Inhibitors of the 6-oxopurine phosphoribosyltransferases

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00643188" target="_blank" >RIV/61388963:_____/25:00643188 - isvavai.cz</a>

Výsledek na webu

<a href="https://hdl.handle.net/11104/0373060" target="_blank" >https://hdl.handle.net/11104/0373060</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Inhibitors of the 6-oxopurine phosphoribosyltransferases

Popis výsledku v původním jazyce

The 6-oxopurine phosphoribosyltransferases (PRTases) play a central role in the growth and cell proliferation of many organisms by synthesizing the 6-oxopurine nucleoside monophosphates required for the production of their required nucleic acids. In Plasmodium falciparum (Pf) and Plasmodium vivax (Pv), the 6-oxopurine PRTases provide the only metabolic route to produce the 6-oxopurine nucleoside monophosphates as these parasites are incapable of synthesizing the purine ring. Trypanosoma brucei (TBr) and Helicobacter pylori (Hp), while also being unable to synthesize the purine ring, possess two additional enzymes, adenine phosphoribosyltransferase (APRT) and adenosine kinase (AK). Therefore, this parasite and this bacterium, are also able to utilize adenine and adenosine as a source of their nucleotides. However, in these two organisms, studies have shown that HG(X)PRT activity is crucial for growth and function. Mycobacterium tuberculosis (Mt) does indeed possess both de novo and salvage but Griffin et al used random transposon mutagenesis to identify that the hpt gene is essential for growth. HG(X)PRT inhibitors have applications as chemotherapeutics not only against pathogenic diseases but may also be viewed as potential anti-cancer agents. HGPRT inhibitors discovered to date include acyclic nucleoside monophosphates (ANPs), aza-ANPs, pyrrolidine nucleoside monophosphates (PNBPs), the transition state analogs (ImmGP and ImmHp), and acyclic immucillin phosphonates (AIPs). In all cases, these compounds contain a purine base and a phosphonate or a phosphate group which binds in the 5′-phosphate binding site. The difference between these inhibitors is the nature of the linker connecting the purine base to the phosphonate/phosphate group and the moieties attached to this linker. Here we present design, synthesis, and properties of pyrrolidine-based phosphonate (I.) or bisphosphonate (II.) derivatives as new inhibitors of HGPRT. Low nanomolar inhibitors were identified in the series and several prodrugs were prepared and tested in cell-based assays. In general, bisphosphonates are more potent inhibitors of HGPRT, however the activity of their prodrugs are rather disappointing. We hypothesize that the problem lies in a) complexity of the prodrugs (four prodrug moieties) and b) need for crossing two different membranes – both the host cell membrane and the intracellular parasite membrane (Plasmodium falciparum resides mostly in erythrocytes, Mycobacterium tuberculosis in macrophages).nThis work was supported by the project National Institute of Virology and Bacteriology (Programme EXCELES, ID Project No. LX22NPO5103) – Funded by the European Union – NextGenerationEU.

Název v anglickém jazyce

Inhibitors of the 6-oxopurine phosphoribosyltransferases

Popis výsledku anglicky

The 6-oxopurine phosphoribosyltransferases (PRTases) play a central role in the growth and cell proliferation of many organisms by synthesizing the 6-oxopurine nucleoside monophosphates required for the production of their required nucleic acids. In Plasmodium falciparum (Pf) and Plasmodium vivax (Pv), the 6-oxopurine PRTases provide the only metabolic route to produce the 6-oxopurine nucleoside monophosphates as these parasites are incapable of synthesizing the purine ring. Trypanosoma brucei (TBr) and Helicobacter pylori (Hp), while also being unable to synthesize the purine ring, possess two additional enzymes, adenine phosphoribosyltransferase (APRT) and adenosine kinase (AK). Therefore, this parasite and this bacterium, are also able to utilize adenine and adenosine as a source of their nucleotides. However, in these two organisms, studies have shown that HG(X)PRT activity is crucial for growth and function. Mycobacterium tuberculosis (Mt) does indeed possess both de novo and salvage but Griffin et al used random transposon mutagenesis to identify that the hpt gene is essential for growth. HG(X)PRT inhibitors have applications as chemotherapeutics not only against pathogenic diseases but may also be viewed as potential anti-cancer agents. HGPRT inhibitors discovered to date include acyclic nucleoside monophosphates (ANPs), aza-ANPs, pyrrolidine nucleoside monophosphates (PNBPs), the transition state analogs (ImmGP and ImmHp), and acyclic immucillin phosphonates (AIPs). In all cases, these compounds contain a purine base and a phosphonate or a phosphate group which binds in the 5′-phosphate binding site. The difference between these inhibitors is the nature of the linker connecting the purine base to the phosphonate/phosphate group and the moieties attached to this linker. Here we present design, synthesis, and properties of pyrrolidine-based phosphonate (I.) or bisphosphonate (II.) derivatives as new inhibitors of HGPRT. Low nanomolar inhibitors were identified in the series and several prodrugs were prepared and tested in cell-based assays. In general, bisphosphonates are more potent inhibitors of HGPRT, however the activity of their prodrugs are rather disappointing. We hypothesize that the problem lies in a) complexity of the prodrugs (four prodrug moieties) and b) need for crossing two different membranes – both the host cell membrane and the intracellular parasite membrane (Plasmodium falciparum resides mostly in erythrocytes, Mycobacterium tuberculosis in macrophages).nThis work was supported by the project National Institute of Virology and Bacteriology (Programme EXCELES, ID Project No. LX22NPO5103) – Funded by the European Union – NextGenerationEU.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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