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Synthesis, characterization and biological evaluation of N-ferrocenylmethyl amino acid benzene carboxamide derivatives and N-ferrocenyl benzoyl amino alkane derivatives as anti-cancer agents.

Butler, William E. (2012) Synthesis, characterization and biological evaluation of N-ferrocenylmethyl amino acid benzene carboxamide derivatives and N-ferrocenyl benzoyl amino alkane derivatives as anti-cancer agents. PhD thesis, Dublin City University.

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Abstract

The aim of this research was to explore the structure-activity relationship (SAR) of ferrocenyl-bioconjugates. A series of N-(ferrocenylmethylamino acid)-fluorinated-benzene carboxamide derivatives and a series of N-(ferrocenyl)-benzoyl-aminoalkane derivatives have been synthesised, structurally characterised and biologically evaluated for their anti-proliferative activity on various cancer cell lines, principally, the (estrogen receptor positive) MCF-7 breast cancer cell line. The anti-cancer effect of ferrocene is due to the generation of a reactive oxygenated species. As part of the primary SAR study, a series of N-(ferrocenylmethylamino acid)-fluorinated-benzene carboxamide derivatives have been synthesised, structurally characterised and biologically evaluated. This series involved the attachment of amino acids, such as glycine, L-alanine and β-alanine and also a fluorobenzoyl unit to a ferrocenylmethylamine moiety in order to enhance the bioavailability of the compounds thus increasing their anti-cancer effect. The synthesis of N-(ferrocenylmethylamino acid) fluorinated benzene carboxamide derivatives was achieved by coupling the free N-terminus of the ferrocenylmethylamine with the carboxylic acid group of the N-(fluorobenzoyl)-amino acid using N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt) coupling protocol. All compounds were characterised by a range of spectroscopic techniques including: 1H, 13C, 19F, DEPT-135, and HMQC NMR in addition to IR, UV, and MS The attachment of a benzoyl spacer lowers the redox potential of the ferrocene moiety thus making the iron atom between the cyclopentadienyl rings, easier and more accessible to oxidation. A series of N-{(ferrocenyl)-benzoyl}-aminoalkanes have also been synthesised and characterised and biologically evaluated on the MCF-7 breast cancer cell line. The main aim was to conduct a structure activity relationship on two key moieties of the molecules, the difference of the substitution pattern around the aromatic benzoyl moiety and also the attachment of the various aminoalkanes, in hope that the biological activity will show a greater anti-proliferative effect against cancer cell lines. The synthesis of the N-{(ferrocenyl)-benzoyl}-aminoalkanes derivatives involved the coupling of the free N-terminus of the amine group of the aminoalkanes to the carboxylic acid group of the ferrocenyl-benzoic acid (ortho-, meta- and para-) using N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) coupling protocol. All compounds were also characterised by the spectroscopic methods as mentioned above. For the biological evaluation of the N-(ferrocenylmethylamino acid) fluorinated benzene carboxamide series of compounds, were tested on the estrogen positive (ER+) breast cancer cell line, MCF-7. Three libraries of novel ferrocene compounds were prepared by incorporating the glycine, L-alanine and β-alanine amino acids and the fluorobenzoyl moiety with the fluorine at the positions 2, 3, 4, (2,6), (2,4), (3,5), (3,4,5) and (2,3,4,5,6). All three libraries were tested in vitro. For comparative reasons, N-(ferrocenylmethyl)-4-fluorobenzene carboxamide, the most active compound from a previous SAR study on the MBA-MD-435-SF, ER(+) breast cancer cell line was also tested to observe the effect from the addition of the amino acid into the model structure. In total of the three libraries tested, there were four active compounds, with N-(ferrocenylmethylalanine)-3,4,5-trifluorobenzene carboxamide being the most active giving an IC50 value of 2.4 µM. This derivative also induced a block in the G2/M phase of the cell cycle. This series of compounds were also screened in vitro for their anti-proliferative effect against the non-small cell lung cancer cell line, H1299 at two concentrations, 10 µM and 1 µM. There was no activity below either of the concentrations and the study was stopped. The biological evaluation of N-{(ferrocenyl)-benzoyl}-aminoalkanes were screened in vitro on the MCF-7 breast cancer cell line. Preliminary screens showed that this type of compound had an anti-proliferative effect on MCF-7 breast cancer cell line. From 27 derivatives synthesised, IC50 data values were achieved. The ortho- series produced eight derivatives having an anti-proliferative effect, six of which were in the range of 2 µM to 6 µM. The meta- series produced two derivatives, with IC50 values of 51.5 µM and 51.2 µM. The para- derivatives also produced eight derivatives having an anti-proliferative effect, three of which were in the range of 2 µM to 6 µM. The most active derivative synthesised was N-{para-(ferrocenyl)-benzoyl}-aminooctane, with an IC50 of 1.10 µM.

Item Type:Thesis (PhD)
Date of Award:17 September 2012
Refereed:No
Supervisor(s):Kenny, Peter T. M.
Uncontrolled Keywords:structure-activity relationships; ferrocenyl-bioconjugates; antiproliferative activity; cancer cell lines
Subjects:Physical Sciences > Chemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:17496
Deposited On:20 Nov 2012 14:15 by Peter Kenny. Last Modified 09 Oct 2013 13:13

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