•N-{para-(ferrocenyl) ethynyl benzoyl} amino acid and dipeptide methyl and ethyl esters were prepared.•The novel structures were characterized by a range of spectroscopic techniques.•They exhibited cytotoxicity on the human lung carcinoma cell line H1299.•Compound 9 was the most active and displayed an IC50 value of 3.8 μM.A series of N-{para-(ferrocenyl) ethynyl benzoyl} amino acid and dipeptide methyl and ethyl esters 4–18 were prepared by coupling para-(ferrocenyl) ethynyl benzoic acid 3 to the amino acids GABA(OMe), GABA(OEt) and the dipeptide esters GlyGly(OMe), GlyGly(OEt), Gly-L-Ala(OMe), Gly-L-Ala(OEt), Gly-D-Ala(OMe), Gly-D-Ala(OEt), Gly-L-Leu(OEt), Gly-L-Phe(OEt), SarGly(OMe), SarGly(OEt), Sar-L-Ala(OEt), L-ProGly(OEt) and L-Pro-L-Ala(OEt) using the standard N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. All the compounds were fully characterized using a combination of I.R., UV-Vis, 1H NMR, 13C NMR, DEPT-135, 1H-13C COSY (HMQC) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Selected compounds 5, 7, 9, 11, 16, 17 and 18 showed micromolar activity in the H1299 NSCLC cell line, with IC50 values in the range of 3.8–8.3 μM.Download high-res image (65KB)Download full-size image

•1-Alkyl-1′-N-meta and ortho-(ferrocenyl) benzoyl dipeptide esters were prepared.•They exhibited cytotoxicity on the human lung carcinoma cell line H1299.•Compound 7 displayed an IC50 value of 2.6 μM.•The cytotoxicity decreases with an increase of the size of the alkyl group.1-Alkyl-1′-N-meta-(ferrocenyl) benzoyl dipeptide esters 7–18 and 1-alkyl-1′-N-ortho-(ferrocenyl) benzoyl dipeptide esters 19–30 were prepared by coupling the alkyl ferrocenyl benzoic acids 1–6 to the dipeptide ethyl esters Gly-Gly(OEt), Gly-L-Ala(OEt), Gly-L-Leu(OEt) and Gly-L-Phe(OEt) using the standard N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. The alkyl groups employed in the synthesis were methyl, ethyl and propyl. The compounds were characterized using a combination of 1H NMR, 13C NMR, DEPT-135 and 1H-13C COSY (HMQC) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Selected compounds showed micromolar activity in the H1299 NSCLC cell line, with IC50 values in the range of 2.6–20.1 μM.1-Alkyl-1′-N-meta and ortho-(ferrocenyl) benzoyl dipeptide ethyl esters 7–30 were prepared by conventional peptide chemistry using the EDC/HOBT protocol. Compounds 7–30 exhibited cytotoxic effects on the human lung carcinoma cell line H1299. 1-Methyl-1′-N-{meta-(ferrocenyl)-benzoyl}-glycine-glycine ethyl ester 7 had an IC50 value of 2.6 μM.

•1-Alkyl-1′-N-para-(ferrocenyl) benzoyl dipeptide ester derivatives were prepared.•They exhibited cytotoxicity on the human lung carcinoma cell line H1299.•Alkylation of the cyclopentadiene ring increases the cytotoxicity.•The cytotoxicity decreases with an increase of the size of the alkyl group.1-Alkyl-1′-N-para-(ferrocenyl) benzoyl dipeptide esters 4–12 were prepared by coupling the alkyl ferrocenyl benzoic acids 1–3 to the dipeptide ethyl esters Gly-L-Ala(OEt), Gly-L-Leu(OEt) and Gly-L-Phe(OEt) using the standard N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. All the compounds were fully characterized using a combination of 1H NMR, 13C NMR, DEPT-135 and 1H–13C COSY (HMQC) spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and cyclic voltammetry (CV). Selected compounds showed micromolar activity in the H1299 NSCLC cell line, with IC50 values in the range of 4.5–6.6 μM.1-Alkyl-1′-N-para-(ferrocenyl) benzoyl dipeptide ethyl esters 4–12 were prepared by conventional peptide chemistry using the EDC/HOBT protocol. Compounds 4–12 exhibited cytotoxic effects on the human lung carcinoma cell line H1299, the most active derivative being 1-methyl-1′-N-{para-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 4 (IC50 = 4.5 μM).

