Recent Developments Centered on Orally Active Iron Chelators

Abstract

Over the past twenty years there has been a growing interest in the orally active iron chelators, deferiprone and deferasirox, both have been extensively studied. The ability of these compounds to mobilize iron from the heart and endocrine tissue has presented the clinician with some advantages over desferrioxamine, the first therapeutic iron chelator. Other orally active iron chelators are currently under development. The critical features necessary for the design of therapeutically useful orally active iron chelators are presented in this review, together with recent studies devoted to the design of such chelators. This newly emerging range of iron chelators will enable clinicians to apply iron chelation methodology to other disease states and to begin to design personalized chelation regimes.

Transient Proteotoxicity of Bacterial Virulence Factor Pyocyanin in Renal Tubular Epithelial Cells Induces ER-Related Vacuolation and Can Be Efficiently Modulated by Iron Chelators

“…A number of iron chelators are approved clinical drugs for both topical and systemic use (Hatcher et al , 2009; Hider, 2014). Pathogenic bacteria require iron for normal growth and employ an arsenal of means, including siderophores and toxins such as PCN, to acquire Fe from the surroundings (Tyrrell and Callaghan, 2016).…”

Hydroxypyridinone-Based Iron Chelators with Broad-Ranging Biological Activities

“…36 The high spin Fe 3+ coordinates with six donor atoms of the ligands to form a complex in an octahedral manner, 37 and the chelator can be classified as hexadentate, tridentate, and bidentate ligand according to the number of donor atoms (Figure 2). 36,38 The pFe 3+ value is a useful parameter for assessing the affinity of ligands to Fe 3+ under biological conditions (pFe 3+ = −log[Fe 3+ ] when [Fe 3+ ] total = 10 −6 M and [ligand] total = 10 −5 M at pH 7.4). The higher the pFe 3+ value, the greater the affinity for Fe 3+ .…”

Klinik Olarak Faydalı Demir Bağlayıcı Ligandların Tasarım Özellikleri

“…Bu yüzden oral olarak aktif, toksik olmayan, seçici bir demir bağlayıcı ligand ait başarılı tasarım, çok aranan bir hedef haline gelmiştir. Yeni geliştirilmiş demir bağlayıcı ligand tasarımı yapılırken yıllar içinde daha iyi tanımlanmış belirli kimyasal özellikler şu şekilde özetlenebilir: − Şelatlama maddesinin ve komplekslerinin uygun toksisite profili; − Komplekslerinin kararlığı; − Demire karşı seçicilik; − Komplekslerin uygun redoks potansiyeli; − Enzim inhibisyonu, kompleks yapısı, lipofilik ve moleküler ağırlığı; − Vücutta aktif olmayan metabolitlere dönüştürülmemelidir; − İyi bağırsak absorpsiyonu ve hedef hücrelere iyi biyoyararlanımı; − Şelatlayıcı ve endojen ligandlar arasında demirin hızlı kinetik değişimi; − Oluşan komplekslerin atılımını kolaylaştıran faktörler; − Vücut sıvıları metabolik metal dengesini bozmamalı 8,9,10 .…”