phosphonates Dotaz Zobrazit nápovědu
While cidofovir, adefovir and tenofovir are the three acyclic nucleoside phosphonates (ANPs) that have been licensed for clinical use (the latter as a single-, double- and triple-drug combination), there are many more ANPs that await their application for medical or veterinary use: (S)-HPMPA, (S)-HPMPDAP, cPrPMEDAP, (R)-HPMPO-DAPy, PMEO-DAPy, 5-X-PMEO-DAPy, (R)-PMPO-DAPy, (S)-HPMP-5-azaC, and cyclic (S)-HPMP-5-azaC, and alkoxyalkyl prodrugs thereof.
Nedávno bylo firmou Gilead Sciences (Foster City, CA, USA) zveřejněno potenciální cytostatikum GS-9219. Jde o nové lipofilní profarmakum látky cyprPMEDAP, z kterého se in vivo, ve dvou stupních, uvolní účinná látka PMEG. Látka GS-9219 má významný terapeutický potenciál při léčbě spontánního nehodgkinského lymfomu u psů a je perspektivní i pro použití v humánní medicíně. cyprPMEDAP tedy představuje klíčový intermediát v intracelulární aktivaci GS-9219. Oba acyklické nukleosidfosfonáty PMEG i cyprPMEDAP, na jejichž základě byla látka GS-9219 vyvinuta, byly objeveny v Ústavu organické chemie a biochemie AV ČR a tamtéž byl i podrobně prostudován jejich mechanismus účinku. Biologické studie na potkaním lymfomu byly provedeny na 1. LF UK.
Recently, Gilead Sciences (Foster City, CA, USA) presented a potential cytostatic drug GS-9219. It is a novel lipophilic prodrug of cyprPMEDAP, in vivo releasing the active compound PMEG in a two-step process. GS-9219 has shown a substantial therapeutic potential in treatment of spontaneous non- Hodgkin's lymphoma in dogs and its utilization in the human medicine is prospective. Hence, cyprPMEDAP represents a key intermediate in the intracellular activation of GS-9219. Both acyclic nucleoside phosphonates PMEG and cyprPMEDAP, serving as the basis for development of GS-9219, were discovered and their mechanism of action was investigated in detail at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic. The biological studies using the rat lymphoma were carried out at the First Faculty of Medicine, Charles University.
The fluorine atom plays an important role in medicinal chemistry because fluorine substitution has a strong impact on the physical, chemical, and biological properties of bioactive compounds. Such fluorine modifications have also been extensively studied among the pharmaceutically important class of nucleoside phosphonates, nucleotide analogues in which the phosphate group is replaced by the enzymatically and chemically stable phosphonate moiety. The fluorinated nucleoside phosphonates abound with antiviral, antiparasitic, and anticancer properties because they are able to act as inhibitors of important enzymes of nucleoside/nucleotide metabolism. In this paper, we review the biological properties of cyclic and acyclic nucleoside phosphonates modified by the attachment of one or more fluorine atoms to various parts of the molecule, namely to nucleobases, alkylphosphonate groups, cyclic or acyclic linkers, or to prodrug moieties.
- MeSH
- chemie farmaceutická * MeSH
- cyklizace MeSH
- halogenace * MeSH
- lidé MeSH
- nukleosidy chemie farmakologie MeSH
- organofosfonáty chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Acyclic nucleoside phosphonates (ANPs) represent a significant class of antiviral, anticancer, and antiprotozoal compounds. It is therefore highly desirable to have diverse synthetic routes leading towards these molecules. In the past, many structural modifications were explored, but surprisingly, the field of C1'-branched ANPs has been neglected with only a handful of articles reporting their synthesis. Herein we describe and compare five convenient approaches leading to key synthetic 6-chloropurine ANPs bearing the 9-phosphonomethoxyethyl (PME) moiety branched at the C1' position. These intermediates can be further vastly diversified into target C1'-branched ANPs bearing either natural or unnatural nucleobases. The importance of C1'-branched ANPs is emphasized by their analogy with C1'-substituted cyclic nucleotides (such as remdesivir, a broad-spectrum antiviral agent) and evaluation of their biological activity (e.g. antiviral, antineoplastic, and antiprotozoal) will be a tempting subject of further research.