In this article, we report the findings of a comprehensive structure–activity relationship study of N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters, in which novel analogues were designed, synthesized, and evaluated in vitro for antiproliferative effect. Two new compounds, 2 and 16, showed potent nanomolar activity in the H1299 NSCLC cell line, with exceptional IC50 values of 0.13 and 0.14 μM, respectively. These compounds were also found to have significant activity in the Sk-Mel-28 malignant melanoma cell line (IC50 values of 1.10 and 1.06 μM, respectively). Studies were also conducted to elucidate the mode of action of these novel organometallic anticancer compounds. Cell cycle analysis in the H1299 cell line suggests these compounds induce apoptosis, while guanine oxidation studies confirm that 2 is capable of generating oxidative damage via a ROS-mediated mechanism.

Standard peptide coupling reactions were use to prepare the N-(ferrocenyl)2 and N-(ferrocenoyl)2 cystine dimethyl ester derivatives 4–11. The ferrocene carboxylic acids 1 and 3 were treated with 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), l-cystine methyl ester hydrochloride and triethylamine in dichloromethane at 0 °C to furnish compounds 4–9. The preparation of compounds 10 and 11 employed the dipeptide derivatives (glycine)2-l-cystine dimethyl ester and (β-alanine)2-l-cystine dimethyl ester respectively. The N-(ferrocenyl)2 and N-(ferrocenoyl)2 cystine dimethyl ester derivatives 4–11, which are potential anion sensing agents, were spectroscopically characterized by a combination of 1H NMR, 13C NMR, IR, UV, DEPT-135 and 1H–13C COSY (HMQC) spectroscopy, mass spectrometry and cyclic voltammetry.The electrochemical detection of dihydrogen phosphate and adenosine nucleotide anions in aqueous electrolyte by monolayers of {N-(ferrocenoyl)-β-alanine}2-l-cystine dimethyl ester 11 immobilized on gold electrodes using cyclic voltammetry is described. Immobilization of this receptor on a gold electrode surface enabled the recognition process to be detected in aqueous media. The recognition process is as a result of electrostatic interactions between the ferricenium cation and the anion, and hydrogen bonding interactions between the peptide amide bonds and the anion. The complexation process was amperometrically sensed via a reduction in the peak current of the ferrocene/ferricenium redox couple. A linear relationship (R2 = c. 0.99) was observed between anion concentration and change in peak current in both cases.Graphical abstractThe N-(ferrocenyl)2 and N-(ferrocenoyl)2 cystine dimethyl ester derivatives which are potential anion sensing agents, were prepared and spectroscopically characterized. The electrochemical detection of dihydrogen phosphate and adenosine nucleotide anions in aqueous electrolyte by monolayers of {N-(ferrocenoyl)-β-alanine}2-l-cystine dimethyl ester immobilized on gold electrodes using cyclic voltammetry is described. Immobilization of this receptor on a gold electrode surface enabled the recognition process to be detected in aqueous media.Highlights► Potential ferrocene anion sensing agents were prepared. ► Electrochemical detection of dihydrogen phosphate and ATP anions was performed. ► Monolayers of the ferrocene peptide conjugates were formed. ► A linear response of the monolayers to anions was observed.

Resveratrol is a potential chemopreventive agent and can be isolated from grape skins and other dietary sources. The Wittig reaction and the decarbonylative Heck reaction were employed to synthesise analogues of this stilbene. Fluorinated derivatives of this stilbene were synthesised maintaining the 3,4′,5-substitution pattern. The hydroxyl groups were also replaced by amino groups and the biological activity evaluated. The compounds were assayed on a variety of cell lines, primarily the non-small lung carcinoma cell line DLKP-A. Analogues were evaluated alone and in combination with a known chemotherapeutic agent epirubicin.Resveratrol is a potential chemopreventive agent. Fluorinated derivatives of this stilbene were synthesised maintaining the 3,4′,5-substitution pattern. The hydroxyl groups were also replaced by amino groups and the biological activity evaluated.

N-ortho, N-meta and N-para-(ferrocenyl)benzoyl tri- and tetrapeptide esters (2–7) were prepared by coupling ortho, meta and para-ferrocenyl benzoic acids to the tri- and tetrapeptide ethyl esters of GlyGlyGly(OEt) and GlyGlyGlyGly(OEt) in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. The compounds were characterized by a range of NMR spectroscopic techniques, mass spectrometry and cyclic voltammetry. The anti-proliferative effects of the ortho derivatives 2 and 5 were measured in vitro against H1299 lung cancer cells and both gave IC50 values greater than 50 μM. Therefore, extending the length of the peptide chain had a negative effect on activity, relative to N-(ferrocenyl)benzoyl amino acid and dipeptide derivatives.N-(ferrocenyl)benzoyl tri- and tetrapeptide esters (2–7) were prepared by coupling N-ortho, N-meta and N-para-ferrocenyl benzoic acids to the tri- and tetrapeptide ethyl esters of GlyGlyGly(OEt) (2–4) and GlyGlyGlyGly(OEt) (5–7). The anti-proliferative effect of 2 and 5 was measured in vitro against H1299 lung cancer cells.

