A comparative study of the iron-clearing properties of desferrithiocin analogues with desferrioxamine B in a Cebus monkey model

Abstract

A comparative study of the iron-clearing properties of subcutaneously administered desferrioxamine B (DFO) with those of orally administered desferrithiocin sodium salt (1), desmethyl desferrithiocin (2), desazadesmethyl desferrithiocin sodium salt (3), desazadesmethyl desferrithiocin pivaloyloxymethyl ester (4), and desazadesmethyl-5,5- dimethyl desferrithiocin (5) in an iron-loaded Cebus monkey model and a non-iron overloaded bile duct-cannulated rat model is presented. All six drugs, which performed well in rodent studies, demonstrated increased efficiency in the Cebus monkey model. When administered to rodents at a daily dosage of 384 mumol/kg over a period of 10 days, drug 1 demonstrated severe renal toxicity. whereas drugs 3, 4, and 5 exhibited severe gastrointestinal (GI) toxicity. Under the same experimental protocol, drug 2 did not show significant toxic side effects. In addition, to further evaluate the iron-clearing properties of analogue 2, a dose-response study was performed in the primates that showed that iron excretion increased in a dose-dependent fashion.

The Origin of the Differences in (R)‐ and (S)‐Desmethyldesferrithiocin: Iron‐Clearing Propertiesa

“…29 Studies in rodents have demonstrated mobilization of iron from liver ferritin by DFT, 30 and a preliminary investigation in primates 31 suggested that it was indeed an orally active iron chelator. A more comprehensive investigation in our laboratory carried out in a bile duct-cannulated rat model [22][23][24]32 as well as in a Cebus monkey model 22,24,27,[33][34][35] has supported these findings and quantified the drug's effectiveness. [22][23][24]34 Unfortunately, animals chronically exposed to DFT presented with nephrotoxicity.…”

“…Interestingly, the siderophores, microbial iron While most siderophores fall primarily into two structural classes, hydroxamates or catecholamides, [13][14][15][16][17][18][19] there are a number of compounds which do not belong to either family, e.g., pyochelin, 20 rhizobactin, 21 and 2-(3′-hydroxypyrid-2′-yl)-4-methylthiazoline-4(S)carboxylic acid (desferrithiocin, DFT). [22][23][24][25][26][27] DFT, isolated from Streptomyces antibioticus, 28 was shown to form a stable 2:1 complex with iron (III), (K f = 4 × 10 29 M -1 ). 29 Studies in rodents have demonstrated mobilization of iron from liver ferritin by DFT, 30 and a preliminary investigation in primates 31 suggested that it was indeed an orally active iron chelator.…”

Chelator‐induced iron excretion in iron‐overloaded marmosets

“…By placing the animals from a social unit into adjacent metabolic cages, the animals, although separated, could see each other. Bergeron et al (1991Bergeron et al ( , 1992Bergeron et al ( , 1993aBergeron et al ( , b, 1998a 1 Bergeron et al (1991) Urine and faeces were collected in 24-h fractions to determine background iron excretion. After administration of the chelator, the marmosets were maintained in the same metabolic cage for another 48 h. They were frequently observed to note unusual reactions, and again, urine and faeces were collected in 24 h fractions.…”

Desferrithiocin is a more potent antineoplastic agent than desferrioxamine

“…Another more lipophilic chelator, desferrithiocin (DFT), is also a siderophore, isolated from Streptomyces antibioticus 1990; Bergeron et al, 1990;Longueville & Crichton, 1986;Wolfe et al, 1989). Unfortunately, when administered for long time intervals at concentrations sucient to decrease Fe overload, there was evidence of toxicity (probably caused by the Fe chelate, ferrithiocin (FT) (Baker et al, 1992b;Bergeron et al, 1993), resulting in DFT being withdrawn from development for long-term therapy. However, DFT or one of its analogues may hold potential as a short-term chemotherapeutic agent, alone or in conjunction with other agents e.g.…”