes Reynisson; Ivanhoe K.H. Leung; Konstantin P. Volcho; Nariman F. Salakhutdinov; Olga I. Lavrik

doi:10.3390/app9132767

The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

Arina A. Chepanova, Evgenii S. Mozhaitsev, Aldar A. Munkuev, Evgeniy V. Suslov, Dina V. Korchagina, Olga D. Zakharova, Alexandra L. Zakharenko, Jinal Patel, Daniel M. Ayine-Tora, Jóhannes Reynisson, Ivanhoe K.H. Leung, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. Lavrik

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

10 Citations (Scopus)

Abstract

Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC₅₀ value of 0.64 μM. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 μM concentration, displaying strong synergism. This effect was only seen for 46a (IC₅₀-3.3 μM) albeit some other ligands had better IC₅₀ values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

Original language	English
Article number	2767
Journal	Applied Sciences (Switzerland)
Volume	9
Issue number	13
DOIs	https://doi.org/10.3390/app9132767
Publication status	Published - 1 Jul 2019

Keywords

A-549 lung adenocarcinoma cell line l
Chemical space
Fluorescence biosensor assay
Intrinsic tryptophan fluorescence binding assay
Molecular modelling
Synergy
Thermal shift assay
Topoisomerase 1
Topotecan
synergy
EMPIRICAL SCORING FUNCTIONS
fluorescence biosensor assay
REPAIR
FRAGMENTS
intrinsic tryptophan fluorescence binding assay
CAMPTOTHECIN
BIOLOGICAL EVALUATION
chemical space
DERIVATIVES
topotecan
MECHANISM
molecular modelling
thermal shift assay
PROTEIN-LIGAND DOCKING
TDP1
TOPOISOMERASE-I INHIBITORS

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Chepanova, A. A., Mozhaitsev, E. S., Munkuev, A. A., Suslov, E. V., Korchagina, D. V., Zakharova, O. D., Zakharenko, A. L., Patel, J., Ayine-Tora, D. M., Reynisson, J., Leung, I. K. H., Volcho, K. P., Salakhutdinov, N. F., & Lavrik, O. I. (2019). The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges. Applied Sciences (Switzerland), 9(13), [2767]. https://doi.org/10.3390/app9132767

Chepanova, Arina A. ; Mozhaitsev, Evgenii S. ; Munkuev, Aldar A. ; Suslov, Evgeniy V. ; Korchagina, Dina V. ; Zakharova, Olga D. ; Zakharenko, Alexandra L. ; Patel, Jinal ; Ayine-Tora, Daniel M. ; Reynisson, Jóhannes ; Leung, Ivanhoe K.H. ; Volcho, Konstantin P. ; Salakhutdinov, Nariman F. ; Lavrik, Olga I. / The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges. In: Applied Sciences (Switzerland). 2019 ; Vol. 9, No. 13.

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title = "The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges",

abstract = "Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 μM. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 μM concentration, displaying strong synergism. This effect was only seen for 46a (IC50-3.3 μM) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.",

keywords = "A-549 lung adenocarcinoma cell line l, Chemical space, Fluorescence biosensor assay, Intrinsic tryptophan fluorescence binding assay, Molecular modelling, Synergy, Thermal shift assay, Topoisomerase 1, Topotecan, synergy, EMPIRICAL SCORING FUNCTIONS, fluorescence biosensor assay, REPAIR, FRAGMENTS, intrinsic tryptophan fluorescence binding assay, CAMPTOTHECIN, BIOLOGICAL EVALUATION, chemical space, DERIVATIVES, topotecan, MECHANISM, molecular modelling, thermal shift assay, PROTEIN-LIGAND DOCKING, TDP1, TOPOISOMERASE-I INHIBITORS",

author = "Chepanova, {Arina A.} and Mozhaitsev, {Evgenii S.} and Munkuev, {Aldar A.} and Suslov, {Evgeniy V.} and Korchagina, {Dina V.} and Zakharova, {Olga D.} and Zakharenko, {Alexandra L.} and Jinal Patel and Ayine-Tora, {Daniel M.} and J{\'o}hannes Reynisson and Leung, {Ivanhoe K.H.} and Volcho, {Konstantin P.} and Salakhutdinov, {Nariman F.} and Lavrik, {Olga I.}",

year = "2019",

month = jul,

day = "1",

doi = "10.3390/app9132767",

language = "English",

volume = "9",

journal = "Applied Sciences (Switzerland)",

issn = "2076-3417",

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

number = "13",

}

Chepanova, AA, Mozhaitsev, ES, Munkuev, AA, Suslov, EV, Korchagina, DV, Zakharova, OD, Zakharenko, AL, Patel, J, Ayine-Tora, DM, Reynisson, J, Leung, IKH, Volcho, KP, Salakhutdinov, NF & Lavrik, OI 2019, 'The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges', Applied Sciences (Switzerland), vol. 9, no. 13, 2767. https://doi.org/10.3390/app9132767

The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges. / Chepanova, Arina A.; Mozhaitsev, Evgenii S.; Munkuev, Aldar A.; Suslov, Evgeniy V.; Korchagina, Dina V.; Zakharova, Olga D.; Zakharenko, Alexandra L.; Patel, Jinal; Ayine-Tora, Daniel M.; Reynisson, Jóhannes; Leung, Ivanhoe K.H.; Volcho, Konstantin P.; Salakhutdinov, Nariman F.; Lavrik, Olga I.

In: Applied Sciences (Switzerland), Vol. 9, No. 13, 2767, 01.07.2019.

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

TY - JOUR

T1 - The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

AU - Chepanova, Arina A.

AU - Mozhaitsev, Evgenii S.

AU - Munkuev, Aldar A.

AU - Suslov, Evgeniy V.

AU - Korchagina, Dina V.

AU - Zakharova, Olga D.

AU - Zakharenko, Alexandra L.

AU - Patel, Jinal

AU - Ayine-Tora, Daniel M.

AU - Reynisson, Jóhannes

AU - Leung, Ivanhoe K.H.

AU - Volcho, Konstantin P.

AU - Salakhutdinov, Nariman F.

AU - Lavrik, Olga I.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 μM. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 μM concentration, displaying strong synergism. This effect was only seen for 46a (IC50-3.3 μM) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

AB - Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 μM. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 μM concentration, displaying strong synergism. This effect was only seen for 46a (IC50-3.3 μM) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

KW - A-549 lung adenocarcinoma cell line l

KW - Chemical space

KW - Fluorescence biosensor assay

KW - Intrinsic tryptophan fluorescence binding assay

KW - Molecular modelling

KW - Synergy

KW - Thermal shift assay

KW - Topoisomerase 1

KW - Topotecan

KW - synergy

KW - EMPIRICAL SCORING FUNCTIONS

KW - fluorescence biosensor assay

KW - REPAIR

KW - FRAGMENTS

KW - intrinsic tryptophan fluorescence binding assay

KW - CAMPTOTHECIN

KW - BIOLOGICAL EVALUATION

KW - chemical space

KW - DERIVATIVES

KW - topotecan

KW - MECHANISM

KW - molecular modelling

KW - thermal shift assay

KW - PROTEIN-LIGAND DOCKING

KW - TDP1

KW - TOPOISOMERASE-I INHIBITORS

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U2 - 10.3390/app9132767

DO - 10.3390/app9132767

M3 - Article

AN - SCOPUS:85073695940

VL - 9

JO - Applied Sciences (Switzerland)

JF - Applied Sciences (Switzerland)

SN - 2076-3417

IS - 13

M1 - 2767

ER -

The development of Tyrosyl-DNA phosphodiesterase 1 inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

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Keywords

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