Biological evaluation of ferrocene derivatives

Organometallic complexes containing transition metals, such as Ru(II), Os(II), Ir(III), have been moderately and recently used in medicinal chemistry as anticancer, antimalarial, antimicrobial or diagnostic agents. Current trends have led researchers to explore and define new synthetic methods in the quest for the design of new drugs and reduce the inherit associated toxic side-effects by using metal based compounds. Ferrocene based derivatives have been subjected to study for their biological and medicinal applications. Examples include ferrocenophane polyphenol, ferrocenyl quinone methides, ferrocenyl-aminoquinoline-carboxamide and a ferrocene-substituted hydroxytamoxifen, which has been proved as a potential new breast cancer therapeutic. Ferroquine displays antimalarial activity and ferrocifen is a tamoxifen-ferrocene anticancer agent. During the course of our research, we have focused on synthesizing and studying the biological activity of novel organometallic compounds containing the corresponding ferrocene moiety. We aimed to make, at least, 3 different families of compounds, which were cannabinoid receptor (CB1/CB2 receptor agonists), histone deacetylase (HDAC) selective inhibitors and general kinase inhibitors. Firstly, a review covering the state-of-the-art in bioorganometallic chemistry will be presented. Secondly, we started with the synthesis of a small library of compounds containing the following groups: ferrocenylamine, 4-oxo-1, 4-dihydropyridine and dihydroquinoline. We used aminoferrocene as a bioisostere of the adamantylamine group where previous studies of compounds containing the latter group had showed it to effectively interact with the cannabinoid receptors, CB1 and CB2. Some of our compounds displayed good to excellent potency in the nM range against the CB1 and CB2 receptors. Thirdly, we embarked to synthesise HDAC inhibitors knowing their potential as anti-cancer drugs and trying to obtain, wherever possible, enzyme isoform selectivity. One of the well-known HDAC inhibitors is suberoylanilide hydroxamic acid (SAHA). Vorinastat, as it is also known, has received Food and Drug Administration approval for treating patients with cutaneous T-cell lymphoma. The compound developed in our group by replacing ferrocene for the phenyl ring in SAHA, called JAHA, is another example of a highly potent HDAC inhibitor. Our research led to compounds where the hydroxamic acid moiety in JAHA has been replaced by a benzamide group. This transformation has produced a significant effect in delivering a potent HDAC3 selective HDAC inhibitor. This is supported by biological studies and a molecular modelling rationalisation. Next, a series of oxindole based analogues have been synthesized by the Knoevenagel condensation reaction of: 5-(pentafluorosulfanyl)-1,3-dihydro-indol-2-one and 6-(pentafluorosulfanyl)-1,3-dihydro-indol-2-one compound with: ferrocenecarboxaldehyde and pyrrole-2-carboxaldehyde. The compounds thereby synthesised have been studied against a panel of kinases, and kinase inhibitory data will be discussed and presented. In a Future directions section, we will describe the synthesis of FAAH (fatty acid amide hydrolase) inhibitors based on an aminoferrocene backbone.