Iron chelates in the anticancer therapy

Abstract

Iron plays a significant role in the metabolism of cancer cells. In comparison with normal cells, neoplastic ones exhibit enhanced vulnerability to iron. Ferric ions target tumor via the ferroptotic death pathway—a process involving the iron-mediated lipid oxidation. Ferric ion occurs in complex forms in the physiological conditions. Apart from iron, ligands are the other factors to affect the biological activity of the iron complexes. In recent decades the role of iron chelates in targeting the growth of the tumor was extensively examined. The ligand may possess a standalone activity to restrict cancer’s growth. However, a wrong choice of the ligand might lead to the enhanced cancer cell’s growth in in vitro studies. The paper aims to review the role of iron complex compounds in the anticancer therapy both in the experimental and clinical applications. The anticancer properties of the iron complex rely both on the stability constant of the complex and the ligand composition. When the stability constant is high, the properties of the drug are unique. However, when the stability constant remains low, both components—ferric ions and ligands, act separately on the cells. In the paper we show how the difference in complex stability implies the action of ligand and ferric ions in the cancer cell. Iron complexation strategy is an interesting attempt to transport the anticancer Fe2+/3+ ions throughout the cell membrane and release it when the pH of the microenvironment changes. Last part of the paper summarizes the results of clinical trials and in vitro studies of novel iron chelates such as: PRLX 93,936, Ferumoxytol, Talactoferrin, DPC, Triapine, VLX600, Tachypyridine, Ciclopiroxamine, Thiosemicarbazone, Deferoxamine and Deferasirox.

A Comparative Study on the Complexation of the Anticancer Iron Chelator VLX600 with Essential Metal Ions

“…In contrast to [Fe(II)(LH) 2 ](NO 3 ) 2 (Figure6), the hydrogen at N3 is 0.509 Å out of the N2, N3, and C8 plane of the VLX600 ligand due to a strong hydrogen bond to the O of one DMSO molecule. This is also indicated by the elongated bond lengths of N2−N3 = 1.370(3) and N3−C8 = 1.382(3) compared to the respective iron complex [Fe(II)(LH) 2 ](NO 3 ) 2 (Figure5) at N2−N3 = 1.366(2) and N3−C8 = 1.366(3) where this hydrogen is almost in plane.…”

“…12 The most prominent representative is triapine (Chart 1), already studied in more than 30 clinical phase I−III trials, with the inhibition of the iron-containing enzyme ribonucleotide reductase as the main target. 3,5 A novel, recently developed iron chelator is 6-methyl-3-{(2E)-2-[1-(2-pyridinyl)ethylidene]hydrazino}-5H- [1,2,4]triazino [5,6-b]indole (VLX600, Chart 1). 13 It was designed to deplete iron levels and interfere with intracellular iron metabolism, leading to the inhibition of mitochondrial respiration.…”

“…zones (TSCs), bearing an (N,N,S)-donor set. 2,3,5 Notably, thiosemicarbazones are lipophilic molecules preferentially interacting with iron intracellularly. Their iron complexes show moderate redox potentials (varying TSCs: −160 to +40 mV vs NHE), enabling redox cycling.…”

“…These metal ions play a crucial role in the growth and proliferation of rapidly dividing cancer cells. It is evident that cancer cells demonstrate a higher requirement and preference for iron than normal tissue cells. − In line with these facts, the application of iron-chelating compounds is one of the more traditional intervention strategies, and numerous ligands with iron binding capacity were screened for their anticancer properties with some promising results. − Initially, iron chelators were developed to remove excess iron in the blood, mostly in the life-long medical therapy for β-thalassemia, in which metal overload is an unfortunate clinical consequence of repeated blood transfusions. − Iron chelators such as deferoxamine B, deferiprone, or deferasirox (Chart ) are hydrophilic ligands typically featuring hard Lewis base donor atoms (mostly O), which rather selectively bind Fe­(III) ions in an octahedral arrangement . As a result, the redox potentials of the Fe­(III)/Fe­(II) complexes of these ligands are much lower (deferoxamine B: −450 mV, deferiprone: −620 mV, deferasirox: −400 mV vs NHE) compared to the Fe­(III)/Fe­(II) aqua/hydroxido complexes (+770 mV vs NHE at pH < 2.2; +380 mV vs NHE at pH = 7.4) or complexes of ligands with a strong tendency toward Fe­(II) coordination (e.g., 1,10-phenantroline: +1130 mV, 2,2-bipiyridine: +1100 mV vs NHE) .…”

“…As a result, the redox potentials of the Fe­(III)/Fe­(II) complexes of these ligands are much lower (deferoxamine B: −450 mV, deferiprone: −620 mV, deferasirox: −400 mV vs NHE) compared to the Fe­(III)/Fe­(II) aqua/hydroxido complexes (+770 mV vs NHE at pH < 2.2; +380 mV vs NHE at pH = 7.4) or complexes of ligands with a strong tendency toward Fe­(II) coordination (e.g., 1,10-phenantroline: +1130 mV, 2,2-bipiyridine: +1100 mV vs NHE) . Therefore, the iron complexes of chelators applied in hematologic disorders are not involved in redox cycles under physiological conditions due to their low redox potential. − A different behavior is observed with iron complexes of chelators binding both Fe­(III) and Fe­(II) such as α- N -heterocyclic thiosemicarbazones (TSCs), bearing an (N,N,S) -donor set. ,, Notably, thiosemicarbazones are lipophilic molecules preferentially interacting with iron intracellularly. Their iron complexes show moderate redox potentials (varying TSCs: −160 to +40 mV vs NHE), enabling redox cycling .…”