Synthesis, characterisation and biological evaluation of N-(ferrocenyl)naphthoyl amino acid esters as anticancer agents

Abstract

A series of N-(ferrocenyl)naphthoyl amino acid esters 5-18 has been prepared by coupling ferrocenyl naphthoic acids 3-4 to alpha-amino acids and linear amino acids in the presence of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt). The compounds were fully characterised by a range of NMR spectroscopic techniques, UV-Vis spectroscopy, mass spectrometry and cyclic voltammetry. X-ray crystallographic studies of the intermediate compounds 1-2 were also performed. Biological evaluation of the intermediates 1-2 and N-(ferrocenyl)naphthoyl amino acid esters 5-18 was performed in the H1299 non-small cell lung cancer (NSCLC) cell line and the Sk-Mel-28 metastatic melanoma cell line. The intermediates 1-2 failed to produce an effect in either cell line. Compounds 5-18 exhibited a strong anti-proliferative effect in the H1299 cell line, whilst the Sk-Mel-28 cells were slightly more resistant to these compounds. N-(6-ferrocenyl-2-naphthoyl)-gamma-aminobutyric acid ethyl ester 17 shows a particularly high activity in both the H1299 cell line (IC(50) = 0.62 +/- 0.07 microM) and the Sk-Mel-28 cell line (IC(50) = 1.41 +/- 0.04 microM).

Organometallic Complexes: New Tools for Chemotherapy

“…From this observation, it was proposed that ferrocenyl compounds could be oxidized in vivo, and both, ferricinium and ferrocene, could be responsible for the cytotoxic effects [60]. As a result, ferrocene was incorporated into a large number of molecules such as water soluble polymers [61][62][63][64], DNA intercalator [65], phosphino compounds [66][67][68][69], and other biomolecules [70][71][72][73]. Diferrocenyl compounds [74] and a variety of other small ferrocenyl molecules [75][76][77][78][79] have also been investigated for anticancer activity.…”

Ferrocene incorporated selenoureas as anticancer agents

“…Earlier attempts on ferrocene derivatives for their biological applications were individualistic in nature and it was known in 1978 (compound 1) that they are active against lymphocytic leukemia P-388 [19] (Chart 1, compound [1][2][3][4][5][6][7][8][9][10]. Other similar type of findings have shown the activity of ferrocene derivatives against lungs carcinoma (compound 2) [20], 70% tumor growth inhibition (compound 3) against Ca-755 cell lines [21] and 100% inhibition of solid (compound 4) tumor [22]. But detail studies have opened new horizons of research on ferrocene.…”

A tandem mass spectrometric investigation of N‐(3‐ferrocenyl‐2‐naphthoyl) dipeptide ethyl esters and N‐(6‐ferrocenyl‐2‐naphthoyl) dipeptide ethyl esters

“…[14][15][16][17][18] Preliminary in vitro bioassay results showed that the N-ferrocenyl amino acid and peptide derivatives are cytotoxic against the highly invasive H1299 lung cancer cells. [19][20][21][22][23][24] The N-ferrocenyl peptide derivatives are composed of three key moieties, namely, (i) an electroactive core; (ii) a conjugated aromatic linker; and (iii) an amino acid or dipeptide derivative that can interact with other molecules via hydrogen bonds. We have shown that replacing the conjugated linker of N-(ferrocenyl)benzoyl amino acid and dipeptide esters with a naphthoyl linker leads to an improvement in the anti-proliferative effect in the H1299 non-small cell lung cancer (NSCLC) cell line.…”

“…N-(6-Ferrocenyl-2-naphthoyl)g-aminobutyric acid ethyl ester has an IC 50 value of 0.62 mM whereas N-{meta-(ferrocenyl)benzoyl}-GlyAla(OEt), the most active of the N-(ferrocenyl)benzoyl series, was shown to have an IC 50 value of 4.0 mM. [22,24] Thus, replacing the aromatic spacer had a dramatic effect on biological activity. The compounds are also cytotoxic against the Sk-Mel-28 melanoma cell line.…”

“…The redoxactive ferrocenyl unit of these novel ferrocenyl-peptide bioconjugates was shown to be essential for biological activity and the mode of action of these compounds is currently under investigation. [24] The effects of the ferrocenyl derivatives on the generation of intracellular reactive oxygen species and DNA damage, and their effects on the cell cycle and apoptosis, is currently being assessed prior to in vivo studies. It was observed in previous studies of N-(ferrocenyl)benzoyl amino acid and dipeptide esters by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) that a matrix was not required for ionization to occur.…”