α,α-Bisphosphonates (BPs) are well established in the treatment of bone diseases such as osteoporosis and Paget's disease. Their successful application originates from their high affinity to hydroxyapatite. While the initially appreciated features of BPs are already beneficial to many patients, recent developments have further expanded their pleiotropic applications. This review describes the background of the interactions of BPs with bone cells that form the basis of the classical treatment. A better understanding of the mechanism behind their interactions allows for the parallel application of BPs against bone cancer and metastases followed by palliative pain relief. Targeted therapy with bone-seeking BPs coupled with a diagnostic agent in one particle resulted in theranostics which is also described here. For example, in such a system, BP moieties are bound to contrast agents used in magnetic resonance imaging or radionuclides used in positron emission tomography. In addition, another example of the pleiotropic function of BPs which involves targeting the imaging agents to bone tissues accompanied by pain reduction is presented in this work.
- MeSH
- bisfosfonáty chemie farmakologie terapeutické užití MeSH
- lidé MeSH
- nemoci kostí farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Magnetite (Fe3O4) nanoparticles with uniform sizes of 10, 20, and 31 nm were prepared by thermal decomposition of Fe(III) oleate or mandelate in a high-boiling point solvent (>320 °C). To render the particles with hydrophilic and antifouling properties, their surface was coated with a PEG-containing bisphosphonate anchoring group. The PEGylated particles were characterized by a range of physicochemical methods, including dynamic light scattering, transmission electron microscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy, and magnetization measurements. As the particle size increased from 10 to 31 nm, the amount of PEG coating decreased from 28.5 to 9 wt.%. The PEG formed a dense brush-like shell on the particle surface, which prevented particles from aggregating in water and PBS (pH 7.4) and maximized the circulation time in vivo. Magnetic resonance relaxometry confirmed that the PEG-modified Fe3O4 nanoparticles had high relaxivity, which increased with increasing particle size. In the in vivo experiments in a mouse model, the particles provided visible contrast enhancement in the magnetic resonance images. Almost 70% of administrated 20-nm magnetic nanoparticles still circulated in the blood stream after four hours; however, their retention in the tumor was rather low, which was likely due to the antifouling properties of PEG.
- MeSH
- bisfosfonáty chemie MeSH
- magnetická rezonanční tomografie MeSH
- magnetické nanočástice chemie ultrastruktura MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- polyethylenglykoly chemie MeSH
- tkáňová distribuce MeSH
- transmisní elektronová mikroskopie MeSH
- velikost částic MeSH
- železité sloučeniny MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 Å resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC50 of 11.7 ± 3.2 μM against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 ± 11 μM, thus giving it a ∼10-fold selectivity index.
- MeSH
- antimalarika chemie farmakologie MeSH
- bisfosfonáty chemie farmakologie MeSH
- hypoxanthinfosforibosyltransferasa antagonisté a inhibitory chemie metabolismus MeSH
- katalytická doména MeSH
- konformace proteinů MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- molekulární modely MeSH
- pentosyltransferasy antagonisté a inhibitory chemie metabolismus MeSH
- Plasmodium vivax enzymologie MeSH
- proteiny z Escherichia coli chemie MeSH
- racionální návrh léčiv MeSH
- techniky syntetické chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Therapeutic treatment of tuberculosis (TB) is becoming increasingly problematic due to the emergence of drug resistant Mycobacterium tuberculosis (Mt). Thus, new targets for anti-TB drug discovery need to be identified to combat and eradicate this disease. One such target is hypoxanthine-guanine phosphoribosyltransferase (HGPRT) which synthesises the 6-oxopurine nucleoside monophosphates essential for DNA/RNA production. [3R,4R]-4-Hypoxanthin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine and [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine (compound 6) are the most potent inhibitors of MtHGPRT yet discovered having Ki values of 60 nM. The crystal structure of the MtHGPRT.6 complex was obtained and compared with that of human HGPRT in complex with the same inhibitor. These structures provide explanations for the 60-fold difference in the inhibition constants between these two enzymes and a foundation for the design of next generation inhibitors. In addition, crystal structures of MtHGPRT in complex with two pyrrolidine nucleoside phosphosphonate inhibitors plus pyrophosphate provide insights into the final stage of the catalytic reaction. As the first step in ascertaining if such compounds have the potential to be developed as anti-TB therapeutics, the tetra-(ethyl L-phenylalanine) tetraamide prodrug of 6 was tested in cell based assays. This compound arrested the growth of virulent Mt not only in its replicating phase (IC50 of 14 μΜ) but also in its latent phase (IC50 of 29 μΜ). Furthermore, it arrested the growth of Mt in infected macrophages (MIC50 of 85 μΜ) and has a low cytotoxicity in mammalian cells (CC50 of 132 ± 20 μM). These inhibitors are therefore viewed as forerunners of new anti-TB chemotherapeutics.
- MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- bisfosfonáty chemie farmakologie MeSH
- hypoxanthinfosforibosyltransferasa antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis cytologie účinky léků metabolismus MeSH
- nukleosidy chemie farmakologie MeSH
- pyrrolidiny chemie farmakologie MeSH
- THP-1 buňky MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Acyclic nucleoside bisphosphonates (ANbPs) have previously been shown to be good inhibitors of human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and Plasmodium falciparum (Pf) hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). On the basis of this scaffold, a new series of ANbPs was synthesized. One of these new ANbPs, [3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid, exhibited Ki values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low Ki values were achieved by inserting an extra carbon atom in the linker connecting the N(9) atom of guanine to one of the phosphonate groups. The crystal structure of this ANbP in complex with human HGPRT was determined at 2.0 Å resolution and shows that it fills three key pockets in the active site. The most potent phosphoramidate prodrugs of these compounds have IC50 values in the low micromolar range in Pf lines and low toxicity in human A549 cells, demonstrating that these ANbPs are excellent antimalarial drug leads.
