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Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential Full article

Journal Bioorganic and Medicinal Chemistry
ISSN: 0968-0896 , E-ISSN: 1464-3391
Output data Year: 2016, Volume: 24, Number: 21, Pages: 5017-5027 Pages count : 11 DOI: 10.1016/j.bmc.2016.09.045
Tags DNA repair; Topoisomerase; Camptothecin; Top1 inhibitors; Top2 inhibitors; Tyrosyl-DNA phosphodiesterase; Tdp1; Tdp2; Tdp1 inhibitors; Tdp2 inhibitors; Indenoisoquinolines
Authors Laev Sergey S. 1 , Salakhutdinov Nariman F. 1,2 , Lavrik Olga I. 2,3
Affiliations
1 (Данные Web of science) Russian Acad Sci, Vorozhtsov Inst Organ Chem, Siberian Div, Pr Akad Lavrenteva 9, Novosibirsk 630090, Russia
2 (Данные Web of science) Novosibirsk State Univ, Pirogova Str 2, Novosibirsk 630090, Russia
3 (Данные Web of science) Russian Acad Sci, Novosibirsk Inst Chem Biol & Fundamental Med, Siberian Div, Pr Akad Lavrenteva 8, Novosibirsk 630090, Russia

Abstract: DNA topoisomerases are essential during transcription and replication. The therapeutic mechanism of action of topoisomerase inhibitors is enzyme poisoning rather than catalytic inhibition. Tyrosyl-DNA phosphodiesterases 1 or 2 were found as DNA repair enzymes hydrolyzing the covalent bond between the tyrosyl residue of topoisomerases I or II and the 3'- or 5'-phosphate groups in DNA, respectively. Tyrosyl-DNA phosphodiesterase 1 is a key enzyme in DNA repair machinery and a promising target for antitumor and neurodegenerative therapy. Inhibitors of tyrosyl-DNA phosphodiesterase 1 could act synergistically with topoisomerase I inhibitors and thereby potentiate the effects of topoisomerase I poisons. Tyrosyl-DNA phosphodiesterase 2 is an enzyme that specifically repairs DNA damages induced by topoisomerase II poisons and causes resistance to these drugs. Selective inhibition of tyrosyl-DNA phosphodiesterase 2 may be a novel approach to overcome intrinsic or acquired resistance to topoisomerase II-targeted drug therapy. Thus, agents that inhibit tyrosyl-DNA phosphodiesterases 1 and 2 have many applications in biochemical and physiological research and they have the potential to become anticancer and antiviral drugs. The structures, mechanism of action and therapeutic rationale of tyrosyl-DNA phosphodiesterase inhibitors and their development for combinations with topoisomerase inhibitors and DNA damaging agents are discussed. (C) 2016 Elsevier Ltd. All rights reserved.
Cite: Laev S.S. , Salakhutdinov N.F. , Lavrik O.I.
Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential
Bioorganic and Medicinal Chemistry. 2016. V.24. N21. P.5017-5027. DOI: 10.1016/j.bmc.2016.09.045 WOS Scopus РИНЦ OpenAlex
Dates:
Published print: Nov 1, 2016
Identifiers:
Web of science: WOS:000386990200002
Scopus: 2-s2.0-84991704835
Elibrary: 27577142
OpenAlex: W2521459918
Citing:
DB Citing
Web of science 59
Scopus 56
Elibrary 60
OpenAlex 62
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