The Design and Development of Deferiprone (L1) and Other Iron Chelators for Clinical Use: Targeting Methods and Application Prospects

Abstract

Iron is essential for all human cells as well as neoplastic cells and invading microbes. Natural and synthetic iron chelators could affect biological processes involving iron and other metal ions in health and disease states. Iron overload is the most common metal toxicity condition worldwide. There are currently two iron chelating drugs, which are mostly used for the treatment of thalassaemia and other conditions of transfusional iron overload. Deferoxamine was until recently the only approved iron chelating drug, which is effective but very expensive and administered parenterally resulting in low compliance. Deferiprone (L1 or 1,2-dimethyl-3-hydroxypyrid-4-one) is the world's first and only orally active iron chelating drug, which is effective and inexpensive to synthesise thus increasing the prospects of making it available to most thalassaemia patients in third world countries who are not currently receiving any form of chelation therapy. Deferiprone has equivalent iron removal efficacy and comparable toxicity to deferoxamine. There are at least four other known iron chelators, which are currently being developed. Even if successful, these are not expected to become available for clinical use in the next five years and to be as inexpensive as deferiprone. The variation in the chemical, biological, pharmacological, toxicological and other properties of the chelating drugs and experimental chelators provide evidence of the difference in the mode of action of chelators and the need to identify and select molecular structures and substituents based on structure/activity correlations for specific pharmacological activity. Such information may increase the prospects of designing new chelating drugs, which could be targeted and act on different tissues, organs, proteins and iron pools that play important role not only in the treatment of iron overload but also in other diseases of iron and other metal imbalace and toxicity including free radical damage. Chelating drugs could also be designed, which could modify the enzymatic activity of iron and other metal containing enzymes, some of which play a key role in many diseases such as cancer, inflammation and atherosclerosis. Other applications of iron chelating drugs could involve the detoxification of toxic metals with similar metabolic pathways to iron such as Al, Cu, Ga, In, U and Pu.

Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments

“…In study 2, rats (n=113) were assigned to one of six groups: (1) sham (n=23); (2) STZ (n=26); (3) STZ-TETA 20 mg/day per rat (n=23) [3][4][5]; (4) STZ-Def (ACROS, Geel, Belgium; 20 mg/day per rat, n=15) [11,12]; (5) STZPen (Sigma; St. Louis, MO, USA; 6 mg/day per rat, n=15) [2,8]; and (6) STZ-ZnA (Sigma; 0.5 mg day −1 rat −1 , n=11) [9,10]. A spot urine sample was collected from the bladder of each rat immediately before final tissue collection.…”

“…Other compounds that are also used for the treatment of this disease include Dpenicillamine (Pen, a less specific transition-metal chelator) [2,8] and Zn acetate (ZnA, a blocker of enteric Cu absorption) [9,10]. Deferiprone (Def), an orally active Fe chelator that also binds Cu, has also been proposed for this purpose [11,12]. Whether these compounds might cause similar biochemical changes and improve cardiac and renal function, as TETA does in diabetic rats, remains to be determined.…”

A Study of the Charge Transport Process at Nickel Hydroxide-Gold Modified Electrodes employing Rotating Disc Electrode Voltammetry and Ac Impedance Measurements

“…Deferasirox (4-(3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl) benzoic acid) was selected as redox substrate in the present analysis. This drug is an oral iron chelator that is used clinically, mainly in patients with thalassemia [9,10]. The electrocatalytic oxidation and determination of this drug on a nickel hydroxyde-modified electrode was studied in previous works [11].…”

The Effect of Mercury in Iron Metabolism in Rats

“…In vivo, this selectivity is demonstrated by conserved plasma Zn and Cu levels in patients taking deferasirox, and while its efficacy is rather low for inducing negative iron balance, it is effective and well-tolerated [14,15]. Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, DFP or L1, Figure 1), which belongs to the family of α-ketohydroxpyridines, can remove excess iron from various parts of the body of iron-loaded patients, including the liver and, particularly, the heart [16]. The drug is also used worldwide to treat cancer, leukemia, and other diseases.…”