dc.contributor.author |
Zakharenko, AL |
en |
dc.contributor.author |
Luzina, OA |
en |
dc.contributor.author |
Sokolov, DN |
en |
dc.contributor.author |
Kaledin, VI |
en |
dc.contributor.author |
Nikolin, VP |
en |
dc.contributor.author |
Popova, NA |
en |
dc.contributor.author |
Patel, Jinal |
en |
dc.contributor.author |
Zakharova, OD |
en |
dc.contributor.author |
Chepanova, AA |
en |
dc.contributor.author |
Zafar, Ayesha |
en |
dc.contributor.author |
Reynisson, Johannes |
en |
dc.contributor.author |
Leung, Yee Fun |
en |
dc.contributor.author |
Leung, Ka Ho Ivanhoe |
en |
dc.contributor.author |
Volcho, KP |
en |
dc.contributor.author |
Salakhutdinov, NF |
en |
dc.contributor.author |
Lavrik, OI |
en |
dc.date.accessioned |
2019-03-19T04:26:29Z |
en |
dc.date.issued |
2019-01 |
en |
dc.identifier.issn |
0223-5234 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/46102 |
en |
dc.description.abstract |
The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazonothiazole usnic acid derivatives was synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The activity of the compounds was verified by affinity experiments as well as supported by molecular modelling. The most effective Tdp1 inhibitor, 20d, was ton-toxic and increased the effect of topotecan both in vitro and in vivo in the Lewis lung carcinoma model. Furthermore, 20d showed significant increase in the antitumor and antimetastatic effect of topotecan in mice. The results presented here justify compound 20d to be considered as a drug lead for antitumor therapy. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
European journal of medicinal chemistry |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Cell Line, Tumor |
en |
dc.subject |
Animals |
en |
dc.subject |
Mice, Inbred C57BL |
en |
dc.subject |
Humans |
en |
dc.subject |
Mice |
en |
dc.subject |
Lung Neoplasms |
en |
dc.subject |
Neoplasms, Experimental |
en |
dc.subject |
Topotecan |
en |
dc.subject |
Phosphoric Diester Hydrolases |
en |
dc.subject |
Antineoplastic Agents |
en |
dc.subject |
Drug Screening Assays, Antitumor |
en |
dc.subject |
Cell Proliferation |
en |
dc.subject |
Molecular Structure |
en |
dc.subject |
Structure-Activity Relationship |
en |
dc.subject |
Dose-Response Relationship, Drug |
en |
dc.subject |
Quantum Theory |
en |
dc.subject |
Models, Molecular |
en |
dc.subject |
Topoisomerase I Inhibitors |
en |
dc.title |
Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1016/j.ejmech.2018.10.055 |
en |
pubs.begin-page |
581 |
en |
pubs.volume |
161 |
en |
dc.rights.holder |
Copyright: The author |
en |
pubs.end-page |
593 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
756280 |
en |
pubs.org-id |
Academic Services |
en |
pubs.org-id |
Examinations |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Chemistry |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1768-3254 |
en |
pubs.record-created-at-source-date |
2018-11-06 |
en |
pubs.dimensions-id |
30396105 |
en |