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Synthesis, characterisation and biological evaluation of novel nferrocenyl amino acid and dipeptide derivatives as potential anticancer agents.

Tiedt, Rachel (2014) Synthesis, characterisation and biological evaluation of novel nferrocenyl amino acid and dipeptide derivatives as potential anticancer agents. PhD thesis, Dublin City University.

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Abstract

The aim of this research thesis was to extend the structure activity relationship (SAR) of ferrocenyl peptide bioconjugates, a novel class of potential anticancer agents, and to investigate their mode of action in preparation for in vivo testing. A series of N-(6-ferrocenyl-2-naphthoyl), N-{para-(ferrocenyl)cinnamoyl} and N-{para-(ferrocenyl)benzoyl} amino acid and dipeptide derivatives was prepared. Both the conjugated linker and the ester portions of the molecule were varied. The compounds were fully characterised by spectroscopic techniques including 1H NMR, 13C NMR, IR, UV-Vis and MS. A further SAR study was undertaken varying both the substitution pattern of the conjugated linker and replacement of the ester portion of the molecule with the free amine N-terminus on the amino acid or dipeptide. The synthesis of N-(5-ferrocenyl-1-naphthoyl) amino acid and dipeptide esters was attempted by coupling of 1-amino-5-ferrocenyl-naphthalene with the C-terminus of the amino acid or dipeptide. Biological evaluation was performed in vitro in A549 and H1299 non small cell lung cancer and HT-144, Lox-IMVI and Malme-3M metastatic melanoma. The most active derivative, N-(6-ferrocenyl-2-naphthoyl)-glycine-glycine methyl ester had an IC50 of 0.2 μM on A549, Lox-IMVI and HT-144 and 0.3 μM on H1299 and Malme-3M cells. Toxicity studies demonstrated a similar level of toxicity to cisplatin while evaluation in resistant cell lines showed that N-(6-ferrocenyl-2-naphthoyl)- glycine-glycine methyl ester does not share cross resistance with temozolomide on the Malme-3M cell line. Cell cycle analysis showed a significant increase in the sub G0 phase while the TUNEL assay confirmed that the compounds undergo apoptosis leading to cell death. Guanine oxidation studies were carried out via HPLC-EC for N-(6-ferrocenyl-2-naphthoyl)-glycine-glycine ethyl ester and N-(ferrocenylmethyl-L-alanine)-3,4,5-trifluorobenzene carboxamide). This confirmed that both classes of compounds are capable of generating reactive oxygen species (ROS) via Fenton chemistry. DNA binding as a possible mode of action was explored and a B12 conjugate was prepared as a potential drug delivery vehicle to overcome drug solubility issues in vivo.

Item Type:Thesis (PhD)
Date of Award:November 2014
Refereed:No
Supervisor(s):Kenny, Peter T.M.
Uncontrolled Keywords:Ferrocenyl peptide bioconjugates; Potential anticancer agents
Subjects:Physical Sciences > Chemistry
Medical Sciences > Cancer
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
Funders:Health Research Board
ID Code:20188
Deposited On:04 Dec 2014 12:07 by Peter Kenny. Last Modified 24 Apr 2017 15:08

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