Design, synthesis, and molecular docking study of new tyrosyl-dna phosphodiesterase 1 (Tdp1) inhibitors combining resin acids and adamantane moieties

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Design, synthesis, and molecular docking study of new tyrosyl-dna phosphodiesterase 1 (Tdp1) inhibitors combining resin acids and adamantane moieties. / Kovaleva, Kseniya; Yarovaya, Olga; Ponomarev, Konstantin et al.

In: Pharmaceuticals, Vol. 14, No. 5, 422, 01.05.2021.

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

BibTeX

@article{86a3f5bcfab342479c80800058316ecb,

title = "Design, synthesis, and molecular docking study of new tyrosyl-dna phosphodiesterase 1 (Tdp1) inhibitors combining resin acids and adamantane moieties",

abstract = "In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their in-hibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 µM) and demonstrated low cytotox-icity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.",

keywords = "Adamantane, Resin acid, TDP1, Tyrosil-DNA-phosphodiesterase 1",

author = "Kseniya Kovaleva and Olga Yarovaya and Konstantin Ponomarev and Sergey Cheresiz and Amirhossein Azimirad and Irina Chernyshova and Alexandra Zakharenko and Vasily Konev and Tatiana Khlebnikova and Evgenii Mozhaytsev and Evgenii Suslov and Dmitry Nilov and Vytas {\v S}vedas and Andrey Pokrovsky and Olga Lavrik and Nariman Salakhutdinov",

note = "Funding Information: Funding: This work was supported by a grant from the Russian Science Foundation 19-73-00051. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = may,

day = "1",

doi = "10.3390/ph14050422",

language = "English",

volume = "14",

journal = "Pharmaceuticals",

issn = "1424-8247",

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

number = "5",

}

RIS

TY - JOUR

T1 - Design, synthesis, and molecular docking study of new tyrosyl-dna phosphodiesterase 1 (Tdp1) inhibitors combining resin acids and adamantane moieties

AU - Kovaleva, Kseniya

AU - Yarovaya, Olga

AU - Ponomarev, Konstantin

AU - Cheresiz, Sergey

AU - Azimirad, Amirhossein

AU - Chernyshova, Irina

AU - Zakharenko, Alexandra

AU - Konev, Vasily

AU - Khlebnikova, Tatiana

AU - Mozhaytsev, Evgenii

AU - Suslov, Evgenii

AU - Nilov, Dmitry

AU - Švedas, Vytas

AU - Pokrovsky, Andrey

AU - Lavrik, Olga

AU - Salakhutdinov, Nariman

N1 - Funding Information: Funding: This work was supported by a grant from the Russian Science Foundation 19-73-00051. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5/1

Y1 - 2021/5/1

N2 - In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their in-hibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 µM) and demonstrated low cytotox-icity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.

AB - In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their in-hibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 µM) and demonstrated low cytotox-icity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.

KW - Adamantane

KW - Resin acid

KW - TDP1

KW - Tyrosil-DNA-phosphodiesterase 1

UR - http://www.scopus.com/inward/record.url?scp=85105952939&partnerID=8YFLogxK

U2 - 10.3390/ph14050422

DO - 10.3390/ph14050422

M3 - Article

C2 - 34062881

AN - SCOPUS:85105952939

VL - 14

JO - Pharmaceuticals

JF - Pharmaceuticals

SN - 1424-8247

IS - 5

M1 - 422

ER -

ID: 28598851