A series of novel ferrocene-based receptors, 1,1′-N,N′-ferrocenoylbisamino acid methyl esters 2–5 have been prepared and their electrochemical properties determined. The amino acids employed were glycine (2), β-alanine (3), γ-aminobutyric acid (4) and l-norleucine (5). These receptors are composed of an electroactive core and two parallel strands of amino acids that can interact with anions via electrostatic interactions in the oxidized state as well as secondary interactions, such as hydrogen bonding and hydrophobic interactions. Furthermore, the semi-rigid molecular clefts between the two strands of amino acids in these receptors are capable of discerning anions of different geometries and sizes. The anion sensing capabilities of receptors 2–5 were studied using cyclic voltammetry (CV). The anions studied were chloride (Cl−), nitrate (NO3−), dihydrogen phosphate (H2PO4−), hydrogen sulfate (HSO4−), acetate (CH3COO−) and neurologically important anions such as lactate (CH3CH(OH)COO−), pyruvate (CH3COCOO−) and glutamate (HOOC–CH(NH2)CH2CH2COO−). The receptors 2–5 exhibit selectivity towards chloride, dihydrogen phosphate and acetate, over hydrogen sulfate and nitrate ions and generate a redox response in organic media. Also, binding studies of receptor 3 with neurologically important anions show it displays selectivity towards lactate and pyruvate, over glutamate ions and generates a redox response. However the response is ill defined in all cases, with poorly separated “free” and “ion-pair” peaks, which preclude accurate measurement of the response by CV. These results emphasize the considerations required for the design of ferrocene-based receptors and the necessary parameters for efficient electrochemical recognition of small anions by CV.

A series of N-para-ferrocenyl benzoyl amino acid ethyl esters 1–8 have been prepared by coupling para-ferrocenyl benzoic acid with the amino acid esters using the conventional 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol. The amino acids employed in the synthesis were glycine, l-alanine, l-leucine, l-phenylalanine, β-alanine, 4-aminobutyric acid, (±)-2-aminobutyric acid and 2-aminoisobutyric acid. The compounds were fully characterized by a range of spectroscopic techniques such as NMR and mass spectrometry. In addition the X-ray crystal structures of the glycyl 1 and (±)-2-aminobutyrate 7 derivatives have been determined. Analysis of relevant fragments in crystal structures on the Cambridge Structural Database indicates a relative paucity of common fragments such as the α-aminobutyrate group in comparison to the glycyl moiety.N-para-Ferrocenyl benzoyl amino acid ethyl esters 1–8 were prepared by coupling para-ferrocenyl benzoic acid with the appropriate amino acid ethyl ester using the 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol. The compounds were structurally characterized by a combination of NMR and mass spectrometry. The X-ray crystal structures of the glycyl 1 and (±)-2-aminobutyrate 7 derivatives have been determined.

The N-ferrocenoyl amino acid ester derivatives FcCOR {Fc=(η5-C5H5)Fe(η5-C5H4)} where R=Gly(OMe) 1, Gly(OEt) 2, Gly(OBn) 3, l-Ala(OMe) 4, l-Ala(OEt) 5, l-Leu(OMe) 6, l-Leu(OEt) 7, l-Leu(OBn) 8, l-Phe(OMe) 9 and l-Phe(OEt) 10, were prepared by coupling ferrocene carboxylic acid with the appropriate amino acid ester starting materials using the 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol and these have been characterised by spectroscopic techniques. The electrochemical anion sensing behaviour of compounds 1–10 with several anions using a platinum microdisk working electrode is described, together with 1H NMR anion complexation studies. The X-ray single crystal structure of N-ferrocenoyl-l-alanine methyl ester 4 has been determined and contains two molecules which differ slightly in conformation in the asymmetric unit of space group P21 (No. 4); principal dimensions are amide N(H)CO 1.224(6) and 1.231(6) Å, ester CO 1.220(10) and 1.190(7) Å, with N–H⋯OC(amide) as the primary intermolecular hydrogen bond, N⋯O 2.992(6) and 2.971(6) Å and with graph set C(4).N-Ferrocenoyl amino acid ester derivatives were prepared by coupling ferrocene carboxylic acid with the appropriate amino acid esters using the 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol. The electrochemical anion sensing behaviour of the derivatives with several anions is described, together with 1H NMR anion complexation studies. The X-ray single crystal structure of N-ferrocenoyl-l-alanine methyl ester has been determined.