Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential

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

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.

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

Published print:

Nov 1, 2016

Web of science	WOS:000386990200002
Scopus	2-s2.0-84991704835
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