Structure-Based Optimization of Bisphosphonate Nucleoside Inhibitors of Human 5(3)-deoxyribonucleotidases

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00495604" target="_blank" >RIV/61388963:_____/18:00495604 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/18:00501869 RIV/60461373:22330/18:43915889

Výsledek na webu

<a href="http://dx.doi.org/10.1002/ejoc.201800515" target="_blank" >http://dx.doi.org/10.1002/ejoc.201800515</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/ejoc.201800515" target="_blank" >10.1002/ejoc.201800515</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Structure-Based Optimization of Bisphosphonate Nucleoside Inhibitors of Human 5(3)-deoxyribonucleotidases

Popis výsledku v původním jazyce

Cellular 5-nucleotidases, enzymes regulating nucleotide/nucleoside pools, are capable of dephosphorylating phosphomonoesters of important nucleoside analogue drugs, thus decreasing their therapeutic efficacy. Human cytosolic (cdN) as well as mitochondrial (mdN) variants of this enzyme represent interesting targets for development of inhibitory compounds. In this work, bisphosphonate nucleoside derivatives were designed by using a structure-based approach. A second phosphonate group was attached onto a base moiety and by optimization of the linker an increased inhibitor potency towards mdN and cdN was attained. The best compound exhibited inhibition of both enzymes in a nanomolar range, making it the most potent inhibitor of these enzymes prepared to date. In addition, the compounds showed selectivity towards the cdN variant. A series of crystal structures were solved for several inhibitors in the complex with mdN or cdN that provided a structural basis for understanding the inhibition profile of bisphosphonate compounds.

Název v anglickém jazyce

Structure-Based Optimization of Bisphosphonate Nucleoside Inhibitors of Human 5(3)-deoxyribonucleotidases

Popis výsledku anglicky

Cellular 5-nucleotidases, enzymes regulating nucleotide/nucleoside pools, are capable of dephosphorylating phosphomonoesters of important nucleoside analogue drugs, thus decreasing their therapeutic efficacy. Human cytosolic (cdN) as well as mitochondrial (mdN) variants of this enzyme represent interesting targets for development of inhibitory compounds. In this work, bisphosphonate nucleoside derivatives were designed by using a structure-based approach. A second phosphonate group was attached onto a base moiety and by optimization of the linker an increased inhibitor potency towards mdN and cdN was attained. The best compound exhibited inhibition of both enzymes in a nanomolar range, making it the most potent inhibitor of these enzymes prepared to date. In addition, the compounds showed selectivity towards the cdN variant. A series of crystal structures were solved for several inhibitors in the complex with mdN or cdN that provided a structural basis for understanding the inhibition profile of bisphosphonate compounds.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/LO1304" target="_blank" >LO1304: Podpora udržitelnosti Ústavu molekulární a translační medicíny</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Organic Chemistry

ISSN

1434-193X

e-ISSN

—

Svazek periodika

2018

Číslo periodika v rámci svazku

37

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

10

Strana od-do

5144-5153

Kód UT WoS článku

000446662900009

EID výsledku v databázi Scopus

2-s2.0-85054473308