- MeSH
- organofosfonáty * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This review concerns acyclic nucleoside phosphonates (ANP) and describes the concept of the design of isopolar and isosteric nucleotide analogues resistant towards degradation by enzymes in vivo. It describes the development of research which led to the discovery of several structurally related potent antivirals and ultimately resulted in the development of drugs directed against HIV, HBV and DNA-virus infections in general, namely adefovir, cidofovir and tenofovir. In addition to these "classical compounds" the review describes the present development in the field of ANP, the "open-ring ANP" and discusses the present achievements, concept of prodrug design and application.
- MeSH
- antivirové látky farmakologie chemie MeSH
- DNA viry účinky léků MeSH
- financování organizované MeSH
- infekce DNA virem farmakoterapie virologie MeSH
- lidé MeSH
- nukleosidy farmakologie chemie MeSH
- organofosfonáty farmakologie chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Conducting polymers (CP) can be used as pH- and/or electro-responsive components in various bioapplications, for example, in 4D smart scaffolds. The ability of CP to maintain conductivity under physiological conditions is, therefore, their crucial property. Unfortunately, the conductivity of the CP rapidly decreases in physiological environment, as their conducting salts convert to non-conducting bases. One of the promising solutions how to cope with this shortcoming is the use of alternative "doping" process that is not based on the protonation of CP with acids but on interactions relying in acidic hydrogen bonding. Therefore, the phosphonates (dimethyl phosphonate, diethyl phosphonate, dibutyl phosphonate, or diphenyl phosphonate) were used to re-dope two most common representatives of CP, polyaniline (PANI) and polypyrrole (PPy) bases. As a result, PANI doped with organic phosphonates proved to have significantly better stability of conductivity under different pH. It has also been shown that cytotoxicity of studied materials determined on embryonic stem cells and their embryotoxicity, determined as the impact on cardiomyogenesis and erythropoiesis, depend both on the polymer and phosphonate types used. With the exception of PANI doped with dibutyl phosphonate, all PPy-based phosphonates showed better biocompatibility than the phosphonates based on PANI.
- MeSH
- aniliny chemie farmakologie MeSH
- biokompatibilní materiály chemie farmakologie MeSH
- buněčná diferenciace účinky léků MeSH
- buněčné linie MeSH
- elektrická vodivost MeSH
- koncentrace vodíkových iontů MeSH
- myší embryonální kmenové buňky MeSH
- myši MeSH
- organofosfonáty chemie MeSH
- polymery chemie farmakologie MeSH
- pyrroly chemie farmakologie MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Acyclic nucleoside phosphonates (ANPs) are a recognized class of antiviral and anticancer agents. Since the discovery of ANPs in the mid-1980s, ANPs have gained recognition in pharmaceutical research. Approvals of cidofovir (Vistide®) in 1996 and especially of tenofovir (disoproxyl fumarate, Viread®) in 2001 were important milestones in research of ANPs. It became clear that this class of antivirals has a full potential for the use in human medicine. The biological activity of ANPs is not restricted to antiviral and anticancer effects. This review highlights novel types of ANPs with antimalarial properties. The malarial parasites Plasmodium falciparum (Pf) and P. vivax (Pv) lack de novo pathway for synthesis of purine bases and rely on a salvage pathway enzyme, hypoxanthineguanine-( xanthine) phosphoribosyltransferase (HG(X)PRT) for the synthesis of 6-oxopurine nucleoside monophosphates. Specific ANPs can act as analogues of the enzymatic reaction products. They inhibit PfHGXPRT and/or PvHGPRT and show an antiplasmodial activity in vitro. In particular aza-ANP and bisphosphonate analogues were shown to become promising potential antimalarials.
