Identification of the di‐pyridyl ketone isonicotinoyl hydrazone (PKIH) analogues as potent iron chelators and anti‐tumour agents

Abstract

1 In an attempt to develop chelators as potent anti-tumour agents, we synthesized two series of novel ligands based on the very active 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) group. Since lipophilicity and membrane permeability play a critical role in Fe chelation e cacy, the aldehyde moiety of the PCIH series, namely 2-pyridylcarboxaldehyde, was replaced with the more lipophilic 2-quinolinecarboxaldehyde or di-2-pyridylketone moieties. These compounds were then systematically condensed with the same group of acid hydrazides to yield ligands based on 2-quinolinecarboxaldehyde isonicotinoyl hydrazone (QCIH) and di-2-pyridylketone isonicotinoyl hydrazone (PKIH). To examine chelator e cacy, we assessed their e ects on proliferation, Fe uptake, Fe e ux, the expression of cell cycle control molecules, iron-regulatory protein-RNAbinding activity, and 3 H-thymidine, 3 H-uridine and 3 H-leucine incorporation. 2 Despite the high lipophilicity of the QCIH ligands and the fact that they have the same Febinding site as the PCIH series, surprisingly none of these compounds were e ective. In contrast, the PKIH analogues showed marked anti-proliferative activity and Fe chelation e cacy. Indeed, the ability of these ligands to inhibit proliferation and DNA synthesis was similar or exceeded that found for the highly cytotoxic chelator, 311. In contrast to the PCIH and QCIH analogues, most of the PKIH group markedly increased the mRNA levels of molecules vital for cell cycle arrest. 3 In conclusion, our studies identify structural features useful in the design of chelators with high anti-proliferative activity. We have identi®ed a novel class of ligands that are potent Fe chelators and inhibitors of DNA synthesis, and which deserve further investigation.

Iron chelators for the treatment of iron overload disease: Relationship between structure, redox activity, and toxicity

“…However, the abundance of Fe-dependent biochemistry, and the marked effects of chelators on these processes suggest that Fe-chelation dependent effects are predominant. In support of this, pre-formation of the 311-Fe complex has been shown to completely prevent the anti-proliferative effects of 311 [118,119]. Additionally, an analogue of NT was synthesized with a methyl group obstructing coordination of Fe to the aldimine nitrogen [115].…”

A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

“…Previously, the high antiproliferative activity of chelators of the PKIH and DpT classes of ligands were shown in a limited number of cell lines (10,11). Here we examined 28 cell types to determine the spectrum of antitumor activity of the most effective PKIH and DpT analogs ( Table 1, which is published as supporting information on the PNAS web site).…”

“…1 B and C) (10,11). From preliminary screening, one of the most efficient of these chelators identified was di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) (Fig.…”

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…Literature data suggest that the imino carbon of thiosemicarbazones [68], aroylhydrazones [51], arylhydrazones [13] and benzothiazoles [49,50] may be a sensitive position for finetuning the biological activity of these Schiff bases. The role of imino carbon methylation on the toxicity of the investigated compounds is also evident from the structure-activity matrix shown in Figure 4.…”