C1 '-Branched acyclic nucleoside phosphonates mimicking adenosine monophosphate: Potent inhibitors of Trypanosoma brucei adenine phosphoribosyltransferase

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60076658%3A12310%2F21%3A43903336" target="_blank" >RIV/60076658:12310/21:43903336 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60077344:_____/21:00545555 RIV/61388963:_____/21:00545555 RIV/00216208:11310/21:10433677

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0223523421006474?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523421006474?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2021.113798" target="_blank" >10.1016/j.ejmech.2021.113798</a>

Jazyk výsledku

angličtina

Název v původním jazyce

C1 '-Branched acyclic nucleoside phosphonates mimicking adenosine monophosphate: Potent inhibitors of Trypanosoma brucei adenine phosphoribosyltransferase

Popis výsledku v původním jazyce

Some pathogens, including parasites of the genus Trypanosoma causing Human and Animal African Trypanosomiases, cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Thus, their PSP enzymes are considered as promising drug targets, sparsely explored so far. Recently, a significant role of acyclic nucleoside phosphonates (ANPs) as inhibitors of key enzymes of PSP, namely of 6-oxopurine phosphoribosyltransferases (PRTs), has been discovered. Herein, we designed and synthesized two series of new ANPs branched at the C1&apos; position as mimics of adenosine monophosphate. The novel ANPs efficaciously inhibited Trypanosoma brucei adenine PRT (TbrAPRT1) activity in vitro and it was shown that the configuration on the C1&apos; chiral centre strongly influenced their activity: the (R)-enantiomers proved to be more potent compared to the (S)enantiomers. Two ANPs, with K-i values of 0.39 mu M and 0.57 mu M, represent the most potent TbrAPRT1 inhibitors reported to date and they are an important tool to further study purine metabolism in various parasites. (C) 2021 Elsevier Masson SAS. All rights reserved.

Název v anglickém jazyce

C1 '-Branched acyclic nucleoside phosphonates mimicking adenosine monophosphate: Potent inhibitors of Trypanosoma brucei adenine phosphoribosyltransferase

Popis výsledku anglicky

Some pathogens, including parasites of the genus Trypanosoma causing Human and Animal African Trypanosomiases, cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Thus, their PSP enzymes are considered as promising drug targets, sparsely explored so far. Recently, a significant role of acyclic nucleoside phosphonates (ANPs) as inhibitors of key enzymes of PSP, namely of 6-oxopurine phosphoribosyltransferases (PRTs), has been discovered. Herein, we designed and synthesized two series of new ANPs branched at the C1&apos; position as mimics of adenosine monophosphate. The novel ANPs efficaciously inhibited Trypanosoma brucei adenine PRT (TbrAPRT1) activity in vitro and it was shown that the configuration on the C1&apos; chiral centre strongly influenced their activity: the (R)-enantiomers proved to be more potent compared to the (S)enantiomers. Two ANPs, with K-i values of 0.39 mu M and 0.57 mu M, represent the most potent TbrAPRT1 inhibitors reported to date and they are an important tool to further study purine metabolism in various parasites. (C) 2021 Elsevier Masson SAS. All rights reserved.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Svazek periodika

225

Číslo periodika v rámci svazku

DEC 5 2021

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

8

Strana od-do

—

Kód UT WoS článku

000703114900049

EID výsledku v databázi Scopus

2-s2.0-85114366317