New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1

Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the TOP1 inhibito...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Nadezhda S. Dyrkheeva, Aleksandr S. Filimonov, Olga A. Luzina, Kristina A. Orlova, Irina A. Chernyshova, Tatyana E. Kornienko, Anastasia A. Malakhova, Sergey P. Medvedev, Alexandra L. Zakharenko, Ekaterina S. Ilina, Rashid O. Anarbaev, Konstantin N. Naumenko, Kristina V. Klabenkova, Ekaterina A. Burakova, Dmitry A. Stetsenko, Suren M. Zakian, Nariman F. Salakhutdinov, Olga I. Lavrik
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	usnic acid thioether tyrosyl-DNA phosphodiesterase 1 TDP1 inhibitor inhibiting activity TDP2 Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/ffbea489293848d98465c39d785114bf
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ffbea489293848d98465c39d785114bf
record_format	dspace
spelling	oai:doaj.org-article:ffbea489293848d98465c39d785114bf2021-11-11T16:49:04ZNew Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP110.3390/ijms2221113361422-00671661-6596https://doaj.org/article/ffbea489293848d98465c39d785114bf2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11336https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the TOP1 inhibitor topotecan, which is a clinically used anticancer drug. This article reports the synthesis and study of usnic acid thioether and sulfoxide derivatives that efficiently suppress TDP1 activity, with IC<sub>50</sub> values in the 1.4–25.2 μM range. The structure of the heterocyclic substituent introduced into the dibenzofuran core affects the TDP1 inhibitory efficiency of the compounds. A five-membered heterocyclic fragment was shown to be most pharmacophoric among the others. Sulfoxide derivatives were less cytotoxic than their thioester analogs. We observed an uncompetitive type of inhibition for the four most effective inhibitors of TDP1. The anticancer effect of TOP1 inhibitors can be enhanced by the simultaneous inhibition of PARP1, TDP1, and TDP2. Some of the compounds inhibited not only TDP1 but also TDP2 and/or PARP1, but at significantly higher concentration ranges than TDP1. Leader compound <b>10a</b> showed promising synergy on HeLa cells in conjunction with the TOP1 inhibitor topotecan.Nadezhda S. DyrkheevaAleksandr S. FilimonovOlga A. LuzinaKristina A. OrlovaIrina A. ChernyshovaTatyana E. KornienkoAnastasia A. MalakhovaSergey P. MedvedevAlexandra L. ZakharenkoEkaterina S. IlinaRashid O. AnarbaevKonstantin N. NaumenkoKristina V. KlabenkovaEkaterina A. BurakovaDmitry A. StetsenkoSuren M. ZakianNariman F. SalakhutdinovOlga I. LavrikMDPI AGarticleusnic acidthioethertyrosyl-DNA phosphodiesterase 1TDP1 inhibitorinhibiting activityTDP2Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11336, p 11336 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	usnic acid thioether tyrosyl-DNA phosphodiesterase 1 TDP1 inhibitor inhibiting activity TDP2 Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	usnic acid thioether tyrosyl-DNA phosphodiesterase 1 TDP1 inhibitor inhibiting activity TDP2 Biology (General) QH301-705.5 Chemistry QD1-999 Nadezhda S. Dyrkheeva Aleksandr S. Filimonov Olga A. Luzina Kristina A. Orlova Irina A. Chernyshova Tatyana E. Kornienko Anastasia A. Malakhova Sergey P. Medvedev Alexandra L. Zakharenko Ekaterina S. Ilina Rashid O. Anarbaev Konstantin N. Naumenko Kristina V. Klabenkova Ekaterina A. Burakova Dmitry A. Stetsenko Suren M. Zakian Nariman F. Salakhutdinov Olga I. Lavrik New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1
description	Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the TOP1 inhibitor topotecan, which is a clinically used anticancer drug. This article reports the synthesis and study of usnic acid thioether and sulfoxide derivatives that efficiently suppress TDP1 activity, with IC<sub>50</sub> values in the 1.4–25.2 μM range. The structure of the heterocyclic substituent introduced into the dibenzofuran core affects the TDP1 inhibitory efficiency of the compounds. A five-membered heterocyclic fragment was shown to be most pharmacophoric among the others. Sulfoxide derivatives were less cytotoxic than their thioester analogs. We observed an uncompetitive type of inhibition for the four most effective inhibitors of TDP1. The anticancer effect of TOP1 inhibitors can be enhanced by the simultaneous inhibition of PARP1, TDP1, and TDP2. Some of the compounds inhibited not only TDP1 but also TDP2 and/or PARP1, but at significantly higher concentration ranges than TDP1. Leader compound <b>10a</b> showed promising synergy on HeLa cells in conjunction with the TOP1 inhibitor topotecan.
format	article
author	Nadezhda S. Dyrkheeva Aleksandr S. Filimonov Olga A. Luzina Kristina A. Orlova Irina A. Chernyshova Tatyana E. Kornienko Anastasia A. Malakhova Sergey P. Medvedev Alexandra L. Zakharenko Ekaterina S. Ilina Rashid O. Anarbaev Konstantin N. Naumenko Kristina V. Klabenkova Ekaterina A. Burakova Dmitry A. Stetsenko Suren M. Zakian Nariman F. Salakhutdinov Olga I. Lavrik
author_facet	Nadezhda S. Dyrkheeva Aleksandr S. Filimonov Olga A. Luzina Kristina A. Orlova Irina A. Chernyshova Tatyana E. Kornienko Anastasia A. Malakhova Sergey P. Medvedev Alexandra L. Zakharenko Ekaterina S. Ilina Rashid O. Anarbaev Konstantin N. Naumenko Kristina V. Klabenkova Ekaterina A. Burakova Dmitry A. Stetsenko Suren M. Zakian Nariman F. Salakhutdinov Olga I. Lavrik
author_sort	Nadezhda S. Dyrkheeva
title	New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1
title_short	New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1
title_full	New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1
title_fullStr	New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1
title_full_unstemmed	New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1
title_sort	new hybrid compounds combining fragments of usnic acid and thioether are inhibitors of human enzymes tdp1, tdp2 and parp1
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ffbea489293848d98465c39d785114bf
work_keys_str_mv	AT nadezhdasdyrkheeva newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT aleksandrsfilimonov newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT olgaaluzina newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT kristinaaorlova newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT irinaachernyshova newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT tatyanaekornienko newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT anastasiaamalakhova newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT sergeypmedvedev newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT alexandralzakharenko newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT ekaterinasilina newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT rashidoanarbaev newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT konstantinnnaumenko newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT kristinavklabenkova newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT ekaterinaaburakova newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT dmitryastetsenko newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT surenmzakian newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT narimanfsalakhutdinov newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1 AT olgailavrik newhybridcompoundscombiningfragmentsofusnicacidandthioetherareinhibitorsofhumanenzymestdp1tdp2andparp1
_version_	1718432277628715008

New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1

Ejemplares similares