- Klíčová slova
- 6-oxopurinfosforibosyltransferasa,
- MeSH
- antimalarika * farmakokinetika farmakologie chemie klasifikace terapeutické užití MeSH
- antivirové látky farmakokinetika farmakologie chemie klasifikace terapeutické užití MeSH
- inhibitory enzymů terapeutické užití MeSH
- lidé MeSH
- malárie * farmakoterapie MeSH
- nukleotidy farmakokinetika farmakologie chemie klasifikace terapeutické užití MeSH
- pentosyltransferasy farmakokinetika farmakologie chemie terapeutické užití MeSH
- Plasmodium účinky léků MeSH
- prekurzory léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Diphosphates of the antiviral acyclic nucleoside phosphonates (ANPs) were evaluated in telomeric repeat amplification protocol (TRAP) for their ability to inhibit the extension of telomeres by human telomerase. Extracts from human leukaemia HL-60 cells were used as a source of the enzyme. Data show that the most effective compound studied was the guanine derivative PMEGpp (IC50 12.7+/-0.5 micromolL(-1) at 125 micromolL(-1) deoxynucleoside triphosphates (dNTPs)). The inhibitory effects of other PME, PMP and HPMP diphosphates on telomerase reverse transcriptase decreased in the order: (R)-PMPGpp>(R)-HPMPGpp>PMEDAPpp>(S)-PMPGpp>(S)-HPMPApp>PMEO-DAPypp>(R)-6-cyprPMPDAPpp>(R)-PMPApp>(R)-PMPDAPpp> or =PMEApp> or =PMECpp>PMETpp>(S)-PMPApp approximately 6-Me2PMEDAPpp. These results are consistent with the observed antineoplastic activities of the parental guanine (PMEG) and 2,6-diaminopurine (PMEDAP) PME-derivatives. Moreover, structure-activity relationship indicates enantioselectivity of some of these human telomerase inhibitors: (R)-isomers of the PMP-derivatives possess stronger inhibitory potency towards the enzyme than (S)-isomers. The data may contribute to the rational design of telomerase inhibitors based on the structure of acyclic nucleotide analogues.
CE methods have been developed for the chiral analysis of new types of six acyclic nucleoside phosphonates, nucleotide analogs bearing [(3-hydroxypropan-2-yl)-1H-1,2,3-triazol-4-yl]phosphonic acid, 2-[(diisopropoxyphosphonyl)methoxy]propanoic acid, or 2-(phosphonomethoxy)propanoic acid moieties attached to adenine, guanine, 2,6-diaminopurine, uracil, and 5-bromouracil nucleobases, using neutral and cationic cyclodextrins as chiral selectors. With the exception of the 5-bromouracil-derived acyclic nucleoside phosphonate with a 2-(phosphonomethoxy)propanoic acid side chain, the R and S enantiomers of the other five acyclic nucleoside phosphonates were successfully separated with sufficient resolutions, 1.51-2.94, within a reasonable time, 13-28 min, by CE in alkaline BGEs (50 mM sodium tetraborate adjusted with NaOH to pH 9.60, 9.85, and 10.30, respectively) containing 20 mg/mL β-cyclodextrin as the chiral selector. A baseline separation of the R and S enantiomers of the 5-bromouracil-derived acyclic nucleoside phosphonate with 2-(phosphonomethoxy)propanoic acid side chain was achieved within a short time of 7 min by CE in an acidic BGE (20:40 mM Tris/phosphate, pH 2.20) using 60 mg/mL quaternary ammonium β-cyclodextrin chiral selector. The developed methods were applied for the assessment of the enantiomeric purity of the above acyclic nucleoside phosphonates. The preparations of all these compounds were found to be synthesized in pure enantiomeric forms. Using UV absorption detection at 206 nm, their concentration detection limits were in the low micromolar range.
A series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) has been prepared using the optimized Suzuki cross-coupling reaction as the key synthetic step. The final free phosphonates 15a-h were inactive, due to their inefficient transport across cell membranes, but they inhibited Trypanosoma brucei adenine phosphoribosyltransferase (TbrAPRT1) with Ki values of 1.7-14.1 μM. The corresponding phosphonodiamidate prodrugs 14a-h exhibited anti-trypanosomal activity in the Trypanosoma brucei brucei cell-based assay with EC50 values in the range of 0.58-6.8 μM. 7-(4-Methoxy)phenyl-7-deazapurine derivative 14h, containing two phosphonate moieties, was the most potent anti-trypanosomal agent from the series, with EC50 = 0.58 μM and SI = 16. Finally, phosphonodiamidate prodrugs 14a-h exerted low micromolar cytotoxicity against leukemia and/or cancer cell lines tested.
