- Design and synthesis of 5-aminolaevulinic acid/3-hydroxypyridinone conjugates for photodynamic therapy: Enhancement of protoporphyrin IX production and photo-toxicity in tumor cells
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5-Aminolaevulinic acid (ALA) and its derivatives have been widely used in photodynamic therapy (PDT) as precursors of the photosensitizer, protoporphyrin IX (PpIX) in dermatology and urology. However, ALA-PDT is limited by the low bioavailability of ALA due to the fact that ALA is poorly absorbed by cells by virtue of its zwitterionic nature at physiological pH. In order to improve the therapeutic effect and induce higher levels of PpIX, a series of ALA prodrugs were synthesized by the conjugation of ALA to 3-hydroxypyridin-4-one (HPO) iron chelator using an amino acid linkage via amide bonds. Pharmacokinetic studies indicated that one ALA-HPO conjugate significantly enhanced PpIX production in a range of tumor cell lines over ALA alone or the co-administration of ALA and CP94 (1,2-diethyl-3-hydroxypyridin-4-one). The intracellular porphyrin fluorescence levels showed good correlation with cellular photo-toxicity following light exposure, suggesting the potential application of the ALA-HPO conjugates in photodynamic therapy.
- Zhou, Tao,Shao, Le-Le,Battah, Sinan,Zhu, Chun-Feng,Hider, Robert C.,Reeder, Brandon J.,Jabeen, Asma,MacRobert, Alexander J.,Ren, Gerui,Liang, Xinle
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p. 1190 - 1196
(2016/07/06)
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- Design, synthesis, and antimicrobial evaluation of hexadentate hydroxypyridinones with high iron(iii) affinity
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A range of hexadentate 3-hydroxypyridin-4-ones (HPOs) with high affinity for iron(III) has been synthesized. The log stability constants of two HPO-iron complexes (logK1) were determined to be over 34, and pFe values of the two HPOs were determined to be over 31. Antimicrobial assay indicated that they are able to markedly inhibit the growth of both Gram-positive and Gram-negative bacteria. Compounds 14a and 14e were found to exhibit the strongest inhibitory activity against Staphyloccocus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli, with MIC values of 8, 8, 16, and 8 lg/mL, respectively. These results indicate that hexadentate 3-hydroxypyridin-4-ones have potential application as antimicrobial agents, especially in the treatment of wound infection.
- Zhang, Ming-Xia,Zhu, Chun-Feng,Zhou, Ying-Jun,Kong, Xiao-Le,Hider, Robert C.,Zhou, Tao
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p. 659 - 668
(2015/02/19)
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- Synthesis, antiplasmodial activity, and β-hematin inhibition of hydroxypyridone-chloroquine hybrids
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A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM).
- Andayi, Warren A.,Egan, Timothy J.,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
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p. 642 - 646
(2013/07/26)
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- 3-Hydroxy-4-pyrones as precursors of 4-methoxy-3-oxidopyridinium ylides. An expeditious entry to highly substituted 8-azabicyclo[3.2.1]octanes
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3-Hydroxy-4-pyridones, which are easily prepared from commercially available 3-hydroxy-4-pyrones, can be readily transformed into 4-methoxy-3-oxidopyridinium ylides by treatment with methyl trifluoromethanesulfonate and subsequent deprotonation with a non-nucleophilic base. These ylides are capable of undergoing cycloaddition to several electron-deficient alkenes, thus allowing the synthesis of highly functionalized azabicyclo[3.2.1]octane moieties. The rich substitution patterns of these frameworks might allow their divergent conversion to a variety of natural and non-natural tropane alkaloids.
- Rumbo, Antonio,Mourino, Antonio,Castedo, Luis,Mascarenas, Jose L.
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p. 6114 - 6120
(2007/10/03)
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- Synthesis, physicochemical properties, and biological evaluation of N- substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: Orally active iron chelators with clinical potential
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The synthesis of a range of novel bidentate ligands containing the chelating moiety 3-hydroxy-4(1H)-pyridinone is described. The pK(a) values of the ligands and the stability constants of their iron(III) complexes have been determined. The crystal structures of one of the ligands and one of the iron(III) complexes are presented. The distribution coefficients of the ligands are reported and are related to the ability of the ligands to remove iron from hepatocytes. The influence of 3-hydroxy-4(1H)-pyridinones on oxidative damage to cells is described. In contrast to the iron chelator in current therapeutic use, desferrioxamine-B, many of the bidentate ligands described in this study are orally active in iron-overloaded mice.
- Dobbin,Hider,Hall,Taylor,Sarpong,Porter,Xiao,Van der Helm
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p. 2448 - 2458
(2007/10/02)
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- Physical and structural studies of N-substituted-3-hydroxy-2-methyl-4(1H)-pyridinones
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A series of 3-hydroxy-2-methyl-4(1H)-pyridinones has been prepared with the sunstituents H, CH3, n-C6H11, and CH2CH2NH2 at the ring N.The dipyridinone 1,6-bis(3-hydroxy-2-methyl-4(1H)-pyridinon-1-yl)hexane has also been synthesized.The products with H and CH3 subtituents have been studied by single crystal X-ray diffraction.Crystals of 3-hydroxy-2-methyl-4-pyridinone are monoclinic, a=6.8351(4), b=10.2249(4), c=8.6525(4) Angstroem, β=105.215(4) deg, Z=4,space group P21/n and those of 3-hydroxy-1,2-dimethyl-4-pyridinone are orthorhombic, a=7.3036(4), b=13.0490(6), c=13.7681(7) Angstroem, Z=8, space group Pbca.Both structures were solved by direct methods and were refined by full-matrix least-squares procedures to R=0.037 and 0.044 for 914 and 857 reflections with I>/=3?(I), respectively.Bond lengths and angles in the compounds were normal.All the compounds have been studies by mass spectrometry, and by infrared and proton nmr spectroscopies.The importance of hydrogen bonding to both the solution and solid state properties of these compounds has been confirmed by these techniques.
- Nelson, William O.,Karpishin,Timothy B.,Rettig, Steven J.,Orvig, Cris
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p. 123 - 131
(2007/10/02)
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- Iron complexes of hydroxy pyridones useful for treating iron deficiency anemia
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Pharmaceutical compositions containing an iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic hydrocarbon group and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are also replaced by an aliphatic hydrocarbon group, are of value for the treatment of iron deficiency anemia.
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