Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: orally active iron chelators with clinical potential

Dobbin, Paul S.; Hider, Robert C.; Hall, Aaron; Taylor, Paul D.; Sarpong, P; Porter, John B.; Xiao, Gaoyi; Helm, D. van der

doi:10.1021/jm00069a002

Cited by 209 publications

(174 citation statements)

References 19 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…Partition coefficients were measured by using an automated continuous flow method (filter probe method) [23] and the shakeflask method. The two phases used in the determination were Mops buffer (50 mM, pH 7n4, prepared with Milli-Q water) and octan-1-ol, each of which was pre-equilibrated with the other phase before use (the solubility of water in octan-1-ol is 2n3 M) [24].…”

Section: Partition Coefficient Determinationmentioning

confidence: 99%

Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties

Brown

Khodr

Hider

et al. 1998

Biochemical Journal

736

389

View full text Add to dashboard Cite

The flavonoids constitute a large group of polyphenolic phytochemicals with antioxidant properties in vitro. The interactions of four structurally related flavonoids (quercetin, kaempferol, rutin and luteolin) with Cu2+ ions were investigated in terms of the extent to which they undergo complex formation through chelation or modification through oxidation, as well as in their structural dependence. The ortho 3ʹ,4ʹ-dihydroxy substitution in the B ring is shown to be important for Cu2+-chelate formation, thereby influencing the antioxidant activity. The presence of a 3-hydroxy group in the flavonoid structure enhances the oxidation of quercetin and kaempferol, whereas luteolin and rutin, each lacking the 3-hydroxy group, do not oxidize as readily in the presence of Cu2+ ions. The results also demonstrate that the reactivities of the flavonoids in protecting low-density lipoprotein (LDL) against Cu2+ ion-induced oxidation are dependent on their structural properties in terms of the response of the particular flavonoid to Cu2+ ions, whether chelation or oxidation, their partitioning abilities between the aqueous compartment and the lipophilic environment within the LDL particle, and their hydrogen-donating antioxidant properties.

show abstract

Section: Partition Coefficient Determinationmentioning

confidence: 99%

Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties

Brown

Khodr

Hider

et al. 1998

Biochemical Journal

736

389

View full text Add to dashboard Cite

show abstract

“…Newer iron chelators, such as the hydroxypyridinones designed by Hider, Kontoghiorghes, and colleagues (12,20,22,23,31,32), have been developed to produce effective agents that are orally bioavailable and inexpensive to manufacture; the antimalarial activities of these chelators have also been demonstrated (19).…”

mentioning

confidence: 99%

Iron chelators as therapeutic agents against Pneumocystis carinii

Weinberg

1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Iron plays a critical role in host-parasite interactions, and iron chelators have been demonstrated to serve as effective adjunct therapeutic agents against malaria. The effects of the parenteral iron chelator deferoxamine (DFO) on the growth of rat-derived Pneumocystis carinii were studied in a human fibroblast cell culture model and in two in vivo models of experimental infection. In addition, the effects of the investigational oral iron chelator CP20 and its 3-hydroxypyridin-4-one analogs CP51, CP94, and CP96 on the growth of P. carinii in vitro were assessed. DFO suppressed the growth of P. carinii in vitro in a dose-dependent manner, and daily injections of DFO markedly reduced the intensity of P. carinii infection in both mice and rats. Cell cultures treated with iron chelators that are administered orally to humans also showed substantial P. carinii growth inhibition. Reduction of P. carinii numbers after iron chelator therapy correlated with alterations in P. carinii morphology, as viewed by transmission electron microscopy. Since the use of current anti-P. carinii drugs is limited by toxicity or incomplete efficacy, or both, the role of iron chelation as adjunctive anti-P. carinii chemotherapy merits additional investigation.In the absence of specific antimicrobial prophylaxis, Pneumocystis carinii causes pneumonia in the majority of individuals infected with human immunodeficiency virus and remains an important pathogen in persons treated with immunosuppressive therapy for malignancy and after organ transplantation (6). The toxicity and the incomplete efficacy of the standard treatment regimens for P. carinii pneumonia have prompted the development of new or adjunctive modes of therapy (6, 27).The availability of iron plays a critical role in host-parasite interactions (13,28,29,41,42). Iron is required for the growth of nearly all forms of bacterial, fungal, protozoal, plant, and animal cells (43,44). Vertebrate animals have developed elaborate strategies to withhold growth-essential iron from microbial invaders while retaining their own access to the metal (41,42,45). It has been suggested, therefore, that manipulation of iron availability be exploited as a therapeutic tool (13,41,42). In fact, several iron chelators, among them deferoxamine (DFO), demonstrate antimalarial activity in cell culture and animal models (14,33,47,48), and recently, iron chelation with DFO has been shown to be an effective adjunct to traditional antimalarial therapy in asymptomatic parasitemic adults and children with cerebral malaria (16,19,40).Clarkson et al. (11) examined the effects of DFO on the progression of reactivated latent P. carinii pneumonia in rats and showed that DFO therapy reduces the lung cyst count in a dose-dependent manner. A subsequent preliminary study from the laboratory of Weinberg and Shaw (46) showed that DFO suppresses the growth of P. carinii in an established cell culture model at concentrations safely achievable in human serum. However, despite the efficacy and safety of DFO as a chelator, i...

show abstract

“…39 At more clinically relevant (micromolar) concentrations, the 3,4-hydroxypyridinones are not competitive with transferrin for ferric ions. On the other hand, deferiprone has been found to be capable of releasing Fe from the storage protein ferritin, whereas …”

Section: -38mentioning

confidence: 98%

Coordination chemistry and biology of chelators for the treatment of iron overload disorders

Bernhardt

2007

Dalton Trans.

View full text Add to dashboard Cite

Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: orally active iron chelators with clinical potential

Cited by 209 publications

References 19 publications

Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties

Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties

Iron chelators as therapeutic agents against Pneumocystis carinii

Coordination chemistry and biology of chelators for the treatment of iron overload disorders

Contact Info

Product

Resources

About