Identification of the di-pyridyl ketone isonicotinoyl hydrazone (PKIH) analogues as potent iron chelators and anti-tumour agents.
(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 (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 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.
Becker
Erika M
EM
The Department of Medicine, University of Queensland, Royal Brisbane Hospital, Herston, Brisbane, Queensland 4029, Australia.
Lovejoy
David B
DB
Greer
Judith M
JM
Watts
Ralph
R
Richardson
Des R
DR
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
C404192:2-pyridylcarboxaldehyde isonicotinoylhydrazone; D000970:Antineoplastic Agents; D006835:Hydrazones; D007502:Iron Chelating Agents; D011725:Pyridines