Development, Synthesis and Anticancer Evaluation of Trinuclear Platinum Group Metal Organometallic Complexes

Abstract

Over the past few decades metals in medicine have played to play a significant role, especially

after the discovery of the anticancer properties of cisplatin. However, acquired and intrinsic

resistance, toxicity and a host of side-effects have encouraged the research for new metal

based anticancer agents. Organometallic complexes have proved to be successful anticancer

agents and several have commenced clinical trials. The aim of this study was to prepare and

characterize trinuclear platinum group organometallic complexes and investigate their in vitro

activity.

The first series of ester containing complexes were prepared. The ligands were generated by

the preparation of Schiff base ligands obtained from the condensation of 4-

aminophenylmethanol and either benzaldehyde, 2-pyridinecarboxaldehyde or

salicylaldehyde. Trimeric ester ligands were prepared from these monomeric ligands by

reaction with trimesoyl chloride. The trimeric ligands were used to prepare a new series of

trinuclear polyester organometallic complexes using the dimeric precursors, [Ru(η6-p-

PriC6H4Me)Cl2]2, [Rh(η5-C5Me5)Cl2]2 or [Ir(η5-C5Me5)Cl2]2. The Schiff base ligands act as

bidentate donors to each metal. All compounds were characterized using nuclear magnetic

resonance (NMR) and Fourier transform infrared (FT-IR) spectroscopy, elemental analysis

(EA) and electron impact (EI) or electrospray ionization (ESI) mass spectrometry. Model

mononuclear analogues were prepared and the molecular structures of selected compounds

were determined by single crystal X-ray diffraction analysis. The mono- and trimeric ligands

and the metal complexes were evaluated for inhibitory effects against the human ovarian

cancer cell lines A2780 (cisplatin-sensitive) and A2780cisR (cisplatin-resistant), and the model

human skin fibroblast cell line, KMST-6. Upon coordination of the metal center an increase in

the activity against the ovarian cancer cells is observed, compared to the free ligands. The

trinuclear complexes displayed the greatest antiproliferative activity and exhibited selectivity

over the non-tumorigenic skin cells.

The second series of new trinuclear and model mononuclear cationic monodentate Rh(III),

Ir(III) and Ru(II) complexes with alkylated 1,3,5-triaza-7-phosphaadamantane (PTA) moieties

were prepared. Monoalkylation of the PTA moiety was achieved by reaction with

1,3,5-tris-(bromomethyl)benzene for the trimeric ligand or benzylbromide for the monomeric

ligand. The trinuclear cationic complexes were prepared from the dimeric precursors,

[Ru(η6-p-PriC6H4Me)Cl2]2, [Rh(η5-C5Me5)Cl2]2 or [Ir(η5-C5Me5)Cl2]2, and characterized using

NMR and IR spectroscopy, HR-ESI-mass spectrometry and elemental analysis. The ligands

coordinate to the metals via the phosphorous of the PTA, and this was confirmed by

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appropriate shifts in the 31P NMR spectra. The cytotoxicities of all alkylated PTA compounds

were investigated against WHCO1 esophageal cancer cell. The monomeric and trimeric

ligands displayed no activity. The trinuclear Rh(III) and Ir(III) complexes were more active than

the mononuclear analogues. The Ir(III) mononuclear complex proved to be the most cytotoxic

and 1H NMR model studies demonstrated its DNA binding ability, while UV-Vis studies

demonstrated the ability of the iridium mononuclear complex to interact with the double helix

structure of Red Salmon testes DNA.

The third series consists of new water soluble Rh(III) and Ir(III) sulfonated complexes. The

trimeric ligand was prepared via a Schiff base condensation between tris-2-(aminoethyl)amine

and 5-sulfonatosalicylaldehyde. Anionic trinuclear complexes were prepared from the dimeric

precursors, [Ru(η6-p-PriC6H4Me)Cl2]2, [Rh(η5-C5Me5)Cl2]2 or [Ir(η5-C5Me5)Cl2]2. Rh(III) and Ir(III)

complexes were also prepared by displacement of the labile metal-chloro ligand by reaction

with pyridine, 4-methylpyridine, 4-phenylpyridine and 4-ferrocenylpyridine. The sulfonated

complexes were characterized using NMR and IR spectroscopy, HR-ESI-mass spectrometry

and elemental analysis. The cytotoxicities of all sulfonated compounds were investigated

against WHCO1 cancer cells and the metal complexes displayed promising activity, while the

ligands showed no activity. Several of the trinuclear complexes exhibited comparable activity

to that of cisplatin. 1H NMR model studies demonstrated the most active compound’s DNA

binding ability.