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

被引:103
作者
Becker, EM
Lovejoy, DB
Greer, JM
Watts, R
Richardson, DR
机构
[1] Heart Res Inst, Iron Metab & Chelat Grp, Sydney, NSW 2050, Australia
[2] Univ Queensland, Royal Brisbane Hosp, Dept Med, Brisbane, Qld 4029, Australia
[3] Childrens Canc Inst Australia Med Res, Iron Metab & Chelat Program, Sydney, NSW 2031, Australia
关键词
iron (Fe) chelators; Fe metabolism; anti-tumour agents; chemotherapy;
D O I
10.1038/sj.bjp.0705089
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 efficacy, 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 efficacy, we assessed their effects on proliferation, Fe uptake, Fe efflux, the expression of cell cycle control molecules, iron-regulatory protein-RNA-binding activity, and H-3-thymidine, H-3-uridine and H-3-leucine incorporation. 2 Despite the high lipophilicity of the QCIH ligands and the fact that they have the same Fe-binding site as the PCIH series, surprisingly none of these compounds were effective. In contrast, the PKIH analogues showed marked anti-proliferative activity and Fe chelation efficacy. 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 identified a novel class of ligands that are potent Fe chelators and inhibitors of DNA synthesis, and which deserve further investigation.
引用
收藏
页码:819 / 830
页数:12
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