Desferrithiocin Analogue Based Hexacoordinate Iron(III) Chelators

Abstract

Traditional thinking has been that hexacoordinate Fe(III) ligands are more effective at preventing iron's interactions with reactive oxygen species, most particularly the Fe(II)-mediated reduction of hydrogen peroxide to the hydroxyl radical (i.e., Fenton chemistry), than are ligands of lower denticity. Thus, a hexacoordinate derivative of the well-characterized tricoordinate ligand (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-thiazolecarboxylic acid [4'-(HO)-DADMDFT], (S,S)-1,11-bis[5-(4-carboxy-4,5-dihydrothiazol-2-yl)-2,4-dihydroxyphenyl]-4,8-dioxaundecane, was designed with the aid of a molecular modeling program and synthesized. Evaluations both in vitro and in vivo were carried out to determine whether there is any advantage, at the level of prevention of Fenton chemistry, radical trapping, or iron clearance, to constructing a desferrithiocin-based hexacoordinate analogue. The hexacoordinate analogue was more effective at preventing the iron-mediated oxidation of ascorbate at low ligand/metal ratios than was its tricoordinate parent and can function as an excellent radical scavenger. At equivalent iron binding doses in the bile duct cannulated rodent, oral administration of the tricoordinate ligand was 3-fold more effective than was po administration of the hexacoordinate derivative. However, sc administration of the hexacoordinate derivative resulted in an efficiency that was 3 times greater than that of the tricoordinate chelator. Unfortunately, the rodent findings were not substantiated in the primates. The hexacoordinate ligand was only about one-half as efficient as its tricoordinate parent when administered sc. Owing to these results, po dosing was not attempted. Thus, there appears to be no overall advantage to coupling two molecules of 4'-(HO)-DADMDFT to afford a hexacoordinate derivative.

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

“…In vivo studies in the noniron-overloaded, bile ductcannulated rodent model demonstrated that the hexadentate chelator had little iron chelation efficiency when administered orally (Bergeron et al, 2003b). This was found to be within the experimental error of the tridentate unit, 4Ј-(OH)-DADMDFT, at equivalent ironbinding doses.…”

“…4). This design was based on linking two tridentate units by a polyether tether and Job's plot of BDU confirmed the hexadentate nature of this ligand (Bergeron et al, 2003b).…”

“…Due to their additional stability, the majority of natural siderophores are hexadentate. By fully occupying the coordination sphere of iron, hexadentate chelators can prevent the interaction of iron with surrounding molecules, avoiding the formation of ROS through Fenton chemistry (Liu and Hider, 2002a;Bergeron et al, 2003b;Chaston et al, 2004). Owing to these advantages, Bergeron's group synthesized a hexacoordinate chelator based upon the nontoxic tridentate ligand, 4Ј-(OH)-DADMDFT, named (S,S)-1,11-bis[5-(4-carboxy-4,5-dihydrothiazol-2-yl)-2,4-dihydroxyphenyl]-4,8-dioxaundecane (BDU; Fig.…”

“…This was found to be within the experimental error of the tridentate unit, 4Ј-(OH)-DADMDFT, at equivalent ironbinding doses. However, when administered subcutaneously, the iron clearing efficiency of BDU was substantially increased, being 3 times that of the tridentate unit when administered via the same route (Bergeron et al, 2003b). Unfortunately, trials in the iron-overloaded Cebus apella monkey showed a decrease in iron clearing efficiency of BDU when subcutaneously administered.…”

Effects of Sea Buckthorn (Hippophae rhamnoides L.) Fruit Extract on Ultraviolet-induced Apoptosis of Skin Fibroblasts

“…특히, UV조사는 깊은 주름, 거칠기(roughness), 이완(laxity), 색소침착(pigmentation) 등을 특징으로 하는 피 부손상의 가장 주요한 원인으로 고려되고 있다 [10]. 또한, UV 조사에 의해 유발되는 피부변화는 활성산소(reactive oxygen species, ROS)의 증가와도 밀접한 관계가 있으며, 증가된 활성 산소는 피부조직 내에 산화적 스트레스(oxidative stress)와 산 화적 광손상(oxidative photodamage)의 원인일 뿐만 아니라 세포 내 항산화 방어작용의 파괴를 유발할 수 있다 [3,5,17,22,40].…”