- MeSH
- antimalarika chemie farmakologie MeSH
- bisfosfonáty chemie farmakologie MeSH
- lidé MeSH
- nukleosidy chemie farmakologie MeSH
- pentosyltransferasy antagonisté a inhibitory metabolismus MeSH
- Plasmodium falciparum účinky léků enzymologie metabolismus MeSH
- simulace molekulového dockingu MeSH
- tropická malárie farmakoterapie enzymologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)M(BP) (L1). The ligands were labeled with (68)Ga(III) and were evaluated in in vitro binding studies to hydroxyapatite (HA) as well as to human serum albumin. The compounds were finally compared in in vivo PET and ex vivo organ distribution studies in small animals over 6h. Binding studies revealed a consistent affinity of both bisphosphonate tracers to HA. Small animal PET and ex vivo organ distribution studies showed longer blood retention of [(68)Ga]L1. [(68)Ga]BPAMD is initially more efficiently bound to the bone but skeletal accumulation of the modified compound and [(68)Ga]BPAMD equalized at 6h p.i. Ratios of femur epiphyseal plate to ordinary bone showed to be more favorable for [(68)Ga]L1 than for [(68)Ga]BPAMD due to the longer circulation time of the new tracer. Thus, the chemical modification of BPAMD toward an albumin-binding bisphosphonate, L1, resulted in a novel PET tracer which conserves advantages of both functional groups within one and the same molecule. The properties of this new diagnostic tracer are expected to be preserved in (177)Lu therapeutic agent with the same ligand (a theranostic pair).
- MeSH
- adsorpce MeSH
- bisfosfonáty chemie metabolismus farmakokinetika MeSH
- heterocyklické sloučeniny monocyklické chemie MeSH
- hydroxyapatit chemie MeSH
- kosti a kostní tkáň diagnostické zobrazování metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- potkani Wistar MeSH
- pozitronová emisní tomografie MeSH
- radioizotopy galia MeSH
- sérový albumin metabolismus MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs. Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks. On the contrary, it is generally believed that the properties of dendrimers are essentially related to their terminal groups, and that the internal structure plays the minor role of an 'innocent' scaffold. Here we show that such an assertion is misleading, using convergent information from biological data (human monocytes activation) and all-atom molecular dynamics simulations on seven families of dendrimers (13 compounds) that we have synthesized, possessing identical terminal groups, but different internal structures. This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins.
- MeSH
- aza sloučeniny chemie farmakologie MeSH
- biokompatibilní materiály chemie farmakologie MeSH
- bisfosfonáty chemie farmakologie MeSH
- dendrimery chemie farmakologie MeSH
- inhibitory kostní resorpce chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- monocyty účinky léků MeSH
- nanočástice chemie MeSH
- polylysin chemie farmakologie MeSH
- polypropyleny chemie farmakologie MeSH
- průtoková cytometrie MeSH
- silany chemie farmakologie MeSH
- simulace molekulární dynamiky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT.
- MeSH
- bisfosfonáty * chemie farmakokinetika farmakologie MeSH
- femur metabolismus radiografie MeSH
- galium * chemie farmakokinetika farmakologie MeSH
- kontrastní látky * chemie farmakokinetika farmakologie MeSH
- krysa rodu rattus MeSH
- pozitronová emisní tomografie metody MeSH
- radioaktivní indikátory * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This review introduces β-fluorophosphonates as useful synthons and fluoroalkyl transfer reagents. The remarkable biological activity of the phosphonates is also mentioned. The main emphasis is put on synthetic applications of the following fluorinated phosphonates: diethyl (difluoromethyl)phosphonate (1), diethyl (trifluoromethyl)phosphonate (2), tetraethyl (fluoromethylene)bis¬phosphonate (3), diethyl [(fluoromethyl) (phenylsulfonyl)methyl]phosphonate (McCathy’s reagent) (4), and diethyl (fluoronitromethyl)phosphonate (5). The review is focused on the chemistry of the synthons.
- MeSH
- aktivní transport MeSH
- alkylace MeSH
- antivirové látky MeSH
- bisfosfonáty * chemie klasifikace MeSH
- chemie organická MeSH
- farmakologické účinky MeSH
- fluor chemie MeSH
- inhibitory enzymů MeSH
- lidé MeSH
- organofosfonáty * chemie klasifikace MeSH
- pojmy organické chemie MeSH
- vztahy mezi strukturou a aktivitou * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Mixtures of ibandronate monosodium salt with eleven gluco- and/or galacto-pyranoside derivatives as counterions were designed to prepare co-crystals with improved intestinal absorption. In general, gastrointestinal absorption of bisphosphonates after oral administration is approximately 1%. Co-crystals were generated by means of thermodynamically and/or kinetically controlled crystallization processes. Seventy-seven prepared samples were analyzed by means of FT-NIR, FT-Raman spectrometry and solid state NMR spectroscopy. New entities of ibandronate monosodium salt with phenyl-β-D-galactopyranoside were found and characterized. The absorption of these potential new co-crystals was investigated by means of PAMPA experiments. In the present study the relationships between the chemical structures of the studied compounds required for co-crystal generation are discussed.
